Alternative titles; symbols
HGNC Approved Gene Symbol: MLH1
SNOMEDCT: 403824007;
Cytogenetic location: 3p22.2 Genomic coordinates (GRCh38): 3:36,993,466-37,050,846 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p22.2 | Lynch syndrome 2 | 609310 | 3 | |
| Mismatch repair cancer syndrome 1 | 276300 | Autosomal recessive | 3 | |
| Muir-Torre syndrome | 158320 | Autosomal dominant | 3 |
MLH is homologous to the E. coli MutL gene and is involved in DNA mismatch repair (Papadopoulos et al., 1994).
After human homologs of the mutS gene of bacteria and yeast were found to have mutations responsible for hereditary nonpolyposis colorectal cancer (LYNCH1; 120435), Papadopoulos et al. (1994) searched for other human mismatch repair (MMR) genes. A survey of EST databases derived from random cDNA clones revealed 3 additional human MMR genes, all related to the bacterial mutL gene. One of these genes was MLH1. The other 2 genes had a slightly greater similarity to the yeast mutL homolog PMS1 and were therefore denoted PMS1 (600258) and PMS2 (600259), respectively.
Genuardi et al. (1998) characterized the normal alternative splicing of the MLH1 gene and reported a number of splice variants that exist in various tissue types. They observed splice variants lacking exons 6/9, 9, 9/10, 9/10/11, 10/11, 12, 16, and 17. The level of expression varied among different samples. All isoforms were found in 43 to 100% of the mononuclear blood cell samples, as well as in other tissues. The authors cautioned that knowledge of existence of multiple alternative splicing events not caused by genomic DNA changes is important for the evaluation of the results of molecular diagnostic tests based on RNA analysis.
Hypermutable H6 colorectal tumor cells are defective in strand-specific mismatch repair and bear defects in both alleles of the human MLH1 gene. Li and Modrich (1995) purified to near homogeneity an activity from HeLa cells that complemented H6 nuclear extracts to restore repair proficiency on a set of heteroduplex DNAs representing the 8 base-base mismatches as well as a number of slipped-strand, insertion/deletion mispairs. The activity behaved as a single species during fractionation and copurified with proteins of 85 and 100 kD. Microsequence analysis demonstrated both of these proteins to be homologs of bacterial MutL, with the former corresponding to the human MLH1 product and the latter to the product of human PMS2 or a closely related gene. The 1:1 molar stoichiometry of the 2 polypeptides and their hydrodynamic behavior indicated formation of a heterodimer. These observations indicated that interactions between members of the family of the human MutL homologs may be restricted.
Wang et al. (2000) used immunoprecipitation and mass spectrometry analyses to identify BRCA1 (113705)-associated proteins. They found that BRCA1 is part of a large multisubunit protein complex of tumor suppressors, DNA damage sensors, and signal transducers. They named this complex BASC, for 'BRCA1-associated genome surveillance complex.' Among the DNA repair proteins identified in the complex were ATM (607585), BLM (604610), MSH2 (609309), MSH6 (600678), MLH1, the RAD50 (604040)-MRE11 (600814)-NBS1 (602667) complex, and the RFC1 (102579)-RFC2 (600404)-RFC4 (102577) complex. Wang et al. (2000) suggested that BASC may serve as a sensor of abnormal DNA structures and/or as a regulator of the postreplication repair process.
Meiotic recombination between homologous chromosomes generates crossover and noncrossover products, which are derived from the formation of double-strand breaks (DSBs) and result from distinct DSB repair pathways. Guillon et al. (2005) analyzed crossovers and noncrossovers in oogenesis and spermatogenesis in mice and determined that both crossover and noncrossover pathways were Spo11 (605114) dependent. Mlh1 was required for the formation of most crossovers, but not noncrossovers. The remaining 5 to 10% of crossover products did not require Mlh1. Guillon et al. (2005) concluded that the major crossover pathway requires MLH1 for crossover formation and for mismatch repair of heteroduplex DNA.
MutL-alpha is a heterodimer of MLH1 and PMS2 that is required for mismatch repair. Kadyrov et al. (2006) identified human MutL-alpha as a latent endonuclease activated in a DNA mismatch-, MutS-alpha (see 609309)-, RFC-, PCNA (176740)-, and ATP-dependent manner. Incision of a nicked heteroduplex by this 4-protein system was strongly biased to the nicked strand. A mismatch-containing DNA segment spanned by 2 strand breaks was then removed by the 5-prime-to-3-prime activity of MutS-alpha-activated exonuclease-1 (EXO1; 606063). By mutation analysis, Kadyrov et al. (2006) mapped the endonuclease active site to a conserved motif in PMS2.
Germano et al. (2017) genetically inactivated MLH1 in colorectal, breast, and pancreatic mouse cancer cells. The growth of mismatch repair (MMR)-deficient cells was comparable to their proficient counterparts in vitro and on transplantation in immunocompromised mice. By contrast, MMR-deficient cancer cells grew poorly when transplanted in syngeneic mice. The inactivation of MMR increased the mutational burden and led to dynamic mutational profiles, which resulted in the persistent renewal of neoantigens in vitro and in vivo, whereas MMR-proficient cells exhibited stable mutational load and neoantigen profiles over time. Immune surveillance improved when cancer cells, in which MLH1 had been inactivated, accumulated neoantigens for several generations. When restricted to a clonal population, the dynamic generation of neoantigens driven by MMR further increased immune surveillance. Inactivation of MMR, driven by acquired resistance to the clinical agent temozolomide, increased mutational load, promoted continuous renewal of neoantigens in human colorectal cancers, and triggered immune surveillance in mouse models. Germano et al. (2017) concluded that targeting DNA repair processes can increase the burden of neoantigens in tumor cells.
Cannavo et al. (2020) showed that human MutS-gamma, a complex of MSH4 (602105) and MSH5 (603382) that supports crossing over, bound branched recombination intermediates and associated with MutL-gamma, a complex of MLH1 and MLH3, stabilizing the ensemble at joint molecule structures and adjacent double-stranded DNA. MutS-gamma directly stimulated DNA cleavage by the MutL-gamma endonuclease. MutL-gamma activity was further stimulated by EXO1, but only when MutS-gamma was present. RFC and PCNA were additional components of the nuclease ensemble, thereby triggering crossing over. S. cerevisiae strains in which MutL-gamma could not interact with Pcna presented defects in forming crossovers. The MutL-gamma-MutS-gamma-EXO1-RFC-PCNA nuclease ensemble preferentially cleaved DNA with Holliday junctions, but it showed no canonical resolvase activity. Instead, the data suggested that the nuclease ensemble processed meiotic recombination intermediates by nicking double-stranded DNA adjacent to the junction points. The authors proposed that, since DNA nicking by MutL-gamma depends on its cofactors, the asymmetric distribution of MutS-gamma and RFC-PCNA on meiotic recombination intermediates may drive biased DNA cleavage. They suggested that this mode of MutL-gamma nuclease activation may explain crossover-specific processing of Holliday junctions or their precursors in meiotic chromosomes.
Independently, Kulkarni et al. (2020) showed that PCNA was important for crossover-biased resolution. In vitro assays with human enzymes showed that PCNA and RFC were sufficient to activate the MutL-gamma endonuclease. MutL-gamma was further stimulated by the codependent activity of the pro-crossover factors EXO1 and MutS-gamma, the latter of which binds Holliday junctions. The authors found that MutL-gamma also bound various branched DNAs, including Holliday junctions, but it did not show canonical resolvase activity, suggesting that the endonuclease incises adjacent to junction branch points to achieve resolution. In vivo, Rfc facilitated MutL-gamma-dependent crossing over in budding yeast. Moreover, Pcna localized to prospective crossover sites along synapsed chromosomes. Kulkarni et al. (2020) concluded that their data highlight similarities between crossover resolution and the initiation steps of DNA mismatch repair and evoke a novel model for crossover-specific resolution of double Holliday junctions during meiosis.
Ban and Yang (1998) determined the crystal structure of a 40-kD N-terminal fragment of E. coli MutL that retains all of the conserved residues in the MutL family. The structure of MutL is homologous to that of an ATPase-containing fragment of DNA gyrase. The authors demonstrated that MutL binds and hydrolyzes ATP to ADP and Pi. Mutations in the MutL family that cause deficiencies in DNA mismatch repair and a predisposition to cancer mainly occur in the putative ATP-binding site. Ban and Yang (1998) also provided evidence that the flexible, yet conserved loops surrounding this ATP-binding site undergo conformational changes upon ATP hydrolysis, thereby modulating interactions between MutL and other components of the repair machinery.
