% 608935

LUNG CANCER SUSCEPTIBILITY 1; LNCR1


Cytogenetic location: 6q23-q25     Genomic coordinates (GRCh38): 6:130,000,001-160,600,000


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
6q23-q25 {Lung cancer susceptibility} 608935 2

TEXT

For a phenotypic description and a discussion of genetic heterogeneity of lung cancer, see 211980.


Inheritance

Although cigarette smoking and some occupational exposures greatly increase the risk of lung cancer, familial factors also clearly play a major role. Tokuhata and Lilienfeld (1963) provided epidemiologic evidence for familial aggregation of lung cancer after accounting for personal smoking, which suggested the possible interaction of genes, shared environment, and common lifestyle factors in the etiology of lung cancer. Fraumeni et al. (1975) reported an increased risk of lung cancer mortality in sibs of probands with lung cancer, and a positive family history was identified as a risk factor for lung cancer in a number of case-control studies.


Mapping

Bailey-Wilson et al. (2004) conducted a genomewide linkage analysis of 52 extended pedigrees ascertained through probands with lung cancer who had several first-degree relatives with the same disease. Multipoint linkage analysis, under a simple autosomal dominant model, of all 52 families with 3 or more individuals affected by lung, throat, or laryngeal cancer, yielded a maximum heterogeneity lod score (hlod) of 2.79 at 155 cM on chromosome 6q. A subset of 38 pedigrees with 4 or more affected individuals yielded a multipoint hlod of 3.47 at 155 cM. Analysis of a further subset of 23 multigenerational pedigrees with 5 or more affected individuals yielded a multipoint hlod score of 4.26 at the same position. The results localized a major susceptibility locus influencing lung cancer risk to 6q23-q25. To explore the effect of smoking on risk for lung cancer among carriers of the susceptibility haplotype, Bailey-Wilson et al. (2004) obtained the most likely haplotypes from 21 of the 23 multigenerational pedigrees; then all individuals were scored as either carriers (223, of which 87 were affected, and 90.4% of the affected individuals smoked) or noncarriers (344, of which 19 were affected, and 83% of affected individuals smoked). Further analyses showed a mild effect of increasing smoking on risk for lung cancer among carriers, whereas, among noncarriers, there was a significant effect of smoking on risk for lung cancer. When smoking was treated as a categorical yes/no variable, Bailey-Wilson et al. (2004) found that smoking increased risk for both carriers and noncarriers. These sets of observations suggested that smoking at any level increased risk in carriers of inherited susceptibility from a locus on chromosome 6q, whereas increased smoking increased risk for noncarriers.


Molecular Genetics

Veeriah et al. (2010) provided evidence that PARK2 (602544) on chromosome 6q25-q27 can act as a tumor suppressor gene in lung cancer. Among 242 human cancers, different somatic point mutations in the PARK2 gene were found in 4 lung cancers and some other cancers. These somatic mutations in occurred in the same domains as germline Parkinson disease 2 (600116) mutations, including the ubiquitin-like domain (UBL), the RING finger domain, and the in-between RING fingers domain (IBR). In vitro functional studies in tumor cell lines showed that tumor growth was greater in cells with mutant PARK2, that wildtype PARK2 decreased tumor growth in vivo, and that mutant PARK2 caused decreased PARK2 function which could promote tumor cell growth.


REFERENCES

  1. Bailey-Wilson, J. E., Amos, C. I., Pinney, S. M., Petersen, G. M., de Andrade, M., Wiest, J. S., Fain, P., Schwartz, A. G., You, M., Franklin, W., Klein, C., Gazdar, A., and 15 others. A major lung cancer susceptibility locus maps to chromosome 6q23-25. Am. J. Hum. Genet. 75: 460-474, 2004. [PubMed: 15272417, images, related citations] [Full Text]

  2. Fraumeni, J. F., Jr., Wertelecki, W., Blattner, W. A., Jensen, R. D., Leventhal, B. G. Varied manifestations of a familial lymphoproliferative disorder. Am. J. Med. 59: 145-151, 1975. [PubMed: 806230, related citations] [Full Text]

  3. Tokuhata, G. K., Lilienfeld, A. M. Familial aggregation of lung cancer in humans. J. Nat. Cancer Inst. 30: 289-312, 1963. [PubMed: 13985327, related citations]

  4. Veeriah, S., Taylor, B. S., Meng, S., Fang, F., Yilmaz, E., Vivanco, I., Janakiraman, M., Schultz, N., Hanrahan, A. J., Pao. W., Ladanyi, M., Sander, C., Heguy, A., Holland, E. C., Paty, P. B., Mischel, P. S., Liau, L., Cloughesy, T. F., Mellinghoff, I. K., Solit, D. B., Chan, T. A. Somatic mutations of the Parkinson's disease-associated gene PARK2 in glioblastoma and other human malignancies. Nature Genet. 42: 77-82, 2010. [PubMed: 19946270, related citations] [Full Text]


Contributors:
Cassandra L. Kniffin - updated : 1/15/2010
Creation Date:
Victor A. McKusick : 9/21/2004
carol : 08/20/2019
alopez : 02/01/2010
ckniffin : 1/15/2010
alopez : 5/19/2008
alopez : 5/16/2008
alopez : 5/15/2008
terry : 12/21/2005
alopez : 9/21/2004

% 608935

LUNG CANCER SUSCEPTIBILITY 1; LNCR1


DO: 1324;  


Cytogenetic location: 6q23-q25     Genomic coordinates (GRCh38): 6:130,000,001-160,600,000


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
6q23-q25 {Lung cancer susceptibility} 608935 2

TEXT

For a phenotypic description and a discussion of genetic heterogeneity of lung cancer, see 211980.


