ORPHA: 39044; DO: 6039;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3p21.1 | {Uveal melanoma, susceptibility to, 2} | 606661 | Autosomal dominant | 3 | BAP1 | 603089 |
A number sign (#) is used with this entry because of evidence that susceptibility to uveal melanoma-2 (UVM2) is conferred by heterozygous germline mutation in the BAP1 gene (603089) on chromosome 3p21.
Heterozygous germline mutation in the BAP1 gene also causes tumor predisposition syndrome-1 (TPDS1; 614327), which has uveal melanoma as a primary manifestation with additional malignancies such as mesothelioma often observed.
Uveal melanoma (see 155720) is the most common primary intraocular malignancy. Metastases arise in more than 30% of patients, usually to the liver, with a poor prognosis (median survival of 10 months) (summary by Derrien et al., 2021). Somatic monosomy 3, which is an unusual finding in most tumors, is present in approximately 50% of uveal melanomas and is significantly correlated with metastatic disease (summary by Tschentscher et al., 2001). Mutation in the BAP1 gene is known to confer susceptibility to this specific disease. It has been estimated that about 22% of cases of familial uveal melanoma are due to BAP1 mutations. Conversely, uveal melanoma has been reported in about 31% of BAP1 mutation carriers, making it one of the most common manifestations of TPDS1 (Rai et al., 2016; Rai et al., 2017).
For a discussion of genetic heterogeneity of susceptibility to uveal melanoma, see UVM1 (606660), caused by mutation in the MBD4 gene (603574) on chromosome 3q21.
Yu et al. (2020) reported 2 unrelated Caucasian men who developed uveal melanoma at 44 and 54 years, respectively. Both underwent unilateral enucleation of the affected eye. Four years later, both patients developed ciliary body melanoma in the other eye. Neither had other tumors of systemic metastases. Family history in 1 patient was significant for ovarian and bladder cancer in his mother and pancreatic cancer in his maternal great-grandfather. The authors noted that bilateral occurrence of uveal melanoma should suggest an inherited tumor predisposition syndrome.
To obtain positional information on putative tumor suppressor genes on chromosome 3, Tschentscher et al. (2001) investigated tumors from 333 patients by comparative genomic hybridization, microsatellite analysis, or conventional karyotype analysis. A partial deletion of the long arm was found in 8 tumors, and the smallest region of deletion overlap (SRO) spanned 3q24-q26. They found 6 tumors with a partial deletion of the short arm and defined a second SRO of about 2.5 Mb in 3p25. This SRO did not overlap with the von Hippel-Lindau disease gene (608537). Tschentscher et al. (2001) interpreted their findings as suggesting a role for 2 tumor suppressor genes in metastasizing uveal melanoma: one on 3q, here designated UVM1 (606660), and a second on 3p25, here designated UVM2. The involvement of 2 tumor suppressor genes may explain the loss of an entire chromosome 3 in metastatic uveal melanomas.
Parrella et al. (2003) mapped both arms of chromosome 3 in 21 uveal melanomas that did not show monosomy 3 in previous allelotype studies. DNA was isolated from microdissected paraffin sections of posterior uveal melanoma treated by enucleation from 1993 to 1998 and archived by the Eye Pathology Laboratory of the Wilmer Ophthalmologic Institute, Johns Hopkins. In an initial screening, 14 microsatellite markers on 3p and 13 on 3q were used. Loss of heterozygosity for at least 1 marker was found in 9 of 21 tumors (43%) on 3p and 8 of 21 tumors (38%) on 3q. Two common regions of allelic loss on 3p were further mapped with an additional 14 microsatellite markers. A 1.4-Mb minimal region of allelic loss was identified between microsatellite markers D3S3610 and D3S1554 on 3p25.2-p25.1. Ten tumors had allelic loss in this region; 2 of these tumors had corresponding putative homozygous deletions.
In 2 unrelated Caucasian men with bilateral uveal melanoma-2, Yu et al. (2020) identified germline heterozygous frameshift mutations in the BAP1 gene (603089.0015 and 603089.0016). Functional studies of the variants were not performed. Cytogenetic profile of tumor tissue showed somatic changes affecting chromosomes 3, 6, and 8 in both patients. Family history in patient 1 was significant for cancer, although familial genetic segregation studies were not conducted in either proband. The patients did not have other tumors or systemic metastasis.
Derrien, A. C., Rodrigues, M., Eeckhoutte, A., Dayot, S., Houy, A., Mobuchon, L., Gardrat, S., Lequin, D., Ballet, S., Pierron, G., Alsafadi, S., Mariani, O., El-Marjou, A., Matet, A., Colas, C., Cassoux, N., Stern, M. H. Germline MBD4 mutations and predisposition to uveal melanoma. J. Nat. Cancer Inst. 113: 80-87, 2021. [PubMed: 32239153] [Full Text: https://doi.org/10.1093/jnci/djaa047]
Parrella, P., Fazio, V. M., Gallo, A. P., Sidransky, D., Merbs, S. L. Fine mapping of chromosome 3 in uveal melanoma: identification of a minimal region of deletion on chromosomal arm 3p25.1-p25.2. Cancer Res. 63: 8507-8510, 2003. [PubMed: 14679017]
Rai, K., Pilarski, R., Boru, G., Rehman, M., Saqr, A. H., Massengill, J. B., Singh, A., Marino, M. J., Davidorf, F. H., Cebulla, C. M., H Abdel-Rahman, M. Germline BAP1 alterations in familial uveal melanoma. Genes Chromosomes Cancer 56: 168-174, 2017. [PubMed: 27718540] [Full Text: https://doi.org/10.1002/gcc.22424]
Rai, K., Pilarski, R., Cebulla, C. M., Abdel-Rahman, M. H. Comprehensive review of BAP1 tumor predisposition syndrome with report of two new cases. Clin. Genet. 89: 285-94, 2016. [PubMed: 26096145] [Full Text: https://doi.org/10.1111/cge.12630]
Tschentscher, F., Prescher, G., Horsman, D. E., White, V. A., Rieder, H., Anastassiou, G., Schilling, H., Bornfeld, N., Bartz-Schmidt, K. U., Horsthemke, B., Lohmann, D. R., Zeschnigk, M. Partial deletions of the long and short arm of chromosome 3 point to two tumor suppressor genes in uveal melanoma. Cancer Res. 61: 3439-3442, 2001. [PubMed: 11309305]
Yu, M. D., Masoomian, B., Shields, J. A., Shields, C. L. BAP1 germline mutation associated with bilateral primary uveal melanoma. Ocul. Oncol. Path. 6: 10-14, 2020. [PubMed: 32002398] [Full Text: https://doi.org/10.1159/000499570]