Ellison et al. (2001) performed quantitative in vivo DNA mismatch repair (MMR) assays in the yeast S. cerevisiae to determine the functional significance of amino acid replacements in MLH1 and MSH2 genes observed in the human population. Missense codons previously observed in human genes were introduced at the homologous residue in the yeast MLH1 or MSH2 genes. Three classes of missense codons were found: (i) complete loss of function, i.e., mutations; (ii) variants indistinguishable from wildtype protein, i.e., silent polymorphisms; and (iii) functional variants which supported MMR at reduced efficiency, i.e., efficiency polymorphisms. There was a good correlation between the functional results in yeast and available human clinical data regarding penetrance of the missense codon. The authors suggested that differences in the efficiency of DNA MMR may exist between individuals in the human population due to common polymorphisms.
Using bioinformatic analysis, Kosinski et al. (2010) determined that the dimerization of MLH1 and PMS2 occurs via their C-terminal domains and involves residues 531 to 549 and 740 to 756 in MLH1 and residues 679 to 699 and 847 to 862 in PMS2.
Han et al. (1995) reported that the human MLH1 gene consists of 19 coding exons spanning approximately 100 kb. Exons 1 to 7 contain a region that is highly conserved in the MLH1 and PMS1 genes of yeast.
Papadopoulos et al. (1994) mapped the MLH1 gene to chromosome 3p21.3 by fluorescence in situ hybridization. Bronner et al. (1994) mapped the MLH1 gene to the same region, 3p23-p21.3, by fluorescence in situ hybridization.
The mapping of MLH1 to 3p21 was of interest because markers in that area had been linked to hereditary nonpolyposis colon cancer in several families (Lindblom et al., 1993). Searching for mutations in the MLH1 gene, Papadopoulos et al. (1994) performed RT-PCR analyses of lymphoblastoid cell RNA and directly sequenced the coding region of the gene in 10 HNPCC kindreds linked to 3p markers. All affected individuals from 7 Finnish kindreds exhibited a heterozygous deletion of codons 578 to 632. The derivation of 5 of these 7 kindreds could be traced to a common ancestor, and the presence of the same presumptive defect in 2 other kindreds supported a 'founder effect' for many cases of HNPCC in the Finnish population. Codons 578 to 632 were found to constitute a single exon that was deleted from 1 allele in the 7 kindreds. This exon encodes several highly conserved amino acids found at identical positions in yeast MLH1. In another 3p-linked family, Papadopoulos et al. (1994) observed a 4-nucleotide deletion beginning at the first position of codon 727 and producing a frameshift with a new stop codon located 166 nucleotides downstream. As a result, the C-terminal 19 amino acids of MLH1 were substituted with 53 different amino acids, some encoded by nucleotides normally in the 3-prime untranslated region. Another kindred displayed a 4-nucleotide insertion between codons 755 and 756. This insertion resulted in a frameshift and extension of the open reading frame to include 99 nucleotides downstream of the normal stop codon. One cell line showed a transversion from TCA to TAA in codon 252, resulting in conversion of a serine to a stop (120436.0001).
Simultaneously and independently, Bronner et al. (1994) likewise implicated the human MutL homolog, MLH1, in the form of HNPCC that maps to 3p. In 1 chromosome 3-linked HNPCC (LYNCH2; 609310) family, they demonstrated a missense mutation in affected individuals (S44F; 120436.0002).
Hamilton et al. (1995) identified a heterozygous mutation in the MLH1 gene (120436.0003) in a patient with HNPCC. He had hereditary nonpolyposis colon cancer, glioblastoma, and transitional cell carcinoma of the ureter. Tumor tissue samples showed DNA replication errors.
Using PCR-SSCP analysis and DNA sequencing to examine the entire coding region of the MLH1 gene in DNAs of 34 unrelated cancer patients from HNPCC pedigrees, Han et al. (1995) found germline mutations in 8 (24%): 4 missense mutations, 1 intron mutation that would affect splicing, and 3 frameshift mutations resulting in truncation of the gene product downstream of the mutation site.
Maliaka et al. (1996) identified 6 different novel mutations in the MLH1 and MSH2 genes in Russian and Moldavian HNPCC families. Three of these mutations occurred in CpG dinucleotides and led to a premature stop codon, splicing defect, or an amino acid substitution in evolutionarily conserved residues. Analysis of a compilation of published mutations including the new data suggested to the authors that CpG dinucleotides within the coding regions of the MSH2 and MLH1 genes are hotspots for single basepair substitutions.
From a study of unrelated HNPCC families, Wijnen et al. (1996) commented that, whereas the spectrum of mutations at the MSH2 gene is heterogeneous, a cluster of MLH1 mutations were found in the region encompassing exons 15 and 16, which accounts for 50% of all the independent MLH1 mutations described to date. They stated that their finding has great practical value in the design of clinical genetic services.
By screening members of Finnish families displaying HNPCC for predisposing germline mutations in MSH2 and MLH1, Nystrom-Lahti et al. (1995) showed that 2 mutations in MLH1 together account for 63% (19/30) of kindreds meeting international diagnostic criteria. One mutation, originally detected as a 165-bp deletion in MLH1 cDNA comprising exon 16, was shown to represent a 3.5-kb genomic deletion most likely resulting from Alu-mediated recombination (120436.0004). The second mutation destroyed the splice acceptor site of exon 6 (120436.0005). They commented that this was the first report of Alu-mediated recombination causing a prevalent, dominantly inherited predisposition to cancer. Nystrom-Lahti et al. (1995) designed a simple diagnostic test based on PCR for both mutations. Thus 2 ancestral founding mutations account for most Finnish HNPCC kindreds.
Sasaki et al. (1996) studied 43 tumors and corresponding normal tissues from 23 Japanese patients with multiple primary cancers. They found no germline mutations of the MLH1 gene and detected only 2 somatic missense mutations among the 43 tumors examined. These 2 tumors had each shown increased replication error (RER+) at more than 1 of the 5 microsatellite loci examined. Only the second of these 2 mutations occurred in an evolutionarily conserved domain of the protein.
Jager et al. (1997) reported studies based on the Danish HNPCC register comprising 28 families that fulfilled the Amsterdam criteria. They found an intron 14 founder mutation in the MLH1 gene (120436.0007) in approximately 25% of the kindreds and showed that it was associated with an attenuated HNPCC phenotype characterized by a highly reduced frequency of extracolonic tumors. The mutation was a combined 7-bp deletion and 4-bp insertion that 'silenced the mutated allele,' i.e., it was not expressed. Tumors exhibited microsatellite instability (MSI), and loss of the wildtype MLH1 allele was prevalent. Jager et al. (1997) proposed that the mutation resulted in a milder phenotype because the mutated MLH1 protein was prevented from exerting a dominant-negative effect on the concerted action of the mismatch repair system.
Huang et al. (2001) studied a family with HNPCC in which the proband was diagnosed with colorectal cancer at the age of 14 years; her mother, grandmother, and aunt had been diagnosed with HNPCC in their twenties. DNA sequencing revealed that the proband was heterozygous for the R226X mutation (120436.0011).
Shimodaira et al. (1998) described a new method for detecting mutations in MLH1 HNPCC using a dominant mutator effect of MLH1 cDNA expressed in Saccharomyces cerevisiae. Most MLH1 missense mutations identified in HNPCC patients abolish the dominant mutator effect. Furthermore, PCR amplification of MLH1 cDNA from mRNA of an HNPCC patient, followed by in vivo recombination into a gap expression vector, allowed detection of a heterozygous loss-of-function missense mutation in MLH1 using this method. This functional assay offers a simple method for detecting and evaluating pathogenic mutations in MLH1.
Liu et al. (1999) described 2 missense mutations in exon 16 of the MLH1 gene associated with colorectal cancer (see 120436.0012 and 120436.0013). The tumors did not show MSI, raising some potentially important issues. First, even microsatellite-negative colorectal tumors can be associated with germline mutations, and these will be missed if an MSI test is used to select patients for mutation screening. Second, the lack of MSI in these cases suggested that the mechanism involved in the carcinogenesis could be different from that generally hypothesized.
In colorectal cancer arising in young Hong Kong Chinese, a high incidence of microsatellite instability and germline mismatch repair gene mutation has been found. Most of the germline mutations involve the MSH2 gene, which is different from the mutation spectrum in the Western population. In the MLH1 gene, alternative splicing is common, which complicates RNA-based mutation detection methods. In contrast, large deletions in MLH1, commonly observed in some ethnic groups, tend to escape detection by exon-by-exon direct DNA sequencing. Chan et al. (2001) reported the detection of a novel germline 1.8-kb deletion involving exon 11 of the MLH1 gene in a Hong Kong hereditary nonpolyposis colorectal cancer family. The mutation generated an mRNA transcript with deletion of exons 10 and 11, which is indistinguishable from one of the most common and predominant MLH1 splice variants. A diagnostic test based on PCR of the breakpoint region led to the identification of an additional young colorectal cancer patient with this mutation. Haplotype analysis suggested that the 2 patients may share a common ancestral mutation. The results represented a caveat to investigators in the interpretation of alternative splicing and the important implications for the design of MLH1 mutation detection strategy in the Chinese population. The proband of one family developed colorectal cancer at the age of 33 years. The second patient with no family history of cancer developed colorectal cancer at the age of 38 years.
