Notably, mutations in BAP1 and PBRM1 anticorrelate in tumors (P = 3 × 10(-5)), [corrected] and combined loss of BAP1 and PBRM1 in a few RCCs was associated with rhabdoid features (q = 0.0007).
Notably, mutations in BAP1 and PBRM1 anticorrelate in tumors (P = 3 × 10(-5)), [corrected] and combined loss of BAP1 and PBRM1 in a few RCCs was associated with rhabdoid features (q = 0.0007).
However, mutation exclusivity may indicate negative genetic interactions, as proposed herein for PBRM1 and BAP1, and mutations in these genes define RCC with different pathologic features, gene expression profiles, and outcomes.
The clinical phenotype of BAP1 hereditary cancer predisposition syndrome (MIM 614327) includes uveal melanoma (UM), cutaneous melanoma (CM), renal cell carcinoma (RCC), and mesothelioma.
Loss of function germline mutations of BAP1 have been associated with an enhanced risk of uveal and cutaneous melanomas, mesothelioma, clear cell renal cancer and atypical cutaneous melanocytic proliferations.
Germline mutations in BRCA1 predispose individuals to breast, ovarian, fallopian tube, peritoneal, pancreatic and prostate cancers, whereas BAP1 mutations combined with certain types of DNA damage provoke malignant mesothelioma, uveal and cutaneous melanoma, lung adenocarcinoma and renal cell carcinoma.
None of the RCCs had biallelic deletion of BAP1, but five (11.1%) showed a biallelic mutation (four with a sequence-level mutation with monoallelic loss and one with a biallelic sequence-level mutation); these cells were negative for nuclear BAP1 staining.
Compared to patients with PBRM1+ BAP1+ tumors those with PBRM1- BAP1+ lesions were more likely to die of renal cell carcinoma (HR 1.39, p = 0.035), followed by those with PBRM1+ BAP1- and PBRM1- BAP1- tumors (HR 3.25 and 5.2, respectively, each p <0.001).
Our study indicate that common germline genetic variants of <i>BAP1</i> play a role in mediating the risk of developing renal cell carcinoma and lung cancer.
While in clear cell renal cell carcinoma, BAP1 mutation was mutually exclusive with PBRM1 mutations, and BAP1-mutant clear cell renal cell carcinomas also showed significantly worse prognosis than PBRM1-mutant clear cell renal cell carcinomas ( p = 0.001).
Analysis of cancers in the pedigree of the proband carrying the S98R variant and in two other pedigrees carrying clear loss-of-function alleles showed the presence of BAP1-associated cancers such as renal cell carcinoma, mesothelioma and meningioma, but not uveal melanoma.
Though screening and management guidelines for some inherited RCC syndromes (e.g. von Hippel-Lindau disease, Birt-Hogg-Dube syndrome, hereditary leiomyomatosis) are well defined for rare cause of inherited RCC (e.g. germline BAP1 mutations), there is limited information regarding the lifetime RCC risks and the most appropriate screening modalities.
Since then, physicians have considered this diagnosis for patients with a characteristic personal or family history of BAP1-associated tumours (mainly uveal and cutaneous melanoma, pleural/peritoneal mesothelioma, renal cell carcinoma and BAP1-deficient melanocytic lesions).