Inheritance

Although cigarette smoking and some occupational exposures greatly increase the risk of lung cancer, familial factors also clearly play a major role. Tokuhata and Lilienfeld (1963) provided epidemiologic evidence for familial aggregation of lung cancer after accounting for personal smoking, which suggested the possible interaction of genes, shared environment, and common lifestyle factors in the etiology of lung cancer. Fraumeni et al. (1975) reported an increased risk of lung cancer mortality in sibs of probands with lung cancer, and a positive family history was identified as a risk factor for lung cancer in a number of case-control studies.


Mapping

Bailey-Wilson et al. (2004) conducted a genomewide linkage analysis of 52 extended pedigrees ascertained through probands with lung cancer who had several first-degree relatives with the same disease. Multipoint linkage analysis, under a simple autosomal dominant model, of all 52 families with 3 or more individuals affected by lung, throat, or laryngeal cancer, yielded a maximum heterogeneity lod score (hlod) of 2.79 at 155 cM on chromosome 6q. A subset of 38 pedigrees with 4 or more affected individuals yielded a multipoint hlod of 3.47 at 155 cM. Analysis of a further subset of 23 multigenerational pedigrees with 5 or more affected individuals yielded a multipoint hlod score of 4.26 at the same position. The results localized a major susceptibility locus influencing lung cancer risk to 6q23-q25. To explore the effect of smoking on risk for lung cancer among carriers of the susceptibility haplotype, Bailey-Wilson et al. (2004) obtained the most likely haplotypes from 21 of the 23 multigenerational pedigrees; then all individuals were scored as either carriers (223, of which 87 were affected, and 90.4% of the affected individuals smoked) or noncarriers (344, of which 19 were affected, and 83% of affected individuals smoked). Further analyses showed a mild effect of increasing smoking on risk for lung cancer among carriers, whereas, among noncarriers, there was a significant effect of smoking on risk for lung cancer. When smoking was treated as a categorical yes/no variable, Bailey-Wilson et al. (2004) found that smoking increased risk for both carriers and noncarriers. These sets of observations suggested that smoking at any level increased risk in carriers of inherited susceptibility from a locus on chromosome 6q, whereas increased smoking increased risk for noncarriers.


Molecular Genetics

Veeriah et al. (2010) provided evidence that PARK2 (602544) on chromosome 6q25-q27 can act as a tumor suppressor gene in lung cancer. Among 242 human cancers, different somatic point mutations in the PARK2 gene were found in 4 lung cancers and some other cancers. These somatic mutations in occurred in the same domains as germline Parkinson disease 2 (600116) mutations, including the ubiquitin-like domain (UBL), the RING finger domain, and the in-between RING fingers domain (IBR). In vitro functional studies in tumor cell lines showed that tumor growth was greater in cells with mutant PARK2, that wildtype PARK2 decreased tumor growth in vivo, and that mutant PARK2 caused decreased PARK2 function which could promote tumor cell growth.


REFERENCES

  1. Bailey-Wilson, J. E., Amos, C. I., Pinney, S. M., Petersen, G. M., de Andrade, M., Wiest, J. S., Fain, P., Schwartz, A. G., You, M., Franklin, W., Klein, C., Gazdar, A., and 15 others. A major lung cancer susceptibility locus maps to chromosome 6q23-25. Am. J. Hum. Genet. 75: 460-474, 2004. [PubMed: 15272417] [Full Text: https://doi.org/10.1086/423857]

  2. Fraumeni, J. F., Jr., Wertelecki, W., Blattner, W. A., Jensen, R. D., Leventhal, B. G. Varied manifestations of a familial lymphoproliferative disorder. Am. J. Med. 59: 145-151, 1975. [PubMed: 806230] [Full Text: https://doi.org/10.1016/0002-9343(75)90333-2]

  3. Tokuhata, G. K., Lilienfeld, A. M. Familial aggregation of lung cancer in humans. J. Nat. Cancer Inst. 30: 289-312, 1963. [PubMed: 13985327]

  4. Veeriah, S., Taylor, B. S., Meng, S., Fang, F., Yilmaz, E., Vivanco, I., Janakiraman, M., Schultz, N., Hanrahan, A. J., Pao. W., Ladanyi, M., Sander, C., Heguy, A., Holland, E. C., Paty, P. B., Mischel, P. S., Liau, L., Cloughesy, T. F., Mellinghoff, I. K., Solit, D. B., Chan, T. A. Somatic mutations of the Parkinson's disease-associated gene PARK2 in glioblastoma and other human malignancies. Nature Genet. 42: 77-82, 2010. [PubMed: 19946270] [Full Text: https://doi.org/10.1038/ng.491]


Contributors:
Cassandra L. Kniffin - updated : 1/15/2010

Creation Date:
Victor A. McKusick : 9/21/2004

Edit History:
carol : 08/20/2019
alopez : 02/01/2010
ckniffin : 1/15/2010
alopez : 5/19/2008
alopez : 5/16/2008
alopez : 5/15/2008
terry : 12/21/2005
alopez : 9/21/2004