Viel et al. (2002) examined a series of 52 patients belonging to HNPCC or HNPCC-related families, all of whom had previously tested negative for point mutations in MMR genes. Southern blot mutation screening of the MLH1 and MSH2 genes revealed abnormal restriction patterns in 3 patients who carried distinct MLH1 internal deletions. Although Alu repeats are likely to be implicated in most cases of such deletions, different molecular mechanisms may be involved. In particular, HNPCC resulting from L1-mediated recombination was identified by Viel et al. (2002) as another mechanism for MMR inactivating mutations.
Gorlov et al. (2003) evaluated colocalization of pathogenic missense mutations (found in individuals with HNPCC) with high-score exonic splicing enhancer (ESE) motifs in the MSH2 and MLH1 genes. They found that pathogenic missense mutations in these genes are located in ESE sites significantly more frequently than expected. Pathogenic missense mutations also tended to decrease ESE scores, thus leading to a high propensity for splicing defects. In contrast, nonpathogenic missense mutations and nonsense mutations are distributed randomly in relation to ESE sites. Comparison of the observed and expected frequencies of missense mutations in ESE sites showed that pathogenic effects of 20% or more of mutations in MSH2 result from disruption of ESE sites and disturbed splicing. Similarly, pathogenic effects of 16% or more of missense mutations in MLH1 genes are ESE related. Thus, the colocalization of pathogenic missense mutations with ESE sites strongly suggests that their pathogenic effects are splicing related.
Most susceptibility to colorectal cancer (CRC) is not accounted for by known risk factors. Because MLH1, MSH2, and MSH6 mutations underlie high penetrance CRC susceptibility in HNPCC, Lipkin et al. (2004) hypothesized that attenuated alleles might also underlie susceptibility to sporadic CRC. They looked for gene variants associated with HNPCC in Israeli probands with familial CRC unstratified with respect to the microsatellite instability phenotype. Association studies identified a new MLH1 variant (415G-C; 120436.0019) in approximately 1.3% of Israeli CRC individuals self-described as Jewish, Christian, or Muslim. MLH1 415C conferred clinically significant susceptibility to CRC. In contrast to classic HNPCC, CRCs associated with MLH1 415C usually did not have the microsatellite instability (MSI) defect, which is important for clinical mutation screening. Structural and functional analyses showed that the normal ATPase function of MLH1 is attenuated, but not eliminated, by the MLH1 415G-C mutation. These studies suggested that variants of mismatch repair proteins with attenuated function may account for a higher proportion of susceptibility to sporadic microsatellite-stable CRC than theretofore assumed.
Oliveira et al. (2004) investigated KRAS (190070) in 158 HNPCC tumors from patients with germline MLH1, MSH2, or MSH6 mutations, 166 microsatellite-unstable (MSI-H), and 688 microsatellite-stable (MSS) sporadic carcinomas. All tumors were characterized for MSI and 81 of 166 sporadic MSI-H CRCs were analyzed for MLH1 promoter hypermethylation. KRAS mutations were observed in 40% of HNPCC tumors, and the mutation frequency varied upon the mismatch repair gene affected: 48% (29/61) in MSH2, 32% (29/91) in MLH1, and 83% (5/6) in MSH6 (P = 0.01). KRAS mutation frequency was different between HNPCC, MSS, and MSI-H colorectal cancers (P = 0.002), and MSI-H with MLH1 hypermethylation (P = 0.005). Furthermore, HNPCC colorectal cancers had more G13D (190070.0003) mutations than MSS (P less than 0.0001), MSI-H (P = 0.02), or MSI-H tumors with MLH1 hypermethylation (P = 0.03). HNPCC colorectal and sporadic MSI-H tumors without MLH1 hypermethylation shared similar KRAS mutation frequency, in particular G13D. Oliveira et al. (2004) concluded that, depending on the genetic/epigenetic mechanism leading to MSI-H, the outcome in terms of oncogenic activation may be different, reinforcing the idea that HNPCC, sporadic MSI-H (depending on the MLH1 status), and MSS colorectal cancers may target distinct kinases within the RAS/RAF/MAPK pathway.
Mangold et al. (2004) screened for mutations in the MSH2 and MLH1 genes in 41 unrelated index patients diagnosed with Muir-Torre syndrome (MRTES; 158320), most of whom were preselected for mismatch repair deficiency in their tumor tissue. Germline mutations were identified in 27 patients (mutation detection rate of 66%). Mangold et al. (2004) noted that 25 (93%) of the mutations were located in MSH2, in contrast to HNPCC patients without the MRTES phenotype, in whom the proportions of MLH1 and MSH2 mutations are almost equal (p less than 0.001). Mangold et al. (2004) further noted that 6 (22%) of the mutation carriers did not meet the Bethesda criteria for HNPCC and suggested that sebaceous neoplasm be added to the HNPCC-specific malignancies in the Bethesda guidelines.
Alazzouzi et al. (2005) studied the allelic distribution of microsatellite repeat bat26 in peripheral blood lymphocytes of 6 carriers and 4 noncarriers from 2 HNPCC families harboring germline MLH1 and MSH2 mutations, respectively. In noncarriers, there was a gaussian distribution with no bat26 alleles shorter than 21 adenine residues. All 6 MLH1/MSH2 mutation carriers showed unstable bat26 alleles (20 adenine residues or shorter) with an overall frequency of 5.6% (102 of 1814 clones detected). Alazzouzi et al. (2005) suggested that detection of short unstable bat26 alleles may assist in identifying asymptomatic carriers belonging to families with no detectable MMR gene mutations.
Quehenberger et al. (2005) obtained estimates of the risk of colorectal cancer (CRC) and endometrial cancer (EC) for carriers of disease-causing mutations of the MSH2 and MLH1 genes. Families with known germline mutations of these genes were extracted from the Dutch HNPCC cancer registry. Ascertainment-corrected maximum likelihood estimation was carried out on a competing risks model for CRC and EC. The MSH2 and MLH1 loci were analyzed jointly as there was no significant difference in risk (p = 0.08). At age 70, CRC risk for men was 26.7% (95% CI, 12.6 to 51.0%) and for women, 22.4% (10.6 to 43.8%); the risk for EC was 31.5% (11.1 to 70.3%). These estimates of risk were considerably lower than ones previously used which did not account for the selection of families.
Changes in the coding sequence, which may or may not affect the encoded protein sequence, may disrupt exon splicing enhancers (ESEs), leading to exon skipping. ESEs are short, degenerate, frequently purine-rich sequences that are important in both constitutive and alternative splicing. ESEs have been identified in a large number of genes, and their disruption has been linked to several genetic disorders, including HNPCC (Stella et al., 2001), cystic fibrosis (219700), Marfan syndrome (154700), and Becker muscular dystrophy (300376). McVety et al. (2006) studied a 3-bp deletion at the 5-prime end of exon 3 of MLH1 (120436.0023), resulting in deletion of exon 3 from RNA. Splicing assays suggested that the inclusion of exon 3 in mRNA was ESE-dependent. The exon 3 ESE was not recognized by all available motif-scoring matrices, highlighting the importance of RNA analysis in the detection of ESE-disrupting mutations.
Pagenstecher et al. (2006) examined 19 variants in the MLH1 and MSH2 genes detected in patients with HNPCC for expression at the RNA level. Ten of the 19 were found to affect splicing, including several variants which were predicted to be missense mutations in exonic sequences (see, e.g., 120436.0024). The findings suggested that mRNA examination of MLH1 and MSH2 mutations should precede functional tests at the protein levels.
Without preselection and regardless of family history, Barnetson et al. (2006) recruited 870 patients under the age of 55 years soon after they received the diagnosis of colorectal cancer. They studied these patients for germline mutations in DNA mismatch-repair genes MLH1, MSH2 (609309), and MSH6 (600678) and developed a 2-stage model by multivariate logistic regression for the prediction of the presence of mutations in these genes. Stage 1 of the model incorporated only clinical variables; stage 2 comprised analysis of the tumor by immunohistochemical staining and tests for microsatellite instability. The model was validated in an independent population of patients. Furthermore, they analyzed 2,938 patient-years of follow-up to determine whether genotype influenced survival. Among the 870 participants, 38 mutations were found: 15 in MLH1, 16 in MSH2, and 7 in MSH6. Carrier frequencies in men (6%) and women (3%) differed significantly (P less than 0.04). Survival among carriers was not significantly different from that among noncarriers.
