A number sign (#) is used with this entry because of evidence that tumor predisposition syndrome-1 (TPDS1) is caused by heterozygous germline mutation in the BAP1 gene (603089) on chromosome 3p21.

Tumor predisposition syndrome-1 (TPDS1) is inherited in an autosomal dominant pattern. Individuals carrying heterozygous BAP1 mutations are at high-risk for the development of a variety of tumors, including benign melanocytic tumors as well as several malignant tumors, including uveal melanoma (155720), cutaneous melanoma (155600), malignant mesothelioma on exposure to asbestos (156240), and other cancer types, such as lung adenocarcinoma, meningioma, and renal cell carcinoma (summary by Wiesner et al., 2011, Testa et al., 2011, Abdel-Rahman et al., 2011, and Popova et al., 2013).

Genetic Heterogeneity of Tumor Predisposition Syndrome

See also TPDS2 (619975), caused by mutation in the MBD4 gene (603574) on chromosome 3q21; TPDS3 (615848), caused by mutation in the POT1 gene (606478) on chromosome 7q31; and TPDS4 (609265), caused by mutation in the CHEK2 gene (604373) on chromosome 22q12.

Wiesner et al. (2011) reported 2 unrelated families with autosomal dominant inheritance of a skin tumor predisposition syndrome. In the second decade of life, affected individuals progressively developed multiple skin-colored to reddish-brown, dome-shaped to pedunculated, well-circumscribed papules with an average size of 5 mm all over the body. The number of tumors per individual varied markedly, ranging from 5 to over 50. Histopathologic examination showed dermal tumors composed entirely or predominantly of epithelioid melanocytes with abundant amphophilic cytoplasm and prominent nucleoli. The melanocytes often contained large, vesicular nuclei that varied substantially in size and shape. The lesions were distinct from common acquired nevi. Some of the neoplasms showed atypical features such as high cellularity or nuclear pleomorphism, and were classified as 'neoplasms of uncertain malignant potential;' these individuals were managed as if they had melanoma. Both families were identified because of the occurrence of multiple epithelioid melanocytic tumors, but, in each family, 1 affected individual had uveal melanoma, at ages 72 and 44, respectively, and 3 members of family 2 developed cutaneous melanoma. None of the affected individuals had intellectual disabilities or dysmorphic features, or lung or breast cancer.

Testa et al. (2011) reported 2 unrelated families with multiple cases of malignant mesothelioma apparently transmitted in an autosomal dominant pattern. Affected members of both families had only household exposure to asbestos, but not occupational exposure. In 1 family, there were 5 affected individuals spanning 3 generations. There was also 1 case each of ovarian cancer, breast cancer, and renal cell carcinoma in other members of this family. The second family had 7 cases of mesothelioma. In addition, there was 1 case each of squamous cell carcinoma, basal cell carcinoma, and pancreatic cancer in other family members. One of the mesothelioma patients also had a uveal melanoma, and 1 additional family members reportedly had a uveal melanoma, but no DNA was available from the latter patient.

Abdel-Rahman et al. (2011) reported a family in which multiple members spanning 5 generations had different types of cancer. The proband was ascertained due to the onset of uveal melanoma at age 52 years, and she also had lung adenocarcinoma. She was found to carry a heterozygous truncating mutation in the BAP1 gene (Q267X; 603089.0007). Three additional living family members with cancer also carried the mutation: 1 had cutaneous melanoma, 1 had meningioma, and 1 had uveal melanoma and neuroendocrine carcinoma. There were 2 deceased obligate carriers, who had a history of abdominal adenocarcinoma, likely ovarian, and mesothelioma, respectively. One additional mutation carrier was cancer-free at age 55 years. Tumor tissue from lung adenocarcinoma, meningioma, and uveal melanoma of 3 patients all showed somatic loss of heterozygosity for the BAP1 gene, and all had decreased BAP1 nuclear expression by immunohistochemical studies. The findings were consistent with biallelic inactivation of the BAP1 gene. Abdel-Rahman et al. (2011) concluded that this family had a hereditary cancer predisposition syndrome that increased the risk of several different types of tumors. The proband in this family was the only 1 of 53 unrelated patients with uveal melanoma and evidence of a familial cancer syndrome screened for BAP1 mutations who was found to carry a mutation, suggesting that is it a rare cause of hereditary uveal melanoma.

Carbone et al. (2015) reported a large multigenerational kindred (K4) of European descent with TBPS1. The family was identified through 4 probands with malignant mesothelioma who were found to carry the same heterozygous frameshift mutation in the BAP1 gene. The patients originated from different region of the United States, but were later found to be related within the K4 kindred through molecular studies, including haplotype analysis. Detailed genealogic studies identified the ancestors as a Swiss couple born in the 16th century whose descendants emigrated to Germany in the early 1700's and then to North America where they resided in several different states. Multiple family members spanning at least 6 generations showed various types of cancer, including malignant mesothelioma, uveal melanoma, basal cell carcinoma, leiomyosarcoma, renal cell carcinoma, and cutaneous melanoma. One mutation carrier had breast cancer. There was high penetrance of cancer manifestation by age 55 years. None of the patients had exposure to asbestos.

