Alternative titles; symbols
ORPHA: 1331;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p36.12 | {Prostate cancer/brain cancer susceptibility, somatic} | 603688 | 3 | EPHB2 | 600997 |
A number sign (#) is used with this entry because of evidence that susceptibility to prostate cancer/brain cancer is associated with somatic mutation in the EPHB2 gene (600997) on chromosome 1p36.
Because an excess of cases of primary brain cancer has been observed in some studies of families with a high risk of prostate cancer, and because loss of heterozygosity at 1p36 is frequently observed in brain cancer, Gibbs et al. (1999) evaluated 12 families with both a history of prostate cancer and a blood relative with primary brain cancer. The overall lod score in these 12 families was 3.22 at a recombination fraction (theta) of 0.06 with marker D1S507. On the basis of an a priori hypothesis, this group was stratified by age at diagnosis of prostate cancer. In the younger age group (mean age at diagnosis less than 66 years), a maximum 2-point lod score of 3.65 at theta = 0.0 was observed with marker D1S407. This linkage was rejected in both early- and late-onset families without a history of brain cancer. After exclusion of 3 of the 12 families that had better evidence of linkage to previously described prostate cancer susceptibility loci, linkage to the 1p36 region was suggested by a 2-point lod score of 4.74 at theta = 0.0 with marker D1S407. Gibbs et al. (1999) concluded that a significant proportion of these families with a high risk for prostate cancer and a family member with brain cancer show linkage to the 1p36 region.
Badzioch et al. (2000) reported genotype analysis of 207 multiple-case prostate cancer families including 9 families with prostate and brain cancer. They found no evidence of linkage to 1p36 in the total set of families with prostate and brain cancer, but did find suggestive evidence (maximum lod 0.48) of linkage in those families with early onset (earlier than 66 years). Badzioch et al. (2000) concluded that linkage to this region may be a feature of early-onset prostate cancer rather than of the brain/prostate cancer phenotype.
Cancel-Tassin et al. (2001) examined evidence for linkage to the CAPB locus in 64 (37 previously reported and 27 newly identified) families from southern and western Europe with at least 3 affected individuals with prostate cancer and an average age at diagnosis of 66.4 years. Using both parametric and nonparametric linkage methods, no significant evidence of linkage was observed. A subset of 6 pedigrees with 1 case of brain cancer also showed negative lod scores. Even when heterogeneity was assumed, multipoint hlod scores remained negative across the entire interval. The findings suggested that the CAPB locus is not the only one responsible for susceptibility to brain and prostate cancer.
Huusko et al. (2004) sought tumor-suppressor genes in solid tumors by combined nonsense-mediated RNA decay microarrays and array-based comparative genomic hybridization, looking for genes with biallelic inactivation involving nonsense mutations in one allele and loss of the other, wildtype, allele. This approach enabled them to identify previously unknown mutations in the receptor tyrosine kinase gene EPHB2 (600997). In DU 145, a prostate cancer cell line originating from a brain metastasis, Huusko et al. (2004) found a truncating mutation of EPHB2 (Q723X; 600997.0001) and a deletion of the remaining allele. In other prostate cancer samples, frameshift, splice site, missense, and nonsense mutations were found (see, e.g., 600997.0002-600997.0003).
Kittles et al. (2006) demonstrated association between a somatic nonsense mutation (K1019X; 600997.0004) in the EPHB2 gene and prostate cancer in African Americans.
Badzioch, M., Eeles, R., LeBlanc, G., Foulkes, W. D., Giles, G., Edwards, S., Goldgar, D., Hopper, J. L., Bishop, D. T., Moller, P., Heimdal, K., Easton, D., The CRC/BPG UK Familial Prostate Cancer Study Coordinators and Collaborators, The EU Biomed Collaborators, Simard, J. Suggestive evidence for a site specific prostate cancer gene on chromosome 1p36. J. Med. Genet. 37: 947-948, 2000. [PubMed: 11186936] [Full Text: https://doi.org/10.1136/jmg.37.12.947]
Cancel-Tassin, G., Latil, A., Valeri, A., Mangin, P., Fournier, G., Berthon, P., Cussenot, O. PCAP is the major known prostate cancer predisposing locus in families from south and west Europe. Europ. J. Hum. Genet. 9: 135-142, 2001. [PubMed: 11313747] [Full Text: https://doi.org/10.1038/sj.ejhg.5200592]
Gibbs, M., Stanford, J. L., McIndoe, R. A., Jarvik, G. P., Kolb, S., Goode, E. L., Chakrabarti, L., Schuster, E. F., Buckley, V. A., Miller, E. L., Brandzel, S., Li, S., Hood, L., Ostrander, E. A. Evidence for a rare prostate cancer-susceptibility locus at chromosome 1p36. Am. J. Hum. Genet. 64: 776-787, 1999. [PubMed: 10053012] [Full Text: https://doi.org/10.1086/302287]
Huusko, P., Ponciano-Jackson, D., Wolf, M., Kiefer, J. A., Azorsa, D. O., Tuzmen, S., Weaver, D., Robbins, C., Moses, T., Allinen, M., Hautaniemi, S., Chen, Y., and 14 others. Nonsense-mediated decay microarray analysis identifies mutations of EPHB2 in human prostate cancer. Nature Genet. 36: 979-983, 2004. [PubMed: 15300251] [Full Text: https://doi.org/10.1038/ng1408]
Kittles, R. A., Baffoe-Bonnie, A. B., Moses, T. Y., Robbins, C. M., Ahaghotu, C., Huusko, P., Pettaway, C., Vijayakumar, S., Bennett, J., Hoke, G., Mason, T., Weinrich, S., Trent, J. M., Collins, F. S., Mousses, S., Bailey-Wilson, J., Furbert-Harris, P., Dunston, G., Powell, I. J., Carpten, J. D. A common nonsense mutation in EphB2 is associated with prostate cancer risk in African American men with a positive family history. J. Med. Genet. 43: 507-511, 2006. [PubMed: 16155194] [Full Text: https://doi.org/10.1136/jmg.2005.035790]