Tournier et al. (2008) examined potential splicing defects of 56 unclassified variants in the MLH1 gene and 31 in the MSH2 gene that were identified in 82 French patients with Lynch syndrome. The variants comprised 54 missense mutations, 10 synonymous changes, 20 intronic variants, and 3 single-codon deletions. The authors developed an ex vivo splicing assay by inserting PCR-amplified transcripts from patient genomic DNA into a reporter minigene that was transfected into HeLa cells. The ex vivo splicing assay showed that 22 of 85 variant alleles affected splicing, including 4 exonic variants that affected putative splicing regulatory elements. The study provided a tool for evaluating putative pathogenic effects of unclassified variants found in these genes.
Tang et al. (2009) identified pathogenic mutations or deletions in the MLH1 or MSH2 gene in 61 (66%) of 93 Taiwanese families with HNPCC. Forty-two families had MLH1 mutations, including 13 with the R265C mutation (120436.0030) and 5 with a 3-bp deletion (1846delAAG; 120436.0018). Thirteen of the MLH1 mutations were novel, and 6 large MLH1 deletions were also found. One family harbored MLH1 and MSH2 mutations.
Using structural modeling, Kosinski et al. (2010) identified 19 different MLH1 alterations located in the C-terminal domain involved in dimerization with PMS2. Three changes, Q542L, L749P, and Y750X, caused decreased coexpression of PMS2, which was unstable in the absence of interaction with MLH1, suggesting that these 3 alterations interfered with MLH1-PMS2 dimerization. In vitro studies showed that all 3 changes compromised mismatch repair, suggesting that defects in dimerization can abrogate proper MLH1 function. Additional biochemical studies showed that 4 alterations with uncertain pathogenicity (A586P, L636P, T662P, and R755W), could be considered deleterious because of poor expression or poor MMR efficiency. Finally, some variants (e.g., K618A; 120436.0012), which were previously classified as deleterious, were determined to have normal MMR activity.
Constitutional Epigenetic Mutations, 'Germline Epimutation'
Herman et al. (1998) reported that hypermethylation of the 5-prime CpG island of the MLH1 gene is found in most sporadic primary colorectal cancers with MSI and that this methylation was often, but not invariably, associated with loss of MLH1 protein expression. Such methylation also occurred, but was less prominent, in MSI-negative tumors, as well as in MSI-positive tumors with known mutations of a mismatch repair gene. No hypermethylation of MSH2 was found. Hypermethylation of colorectal cancer cell lines with MSI also was frequently observed, and in such cases, reversal of the methylation with 5-aza-2-prime-deoxycytidine not only resulted in reexpression of MLH1 protein, but also in restoration of the mismatch repair capacity in MMR-deficient cell lines. The results suggested that MSI in sporadic colorectal cancer often results from epigenetic inactivation of MLH1 in association with DNA methylation.
Germline defects in DNA mismatch repair genes account for the inherited familial cancer syndrome of hereditary nonpolyposis colon cancers in which affected individuals show accelerated development of cancers of the proximal colon, endometrium (608089), and stomach. These cancers typically demonstrate inactivation of the residual wildtype MMR allele inherited opposite the germline mutant, absence of DNA MMR activity in in vitro assays, and acquisition of an in vivo mutator phenotype showing up to 1,000-fold increased gene mutation rates. Additionally, these cancers display an associated instability of genomic MSI. MSI is similarly found in approximately 15 to 20% of sporadic colon cancers that arise in individuals without any family history of colon cancer. Like HNPCC-associated colon cancers, sporadic MSI colon cancers arise predominantly in the proximal colon and show a high rate of frameshift mutations at a mutation hotspot in the transforming growth factor-beta type II receptor tumor suppressor gene (TGFBR2; 190182). Familial and sporadic MSI colon cancers thus appear to share a common carcinogenic pathway. Liu et al. (1995) established that MMR gene inactivation via somatic mutation was the cause of some cases of sporadic MSI colon cancers. However, unexpectedly, in many sporadic MSI colon cancers, MMR genes were found to remain wildtype. MMR coding sequences were similarly reported to be wildtype in many sporadic MSI endometrial cancers (Katabuchi et al., 1995). Kane et al. (1997) described methylation of the MLH1 promoter region in some MSI tumors. Veigl et al. (1998) investigated a group of MSI cancer cell lines, most of which were documented as established from antecedent MSI-positive malignant tumors. In 5 of 6 such cases, they found that MLH1 protein was absent, even though MLH1-coding sequences were wildtype. In each case, absence of MLH1 protein was associated with the methylation of the MLH1 gene promoter. Furthermore, in each case, treatment with the demethylating agent 5-azacytidine induced expression of the absent MLH1 protein. Moreover, in single cell clones, MLH1 expression could be turned on, off, and on again by 5-azacytidine exposure, washout, and reexposure. This epigenetic inactivation of MLH1 additionally accounted for the silencing of both maternal and paternal tumor MLH1 alleles, both of which could be reactivated by 5-azacytidine. Thus, substantial numbers of human MSI cancers appear to arise by MLH1 silencing via an epigenetic mechanism that can inactivate both of the MLH1 alleles. Promoter methylation is intimately associated with this epigenetic silencing mechanism.
Approximately 20% of endometrial cancers, the fifth most common cancer of women worldwide, exhibit MSI. Although the frequency of MSI is higher in endometrial cancers than in any other common malignancy, the genetic basis of MSI in these tumors had remained elusive. Simpkins et al. (1999) investigated the role that methylation of the MLH1 DNA mismatch repair gene plays in the genesis of MSI in a large series of sporadic endometrial cancers. The MLH1 promoter was methylated in 41 of 53 (77%) MSI-positive cancers investigated. In MSI-negative tumors, on the other hand, there was evidence for limited methylation in only 1 of 11 tumors studied. Immunohistochemical investigation of a subset of the tumors revealed that methylation of the MLH1 promoter in MSI-positive tumors was associated with loss of MLH1 expression. Immunohistochemistry proved that 2 MSI-positive tumors lacking MLH1 methylation failed to express the MSH2 mismatch repair gene. Both of these cancers came from women who had family and medical histories suggestive of inherited cancer susceptibility. These observations suggested that epigenetic changes in the MLH1 locus account for MSI in most cases of sporadic endometrial cancers and provide additional evidence that the MSH2 gene may contribute substantially to inherited forms of endometrial cancer.
Wheeler et al. (2000) studied 10 MSI-positive sporadic colorectal cancers and 10 colorectal cancers from individuals with HNPCC. The promoter region of the MLH1 gene was hypermethylated in 7 of the 10 MSI-positive sporadic cancers but in none of the HNPCC cancers. LOH at MLH1 was observed in 8 of the 10 HNPCC colorectal cancers. Wheeler et al. (2000) concluded that while the mutations and allelic loss are responsible for the MSI-positive phenotype in HNPCC cancers, the majority of MSI-positive sporadic cancers are hypermethylated in the promoter region of MLH1; therefore, tumors from HNPCC patients acquire a raised mutation rate through a different pathway than MSI-positive sporadic tumors.
Epigenetic silencing can mimic genetic mutation by abolishing expression of a gene. Suter et al. (2004) hypothesized that an epimutation could occur in any gene as a germline event that predisposes to disease and looked for examples in tumor suppressor genes in individuals with cancer. They reported 2 individuals with soma-wide, allele-specific and mosaic hypermethylation of the DNA mismatch repair gene MLH1. Both individuals lacked evidence of genetic mutation in any mismatch repair gene but had had multiple primary tumors that showed mismatch repair deficiency, and both met clinical criteria for hereditary nonpolyposis colorectal cancer.
Suter et al. (2004) reported methylation of the MLH1 promoter in a small proportion of FACS-sorted spermatozoa from an individual who harbored a soma-wide MLH1 epimutation. In an addendum to the report of Suter et al. (2004) and in a correspondence, Hitchins and Ward (2007) described reassessment of spermatozoa from the original individual using 2 quantitative techniques. They included methylation analysis of the imprinted control gene SNRPN (182279), which is unmethylated in spermatozoa cells. Their new data indicated that the MLH1 methylation previously reported in spermatozoa was most likely an artifact, attributable to a low level of contamination of the sample with either somatic cells or free DNA derived from somatic cells. These data altered the original interpretation that incomplete resetting of the epigenetic mark on MLH1 had occurred in a proportion of the individual's spermatozoa and suggested instead that reversal is complete in the actual gametes.