The transmission pattern of TBPS1 in the family reported by Carbone et al. (2015) was consistent with autosomal dominant inheritance with variable expressivity.

Using array-based comparative genomic hybridization, Wiesner et al. (2011) found loss of chromosome 3p in 50% of skin tumors from 3 affected individuals in a family with melanocytic tumors, suggesting that this was a second hit resulting in the elimination of the remaining wildtype allele of a mutated tumor suppressor gene in this chromosomal region. Haplotype analysis showed segregation of the maternal allele in affected family members of 2 generations, and sequence analysis of this region identified a heterozygous germline mutation in the BAP1 gene (603089.0001) that segregated with the phenotype. Reexamination of tumor tissue confirmed loss of BAP1 in 29 skin tumors and a uveal melanoma. Tumors that did not show loss of 3p21 showed loss of BAP1 through additional somatic mechanisms, such as point mutation. Immunohistochemical studies showed loss of BAP1 nuclear expression in the melanocytic neoplasms. Molecular analysis of a second family with a similar phenotype identified a different heterozygous germline mutation in the BAP1 gene (603089.0002). Somatic inactivation of the remaining allele, as determined by loss of heterozygosity (LOH), was found in 9 of 13 skin tumors, in the 1 uveal melanoma, and in a cutaneous melanoma from 1 patient. A metastatic melanoma from another family member did not show LOH for BAP1, but no additional tissue was available to investigate alternative mechanisms of BAP1 inactivation. In contrast, microscopic examination of common acquired flat nevi from these patients showed small uniform melanocytes and strong nuclear expression of BAP1. In addition, 37 (88%) of 42 tumors in both families showed a somatic V600E mutation in the BRAF gene (164757.0001). Notably, the families had a low number of melanomas compared to the number of papular melanocytic tumors, suggesting that the risk of malignant progression in individual tumors from patients with this disorder is low.

Using array-comparative genomic hybridization, Testa et al. (2011) found loss of BAP1 at 3p21 in 2 malignant mesothelioma tumors from 2 unrelated families. Subsequent linkage analysis of these families identified an inherited susceptibility locus on chromosome 3p21, and sequence analysis identified a heterozygous mutation in the BAP1 gene (603089.0003 and 603089.0004, respectively) in each family that segregated with the phenotype. Tumor tissue showed loss of BAP1 nuclear expression by immunohistochemistry. The findings were consistent with somatic loss of the second BAP1 allele in tumor tissue. Further analysis of 26 germline DNA samples from patients with sporadic mesothelioma found that 2 carried heterozygous BAP1 deletions (603089.0005 and 603089.0006, respectively). Each of these patients also had a history of uveal melanoma.

In affected members of a large family with a tumor predisposition syndrome characterized mainly be renal cell carcinoma (RCC), Popova et al. (2013) identified a heterozygous germline mutation in the BAP1 gene (603089.0008). The mutation was identified using a combination of whole-exome sequencing and tumor profiling, and was confirmed by Sanger sequencing. Three renal cell carcinomas from this family showed loss of heterozygosity for BAP1, consistent with the 2-hit hypothesis of cancer development. Subsequently, sequence analysis identified heterozygous truncating mutations in the BAP1 gene (see, e.g., 603089.0009-603089.0010) in 11 (18%) of 60 unrelated families with either uveal melanoma, cutaneous melanoma, or mesothelioma. A total of 33 individuals were diagnosed with these 3 cancers in diverse associations; 14 individuals had other cancers, including renal, lung, breast, prostatic, thyroid, and bladder carcinomas. Nine RCCs were reported in 6 of the 11 families with BAP1 mutations, indicating that RCC should be added to the tumor spectrum of this syndrome. However, no BAP1 mutations were detected in a separate series of 32 French families with only RCC, suggesting that germline BAP1 mutations rarely explain families affected only with RCC.

In 6 affected members of a large multigenerational kindred (K4) of European origin with TPDS1, Carbone et al. (2015) identified a heterozygous germline frameshift mutation in the BAP1 gene (c.1717delC; 603089.0015). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family in those who were genotyped. The mutant protein was predicted to lack the nuclear localization signal, and immunohistochemical studies of mesothelioma tissue showed lack of nuclear BAP1 staining with only cytoplasmic localization. Somatic loss of heterozygosity of the BAP1 gene was confirmed in available tumor tissue. These findings were consistent with BAP1 being a tumor suppressor gene. Carbone et al. (2015) emphasized the importance of identifying mutation carriers in this family who can then be monitored for malignant mesothelioma or other cancers, because early detection and diagnosis can lead to effective treatment.