Persons who have hypermethylation of 1 allele of MLH1 in somatic cells throughout the body (a germline epimutation) have a predisposition for the development of cancer in a pattern typical of hereditary nonpolyposis colorectal cancer. By studying the families of 2 such persons, Hitchins et al. (2007) found evidence that the epimutation was transmitted from a mother to her son but was erased in his spermatozoa. The affected maternal allele was inherited by 3 other sibs from these 2 families, but in those offspring the allele had reverted to the normal active state. These findings demonstrated a novel pattern of inheritance of cancer susceptibility and were consistent with transgenerational epigenetic inheritance.
Gosden and Feinberg (2007) referred to genetics and epigenetics as 'nature's pen-and-pencil set.' They suggested that transmission of epimutations in MLH1 may have more general relevance than appears at first site. Perhaps it is rather common for disease to be caused by the failure of both the pen and pencil to write correctly. Bjornsson et al. (2004) suggested an integrated epigenetic and genetic approach to common human disease. The genetic and epigenetic model of common diseases--including neuropsychiatric and rheumatologic diseases and cancer--suggest that the epigenotype modulates genetic effects. The epigenotype, in turn, is affected by the environment, the epigenotype of the parents, age, and the genotype at loci that regulate DNA methylation and chromatin.
Hitchins and Ward (2009) reviewed the etiologic role of constitutional MLH1 epimutations (see, e.g., 120436.0015) in the development of HNPCC-related cancers.
Crepin et al. (2012) identified constitutional MLH1 epimutations in 2 (1.5%) of 134 patients suspected of having Lynch syndrome who did not have germline mutations in the MMR genes. One patient was a man who developed colorectal cancer at age 35 years. Tumor tissue showed MSI, and analysis of lymphocyte DNA showed complete hypermethylation of the promoter of 1 MLH1 allele. The second patient was a woman with colorectal cancer, who had a son with colorectal cancer and 2 daughters with dysplastic colonic polyps. Blood from the mother showed 20% hypermethylation at the MLH1 promoter, suggesting mosaicism. The son and 1 affected daughter also showed partial hypermethylation in blood, suggesting transmission of the epimutation through the germline. Tumor tissue from the 3 patients in the second family also showed partial hypermethylation at MLH1, and tumor tissue from the daughter also carried a somatic BRAF mutation (164757.0001).
Ward et al. (2013) screened 416 individuals with colorectal cancer showing loss of MLH1 expression but without deleterious germline mutations in MLH1. Constitutive DNA samples were screened for MLH1 methylation in all subjects and for promoter sequence changes in 357 individuals. Constitutional MLH1 epimutations were identified in 16 subjects. Of these, 7 (1.7%) had mono- or hemi-allelic methylation and 8 had low-level methylation (2%). Ward et al. (2013) concluded that although rare, sequence changes in the regulatory region of MLH1 and aberrant methylation may alone or together predispose to the development of cancer and suggested that screening for these changes is warranted in individuals who have a negative germline sequence screen of MLH1 and loss of MLH1 expression in their tumor.
Mismatch Repair Cancer Syndrome
Mismatch repair cancer syndrome (see MMRCS1, 276300), sometimes referred to as brain tumor-polyposis syndrome-1 or Turcot syndrome, results from biallelic mutations in the mismatch repair genes. The phenotype classically includes colorectal adenomas and brain tumors, most often glioblastoma. However, Trimbath et al. (2001) and Ostergaard et al. (2005) noted that the original definition may be too restrictive, and suggested that the full manifestation of biallelic mutations in MMR genes includes the additional findings of early-onset hematologic malignancies and cafe-au-lait spots suggestive of neurofibromatosis-1 (NF1; 162200).
Ricciardone et al. (1999) reported 3 sibs in an HNPCC family who developed hematologic malignancy at a very early age, 2 of whom displayed signs of NF1. DNA sequence analysis and allele-specific amplification in 2 of the sibs revealed a homozygous MLH1 mutation (120436.0010). Wang et al. (1999) described a typical HNPCC family in which MMR-deficient children who were homozygous for an MLH1 mutation (120436.0011) exhibited clinical features of de novo NF1 and early onset of extracolonic cancers. The observations demonstrated that MMR deficiency is compatible with human development but may lead to mutations during embryogenesis. Based on these observations, Wang et al. (1999) speculated that the NF1 gene is a preferential target for such alterations. Wang et al. (2003) demonstrated that somatic mutations of the NF1 gene occur more commonly in MMR-deficient cells. They observed NF1 alterations in 5 of 10 tumor cell lines with microsatellite instability compared to none of 5 MMR-proficient tumor cell lines. Somatic NF1 mutations were also detected in 2 primary tumors exhibiting microsatellite instability.
Baker et al. (1996) generated mice with a null mutation of the Mlh1 gene. They reported that in addition to compromising replication fidelity, Mlh1 deficiency appeared to cause both male and female sterility associated with reduced levels of chiasmata. Mlh1-deficient spermatocytes exhibited high levels of prematurely separated chromosomes and cell cycle arrest occurred in the first division of meiosis. Baker et al. (1996) also carried out analysis of the Mlh1 protein in spermatocytes and oocytes using immunostaining. They demonstrated that Mlh1 localizes at chiasma sites on meiotic chromosomes. They concluded that Mlh1 in the mouse is involved in both DNA mismatch repair and meiotic crossing over.
Linkage maps constructed from genetic analysis of gene order and crossover frequency provide few clues to the basis of genomewide distribution of meiotic recombination which might point to variation in chromosome structure that influences meiotic recombination. To bridge that gap, Froenicke et al. (2002) generated a cytologic recombination map that identified individual autosomes in the male mouse. They prepared synaptonemal complex (SC) meiotic chromosome spreads from mouse spermatocytes, identified each autosome by multicolor FISH using chromosome-specific DNA libraries, and mapped more than 2,000 sites of recombination along individual autosomes, using immunolocalization of Mlh1, which as a mismatch repair protein marks crossover sites. They showed that SC length strongly correlated with crossover frequency and distribution. Although the length of most of these SCs corresponded to that predicted from their mitotic chromosome length rank, several SCs were longer or shorter than expected, with corresponding increases and decreases in Mlh1 frequency. Although all bivalents shared certain recombination features, such as few crossovers near the centromeres and a high rate of distal recombination, individual bivalents had unique patterns of crossover distribution along their length. In addition to SC length, other unidentified factors influenced crossover distribution, leading to hot regions on individual chromosomes with recombination frequencies as much as 6 times higher than average, as well as coldspots with no recombination. By reprobing the SC spreads with genetically mapped BACs, Froenicke et al. (2002) demonstrated a robust strategy for integrating genetic linkage and physical contig maps with mitotic and meiotic chromosome structure.
Avdievich et al. (2008) generated transgenic mice with a G67R mutation in the Mlh1 gene located in 1 of the ATP-binding domains. Although cells derived from homozygous mice showed defects in DNA repair, the mutation did not affect the cellular response to DNA damage, including the apoptotic response of epithelial cells in the intestinal mucosa. The mice displayed a strong predisposition to cancer but developed significantly fewer intestinal tumors compared to Mlh1-null mice. Mlh1-null mice did show defects in the cellular response to DNA damage. These findings suggested that missense mutations in the Mlh1 gene may affect MMR tumor suppressor function in a tissue-specific manner. In addition, homozygous G67R mice were sterile due to the inability of the mutant protein to interact with meiotic chromosomes at pachynema, demonstrating that the ATPase activity of Mlh1 is essential for fertility in mammals.
In a colorectal tumor cell line (H6) manifesting microsatellite instability (LYNCH2; 609310), Papadopoulos et al. (1994) used a technique that involves the transcription and translation in vitro of PCR products to demonstrate that only a truncated polypeptide was produced. Sequence analysis of the cDNA revealed a C-to-A transversion at codon 252, resulting in the substitution of a stop codon for serine. No band at the normal C position was identified in the cDNA or genomic DNA from the H6 cells, indicating that these cells were devoid of a wildtype MLH1 allele.
In a family with hereditary nonpolyposis colon cancer (LYNCH2; 609310), Bronner et al. (1994) found that 4 affected individuals were heterozygous for a C-to-T substitution in an exon encoding amino acids 41 to 69, which corresponds to a highly conserved region of the protein. The nucleotide substitution resulted in a ser44-to-phe amino acid change.
In a man (patient 14) with hereditary nonpolyposis colon cancer (HNPCC2; 609310), Hamilton et al. (1995) identified a 3-bp deletion (AAG) in the MLH1 gene, resulting in the loss of a lysine at codon 618. The patient had adenocarcinomas of the ascending and transverse colon at the age of 30, adenomas of the descending and sigmoid colon at the ages of 32 and 33, and an ileal adenocarcinoma and a glioblastoma multiforme at the age of 33. There was a family history of HNPCC. The patient was also reported to have a transitional cell carcinoma of the ureter.
Nystrom-Lahti et al. (1995) found that a 3.5-kb genomic deletion in the MLH1 gene was responsible for 14 of 30 Finnish kindreds meeting international diagnostic criteria for HNPCC (HNPCC2; 609310). The origins of the families were clustered in the south-central region of Finland. The mutation consisted of exon 15 and the proximal 2.4 kb of intron 15 joined to a distal half of intron 16 followed by intron 17. Introns 15 and 16 were found to be rich in Alu repetitive sequences. Sequence analysis of the deletion breakpoint region in both mutant and normal alleles suggested to Nystrom-Lahti et al. (1995) that the deletion may have been due to recombination between 2 Alu repeat elements, 1 in intron 15 and another in intron 16.
This large deletion mutation and the splice site mutation leading to deletion of exon 6 (120436.0005), referred to by Moisio et al. (1996) as mutations 1 and 2, respectively, are frequent among Finnish kindreds with HNPCC. In order to assess the ages and origins of these mutations, Moisio et al. (1996) constructed a map of 15 microsatellite markers around MLH1 and used this information and haplotype analyses of 19 kindreds with mutation 1 and 6 kindreds with mutation 2. All kindreds with mutation 1 showed a single allele for the intragenic marker D3S1611 that was not observed on any unaffected chromosome. They also shared portions of a haplotype of markers encompassing 2.0 to 19.0 cM around MLH1. All kindreds with mutation 2 shared another allele for D3S1611 and a conserved haplotype of 5 to 14 markers spanning 2.0 to 15.0 cM around MLH1. The degree of haplotype conservation was used to estimate the ages of these 2 mutations. The analyses suggested to the authors that the spread of mutation 1 started 16 to 43 generations (400 to 1,075 years) ago and that of mutation 2 started 5 to 21 generations (125 to 525 years) ago. These datings were compatible with genealogic results identifying a common ancestor born in the 16th and 18th century, respectively. The results indicated to Moisio et al. (1996) that all Finnish kindreds studied to date showing either mutation 1 or mutation 2 were the result of single ancestral founding mutations relatively recent in origin in the population. Alternatively, it is possible that the mutations arose elsewhere and were introduced into Finland more recently.
In 5 Finnish families with hereditary nonpolyposis colorectal cancer (HNPCC2; 609310), Nystrom-Lahti et al. (1995) found that a splice site mutation in the MLH1 gene was responsible. The mutation consisted of a G-to-A transition in the -1 position of the splice acceptor site in intron 5. This resulted in deletion of the 92-bp segment corresponding to exon 6 and caused a frameshift that led to a premature stop codon 24-bp downstream.
See also Moisio et al. (1996) and 120436.0004.
Muir-Torre syndrome (MRTES; 158320) is an autosomal dominant disorder characterized by development of sebaceous gland tumors and skin cancers, including keratoacanthomas and basal cell carcinomas. Affected family members may manifest a wide spectrum of internal malignancies, which include colorectal, endometrial, urologic, and upper gastrointestinal neoplasms. Sebaceous gland tumors, which are rare in the general population, are considered to be the hallmark of MRTES, and may arise prior to the development of other visceral cancers. Hereditary nonpolyposis colorectal cancer shares many features in common with MRTES, leading Lynch et al. (1985) to propose that these 2 syndromes have a common genetic basis. Bapat et al. (1996) found a mutation in MLH1 locus in a large, well-characterized kindred in which 17 affected family members had colorectal and endometrial cancers, sebaceous gland tumors, and hematopoietic malignancies. The family was originally reported by Green et al. (1994) who excluded linkage to the MSH2 locus (609309). Paraf et al. (1995) also described this family. Bapat et al. (1996) studied 2 affected sibs and found by a protein-truncation test (PTT) a truncated gene product of approximately 41 kD in addition to the expected wildtype MLH1 protein of 53.9 kD. Further analysis discovered a deletion of 370 bp (codons 346-467) corresponding to exon 12 of MLH1 cDNA. An examination of the MLH1 sequence indicated that deletion generated a frameshift resulting in a stop codon at nucleotides 1472-1474 in exon 13 and a truncated protein of 40.8 kD. Linkage analysis with an intragenic marker indicated that the affected parent was heterozygous and the unaffected parent homozygous for the wildtype allele.
In 5 of 21 Danish families with hereditary nonpolyposis colorectal cancer (HNPCC2; 609310) satisfying the Amsterdam criteria, Jager et al. (1997) found a splice-donor mutation in intron 14 of MLH1: a combined 7-bp deletion and 4-bp insertion that led to the exchange of the obligatory thymidine at position +2 and the exchange of conserved purines at positions +3 to +5 in the splice donor site. Only 2 of 25 affected individuals suffered from extracolonic cancer. One patient had endometrial cancer by the age of 33 years and 3 successive colorectal cancers. The second patient had cancer of the ampulla of vater by the age of 54 years and 4 colorectal cancers. The phenotype in the families with the intron 14 mutation corresponded to Lynch syndrome I. In 4 families with other types of intronic and splice site mutations, almost 50% of affected individuals had extracolonic tumors corresponding to Lynch syndrome II. Jager et al. (1997) suggested that clinical surveillance could be restricted to colonic examinations in HNPCC gene carriers with monoallelic MLH1 expression.
In a family that fulfilled the Amsterdam criteria of hereditary nonpolyposis colorectal cancer (HNPCC2; 609310), previously reported by Vasen et al. (1991), Wang et al. (1997) identified a his329-to-pro germline mutation. That this mutation was of pathogenetic significance was proved by finding the same missense mutation as a somatic event ('second hit') in colonic tumors of 2 other HNPCC patients who had germline mutations at different sites of the MLH1 gene.
In a French Canadian kindred, Yuan et al. (1998) found that a novel truncating mutation, 1784delT, was associated with hereditary nonpolyposis colorectal cancer (HNPCC2; 609310). The I1307K APC polymorphism (175100.0029) was also segregating in the family. This polymorphism, associated with an increased risk of colorectal cancer, had previously been identified only in individuals of self-reported Ashkenazi Jewish origin. In the French Canadian family, there appeared to be no relationship between the I1307K polymorphism and the presence or absence of cancer.
In a Turkish family with hereditary nonpolyposis colorectal cancer (HNPCC2; 609310), Ricciardone et al. (1999) identified 3 sibs, born of consanguineous parents, who developed hematologic malignancy at a very early age, 2 of whom displayed signs of type I neurofibromatosis (NF1; 162200). Sequence analysis in the 3 sibs demonstrated homozygosity for a 676C-T mutation in the MLH1 gene, leading to an arg226-to-ter mutation (R226X). Hematologic malignancy was diagnosed in all 3 by the age of 3 years. Both parents were heterozygous for the mutation and had colon cancer at an early age. The phenotype in the sibs was consistent with the mismatch repair cancer syndrome (MMRCS1; 276300), which manifests features of NF1 and hematologic malignancies.
Huang et al. (2001) studied a family with HNPCC in which the proband was diagnosed with colorectal cancer at the age of 14 years; her mother, grandmother, and aunt had been diagnosed with HNPCC in their twenties. DNA sequencing revealed that she was heterozygous for the R226X mutation. As this mutation is 2 bp from the 3-prime end of exon 8 and might affect donor splicing, an in vitro transcription translation assay was performed and confirmed the presence of the truncated peptide, which lacked the critical PMS2-binding regions at its C terminus.
In 2 affected members of a consanguineous North African family in which 11 members of multiple generations developed colorectal cancers (HNPCC2; 609310), 8 of them before the age of 50 years, Wang et al. (1999) identified a heterozygous G-to-T transversion in exon 2 of the MLH1 gene, resulting in a gly67-to-trp (G67W) substitution. Two female children who were homozygous for the mutation had early onset of hematologic neoplastic disorders, including undifferentiated non-Hodgkin malignant lymphoma, acute myeloid leukemia, and a medulloblastoma, consistent with mismatch repair cancer syndrome (MMRCS1; 276300). In addition, both sisters had clinical features of type I neurofibromatosis (NF1; 162200): one had multiple but strictly hemicorporal cafe-au-lait macules and a pseudarthrosis of the tibia, whereas the other had 9 cafe-au-lait spots. No other family member had NF1.
This variant, formerly titled COLON CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2, has been reclassified based on the findings of Kosinski et al. (2010).
Liu et al. (1999) described 2 germline missense mutations in exon 16 of the MLH1 gene associated with colorectal cancer (609310): lys618-to-ala (K618A) and glu578-to-gly (E578G; 120436.0013). The tumors did not show the usual DNA microsatellite instability (MSI) and would have been missed if this method was used for selection of patients for mutation screening.
Using in vitro functional expression studies, Kosinski et al. (2010) demonstrated that the K618A variant was fully expressed and retained MMR activity, and that PMS2 (600259) was stable. The authors classified K618A as a variant of uncertain significance rather than as a disease-causing variant.
This variant, formerly titled COLON CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2, has been reclassified based on the findings of Kosinski et al. (2010).
Liu et al. (1999) described 2 germline missense mutations in exon 16 of the MLH1 gene associated with colorectal cancer (609310): lys618-to-ala (K618A; 120436.0012) and glu578-to-gly (E578G). The tumors did not show the usual DNA microsatellite instability (MSI) and would have been missed if this method was used for selection of patients for mutation screening.
Using in vitro functional expression studies, Kosinski et al. (2010) demonstrated that the K618A variant was fully expressed and retained MMR activity, and that PMS2 (600259) was stable. The authors classified K618A as a variant of uncertain significance rather than as a disease-causing variant.
Vilkki et al. (2001) identified a homozygous deletion of exon 16 of the MLH1 gene in a 4-year-old girl who died unexpectedly of brain hemorrhage caused by glioma. She also had cafe-au-lait spots, including multiple axillary freckles characteristic of NF1 (see 162200) without other features of NF1. The phenotype in this girl was consistent with the spectrum of mismatch repair cancer syndrome (MMRCS1; 276300). Both parents, who had family histories of hereditary nonpolyposis colorectal cancer (HNPCC2; 609310), were heterozygous for the deletion.
Gazzoli et al. (2002) examined 14 cases suspected to represent hereditary nonpolyposis colorectal carcinoma (HNPCC2; 609310) with microsatellite instability (MSI), but in which no germline MSH2 (609309), MSH6 (600678), or MLH1 mutations were detected, for hypermethylation of CpG sites in the critical promoter region of MLH1. The methylation patterns were determined using methylation-specific PCR and by sequence analysis of sodium bisulfite-treated genomic DNA. In 1 case, DNA hypermethylation of 1 allele was detected in DNA isolated from blood. In the tumor from this case, which showed high microsatellite instability, the unmethylated MLH1 allele was eliminated by loss of heterozygosity, and the methylated allele was retained. This biallelic inactivation resulted in loss of expression of MLH1 in the tumor as confirmed by immunohistochemistry. These results suggested a novel mode of germline inactivation of a cancer susceptibility gene.
Morak et al. (2008) identified hypermethylation of the MLH1 proximal promoter region in peripheral blood cells of 12 (13%) of 94 unrelated patients with tumors and loss of MLH1 protein expression without mutations in the MLH1 gene. Normal colonic tissue, buccal mucosa, and tumor tissue available from 3 patients also showed abnormal methylation at the MLH1 promoter. Seven patients who were heterozygous for informative SNPs showed allele-specific methylation that was not restricted to either allelic variant. Five patients had about 50% methylation, consistent with complete methylation of 1 allele. One patient showed 100% methylation, and the rest showed mosaicism or incomplete methylation. Hypermethylation was found in 1 mother-son pair, suggesting familial predisposition for an epimutation. However, there was no evidence for epigenetic inheritance in the remaining families, and 6 patients showed a mosaic or incomplete methylation pattern, which argued against inheritance. Morak et al. (2008) concluded that MLH1 hypermethylation in normal body cells may constitute a pre-lesion, and that patients with such defects should be under surveillance.
Crepin et al. (2012) identified constitutional MLH1 epimutations in 2 (1.5%) of 134 patients suspected of having Lynch syndrome who did not have germline mutations in the MMR genes. One patient was a man who developed colorectal cancer at age 35 years. Tumor tissue showed MSI, and analysis of lymphocyte DNA showed complete hypermethylation of the promoter of 1 MLH1 allele. The second patient was a woman with colorectal cancer, who had a son with colorectal cancer and 2 daughters with dysplastic colonic polyps. Blood from the mother showed 20% hypermethylation at the MLH1 promoter, suggesting mosaicism. The son and 1 affected daughter also showed partial hypermethylation in blood, suggesting transmission of the epimutation through the germline. Tumor tissue from the 3 patients in the second family also showed partial hypermethylation at MLH1, with loss of MLH1 expression in 2. Finally, tumor tissue from the daughter also carried a somatic BRAF mutation (164757.0001).
Green et al. (2003) described, in a Newfoundland kindred, the first report of a heritable MLH1 promoter mutation in hereditary nonpolyposis colorectal cancer (HNPCC2; 609310). The -42C-T mutation was within a putative Myb protooncogene (189990) binding site. Using electrophoretic mobility shift assays, they demonstrated that the mutated Myb binding sequence was less effective in binding nuclear proteins than the wildtype promoter sequence. Using in vivo transfection experiments in HeLa cells, they further demonstrated that the mutated promoter had only 37% of the activity of the wildtype promoter in driving the expression of a reporter gene. The average age of onset in 6 family members affected with colorectal cancer was 62 years, which is substantially later than the typical age of onset in HNPCC families. This finding was considered consistent with the substantial decrease, but not total elimination, of mismatch repair function in affected members of this kindred.
The majority of mutations associated with HNPCC (Lynch syndrome) occur in the MSH2 (609309) and MLH1 genes. Wei et al. (2003) studied these 2 genes in 15 Taiwanese HNPCC kindreds meeting the Amsterdam criteria, using both RNA- and DNA-based methods. In the 15 kindreds they found no MSH2 mutations and mutations in MLH1 in 3 kindreds (20%), which is lower than that reported in other countries. Two novel deletions were found and 1 mutation had been reported several times in western countries (Maliaka et al., 1996; Liu et al., 1996; Trojan et al., 2002). A C-to-T transition in codon 117 in exon 4 resulted in an amino acid change from threonine to methionine (LYNCH2; 609310).
In 4 cases of hereditary nonpolyposis colorectal cancer (LYNCH2; 609310), Taylor et al. (2003) found deletion of 3 nucleotides, 1846_1848delAAG, resulting in deletion of lys616 (K616del) from the MLH1 protein. This mutation had previously been observed by Miyaki et al. (1995). Taylor et al. (2003) used the multiplex ligation-dependent probe amplification (MLDA) assay to demonstrate the deletion.
Tang et al. (2009) identified a heterozygous 1846_1848delAAG mutation in affected members of 5 Taiwanese families with HNPCC2.
Using a novel high density oligonucleotide array (HNPCC Chip) to look for variants in the MLH1, MSH2 (609309), and MSH6 (600678) genes in Israeli probands with familial colorectal cancer (CRC; 114500) unstratified with respect to the microsatellite instability phenotype, Lipkin et al. (2004) identified a 415G-C translation in the MLH1 gene, resulting in an asp132-to-his (D132H) amino acid substitution. MLH1 415C conferred clinically significant susceptibility to CRC. In contrast to classic HNPCC, CRCs associated with MLH1 415C usually did not have the microsatellite instability (MSI) defect, which is important for clinical mutation screening. Structural and functional analyses showed that the normal ATPase function of MLH1 was attenuated, but not eliminated, by the MLH1 415G-C mutation.
In 8 affected members of the Danish family with hereditary nonpolyposis colorectal cancer (LYNCH2; 609310) reported by Bisgaard et al. (2002), Raevaara et al. (2004) identified a pro648-to-ser (P648S) mutation in the MLH1 gene. Only 1 member, a 6-year-old child with first-cousin parents, was homozygous for the mutation. She had mild features of type I neurofibromatosis (NF1; 162200) and no hematologic cancers. She displayed cafe-au-lait spots and a skin tumor clinically diagnosed as a neurofibroma, but no axillary freckles or other abnormalities. The phenotype was consistent with the spectrum of mismatch repair cancer syndrome (MMRCS1; 276300). Raevaara et al. (2004) commented that the mutated protein was unstable but still functional in mismatch repair, suggesting that the cancer susceptibility in the family and possibly also the mild disease phenotype in the homozygous individual were linked to shortage of the functional protein.
In a 30-year-old patient who had developed colon cancer (LYNCH2; 609310) at the age of 22 years, Rey et al. (2004) identified a homozygous 806C-G transversion in exon 10 of the MLH1 gene, resulting in a ser269-to-thr (S269T) substitution. Many members of the paternal and maternal families presented with colon cancer, gastric polyposis, or breast cancer. A founder effect was proposed because both ancestral families originated from the same small region in the south of France. A complete MLH1 inactivation was thought to have been responsible for the precocity of colon cancer and the more aggressive phenotype in this patient. Relatives could not be studied.
In a screen of 226 patients from families matching the Amsterdam II diagnostic criteria or suspected hereditary nonpolyposis colorectal cancer criteria for MSH2 (609309) and MLH1 germline mutations, Kurzawski et al. (2006) found the ala681-to-thr (A681T) change of MLH1 in 8 Polish families, consistent with HNPCC2 (LYNCH2; 609310). They concluded that this, the most frequently occurring mutation of MLH1 in Poland, was a founder mutation. The amino acid substitution resulted from a 2041G-to-A transition in exon 18.
McVety et al. (2006) demonstrated the presence of an exon splicing enhancer (ESE) in exon 3 of MLH1 and showed that a 3-bp in-frame deletion (213_215delAGA) in this ESE was the cause of hereditary nonpolyposis colorectal cancer (LYNCH2; 609310) in a Quebec family. The deletion resulted in loss of codon 71 and caused skipping of exon 3 during mRNA splicing.
In 4 unrelated patients with hereditary nonpolyposis colorectal cancer (LYNCH2; 609310), Pagenstecher et al. (2006) identified a heterozygous 2103G-C transversion in the MLH1 gene. The change was predicted to result in a gln701-to-his (Q701H) substitution, but RNA analysis showed that it resulted in a splicing defect and complete loss of exon 18.
Some epigenetic changes can be transmitted unchanged through the germline (termed 'epigenetic inheritance'). Evidence that this mechanism occurs in humans was provided by Suter et al. (2004) by the identification of individuals in whom 1 allele of the MLH1 gene was epigenetically silenced throughout the soma (implying a germline event). These individuals were affected by hereditary nonpolyposis colorectal cancer (LYNCH2; 609310) but did not have identifiable mutations in MLH1, even though it was silenced, which demonstrated that an epimutation can phenocopy a genetic disease.
This variant, formerly titled COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 2, has been reclassified based on a review of the dbSNP and 1000 Genomes Project databases by Hamosh (2018).
Hitchins et al. (2007) described a family in which a 66-year-old woman, the mother of 3 sons by 2 different men, had the clinical picture of hereditary nonpolyposis colorectal cancer (see LYNCH2, 609310). She had metachronous carcinomas that had microsatellite instability and lacked MLH1 expression. The diagnosis of cancer of the endometrium was made at the age of 45; of the colon at age 59; and of the rectum at 60 years. She was heterozygous for a SNP within the MLH1 promoter (rs1800734), with methylation confined to the A allele. In this woman methylation of the A allele on approximately 50% of chromosomes was confirmed by sulfite sequencing. Hitchins et al. (2007) identified an expressible C-T SNP within MLH1 exon 16 in her son, which was used to demonstrate that he was transcribing RNA only from the MLH1 allele inherited from his father. The data were consistent with transmission of the MLH1 epimutation from the proband to her son. In DNA from peripheral blood leukocytes obtained from this son, approximately half of the MLH1 alleles were methylated. In contrast, his sperm had no trace of MLH1 methylation, despite containing equal proportions of alleles derived from his father and mother. Furthermore, analysis of the RNA in his sperm at the MLH1 exon 16 C-T SNP showed reactivation of the maternally derived MLH1 allele. These results indicated reversion of the MLH1 epimutation to normality during spermatogenesis, suggesting a negligible risk of transmission from that family member.
Hamosh (2018) found that the c.-93G-A (NM_000249.3) MLH1 promoter variant was present at a minor allele frequency (MAF) of 0.32 in dbSNP and in 552 of 1,008 East Asian alleles (MAF 55%) in the 1000 Genomes Project database (April 20, 2018), suggesting that the variant is not pathogenic.
In a 4-year-old boy (case I) with glioblastoma, nephroblastoma, and cafe-au-lait spots consistent with mismatch repair cancer syndrome (MMRCS1; 276300), Poley et al. (2007) identified compound heterozygosity for 2 mutations in the MLH1 gene: a 2-bp deletion (593delAG) and a met35-to-asn (M35N; 120436.0028) substitution. Both tumors and normal tissue were negative for the MLH1 protein. The nephroblastoma showed microsatellite instability, but the glioblastoma did not. Both parents, who were each heterozygous for a respective mutation, came from families with HNPCC2 (LYNCH2; 609310).
For discussion of the met35-to-asn (M35N) mutation in the MLH1 gene that was found in compound heterozygous state in a patient with mismatch repair cancer syndrome (MMRCS1; 276300) by Poley et al. (2007), see 120436.0027.
In affected members of a family with hereditary nonpolyposis colorectal cancer (LYNCH1; 609310), Clyne et al. (2009) identified a heterozygous 200G-A transition in exon 2 of the MLH1 gene, resulting in a gly67-to-glu (G67E) substitution. The male proband had breast cancer, leiomyosarcoma of the thigh, colon cancer, and prostate cancer. Other relatively unusual tumors in other affected family members included esophageal cancer, cervical adenosquamous carcinoma, oligodendroglioma, and prostate cancer. In vitro functional expression assays in yeast showed that the G67E-mutant protein interfered with the ability to prevent the accumulation of mutations, consistent with a loss of function.
In affected members of 13 Taiwanese families with hereditary nonpolyposis colorectal cancer (LYNCH2; 609310), Tang et al. (2009) identified a heterozygous 793C-T transition in exon 10 of the MLH1 gene, resulting in an arg265-to-cys (R265C) substitution. The mutation was not found in 300 controls. Cancers that occurred included colon, rectal, gastric, endometrial, ovarian, breast, and others. Haplotype analysis indicated 2 common haplotypes, 1 of which was shared by 10 families, suggesting a common origin in China several centuries ago.
In 14 unrelated patients and 95 family members among a series of 84 Lynch syndrome (see LYNCH2, 609310) families with germline mutations in MLH1, MSH2 (609309), or MSH6 (600678), Pinheiro et al. (2011) identified an identical exonic rearrangement affecting MLH1 and the contiguous LRRFIP2 gene (614043). All 14 probands harbored an 11,627-bp deletion comprising exons 17 through 19 of the MLH1 gene and exons 26 through 29 of the LRRFIP2 gene. The 5-prime and 3-prime breakpoints were located 280 bp downstream of MLH1 exon 16 and 678 bp upstream of LRRFIP2 exon 25, respectively (chr3:37.089-37.101 Mb, GRCh37). The mutation was therefore designated 1896+280_oLRRFIP2:1750-678del. This mutation represented 17% of all deleterious mismatch repair mutations in their series. Haplotype analysis showed a conserved region of approximately 1 Mb, and the mutation age was estimated to be 283 +/- 78 years, or to the beginning of the 18th century. All 14 families originated from the Porto district countryside. Pinheiro et al. (2011) recommended using this mutation as first line screening for Lynch syndrome among families of Portuguese descent.
In 17 Spanish families originating from northern Spain with hereditary nonpolyposis colorectal cancer (LYNCH2; 609310), Borras et al. (2010) identified a G-to-A transition in intron 3 of the MLH1 gene (306+5G-A). RT-PCR on patient lymphocytes showed an aberrant mRNA transcript expected to generate a truncated protein. This transcript was associated with an increased amount of a transcript corresponding to the in-frame skipping of exon 3. Although the variant is pathogenic at the RNA level, neither abnormal bands nor differences in protein expression were observed in lymphocytes from carriers, suggesting that the mutant protein was unstable. By age 70, the lifetime risk of colorectal cancer in carriers was estimated at 20.1% in men and 14.1% in women. A common haplotype was identified, consistent with a founder effect, and the age of the mutation was estimated to be from 53 to 122 generations.
In 12 Spanish families originating from southern Spain with hereditary nonpolyposis colorectal cancer (LYNCH2; 609310), Borras et al. (2010) identified a 1865T-A transversion in the MLH1 gene, resulting in a leu622-to-his (L622H) substitution in a highly conserved residue at the interaction domain for MutL. In vitro functional expression studies showed that the substitution resulted in decreased amounts of the MLH1 protein. Five of 6 tumors analyzed lost the MLH1 wildtype allele, suggesting a growth advantage with loss of the wildtype protein. By age 70, the lifetime risk of colorectal cancer in carriers was estimated at 6.8% in men and 7.26% in women. A common haplotype was identified, consistent with a founder effect, and the age of the mutation was estimated to be from 12 to 22 generations.
In a boy (patient 2) with mismatch repair cancer syndrome (MMRCS1; 276300), Baas et al. (2013) identified a homozygous c.218T-G transversion in exon 3 of the MLH1 gene, resulting in a leu73-to-arg (L73R) substitution. His parents were unrelated, but originated from the same Polynesian Pacific Island population. In vitro functional expression studies showed that the mutant protein had no DNA repair activity. The patient first presented with a glioblastoma multiforme and later developed a T-cell lymphoblastic lymphoma. He died of sepsis at the end of treatment. Brain imaging showed near complete agenesis of the corpus callosum, interhemispheric and intracerebral cysts, and right subcortical and periventricular heterotopia. He was also noted to have multiple cafe-au-lait spots. The maternal family history was positive for colorectal cancer.
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