Germline BAP1 Mutations Predispose to Renal Cell Carcinomas

Abstract

The genetic cause of some familial nonsyndromic renal cell carcinomas (RCC) defined by at least two affected first-degree relatives is unknown. By combining whole-exome sequencing and tumor profiling in a family prone to cases of RCC, we identified a germline BAP1 mutation c.277A>G (p.Thr93Ala) as the probable genetic basis of RCC predisposition. This mutation segregated with all four RCC-affected relatives. Furthermore, BAP1 was found to be inactivated in RCC-affected individuals from this family. No BAP1 mutations were identified in 32 familial cases presenting with only RCC. We then screened for germline BAP1 deleterious mutations in familial aggregations of cancers within the spectrum of the recently described BAP1-associated tumor predisposition syndrome, including uveal melanoma, malignant pleural mesothelioma, and cutaneous melanoma. Among the 11 families that included individuals identified as carrying germline deleterious BAP1 mutations, 6 families presented with 9 RCC-affected individuals, demonstrating a significantly increased risk for RCC. This strongly argues that RCC belongs to the BAP1 syndrome and that BAP1 is a RCC-predisposition gene.

Mesothelioma families without inheritance of a BAP1 predisposing mutation

“…IHC findings in three epithelioid MM cases (C-II-1, D-II-3, O-II-3) suggest that the loss of nuclear staining occurred via somatic mutation Page 10 of 19 (see Figure 1). BAP1 nuclear staining retained in one sarcomatoid MM (G-II-8) is in agreement with other studies reporting data of positive BAP1 staining on sarcomatoid MM [25] and on the absence of BAP1 mutation [9,10,18,19]. Considering all families with multiple cases of MM analyzed to date for BAP1 germline mutations (see Table 2), those described in the present study without a predisposing germline BAP1 mutation are similar to those reported by other investigators [9,10,19].…”

“…We cannot exclude large deletions of BAP1 that are undetectable by Sanger sequencing [3,9,11,19]. However, large deletions of BAP1 have never been detected in germline configuration in families either with multiple MM [3,9,11,[32][33][34][35][36][37] or without MM [26,28,29]. The loss of nuclear BAP1 immunostaining suggests that these tumors may harbor somatic alterations of the BAP1 gene, a frequent event in sporadic epithelial MM [21,24,26,27].…”

“…The absence of a germline mutation in coding regions and intron-exon boundaries of BAP1 gene was proven in the normal tissue DNA belonging to one index case (D-II-4) and by excluding single point mutations and small InDels in tumor DNA belonging to the other three index cases (C-II-2, O-III-1, G-II-6). We cannot exclude large deletions of BAP1 that are undetectable by Sanger sequencing [3,9,11,19]. However, large deletions of BAP1 have never been detected in germline configuration in families either with multiple MM [3,9,11,[32][33][34][35][36][37] or without MM [26,28,29].…”

“…As of March 2016, forty-six families with multiple cases of MM have been analyzed for BAP1 germline alterations. Some families were proven to carry BAP1 germline alterations in association with family history of either typical BAP1-TPDS cancers [9,10,17] or not typical BAP1-TPDS cancers [9,10,18,19]. In addition, families with multiple cases of MM without inheritance of a predisposing germline BAP1 mutation have been reported [20].…”

“…BAP1 regulates cell cycle control, target genes transcription, and DNA damage repair [2]. The germline mutation in the BAP1 gene is associated with a hereditary tumor predisposition syndrome (BAP1-TPDS, OMIM#614327) that occurs in family members with several cancer types: MM, uveal/cutaneous melanoma, renal cell carcinoma, basal cell carcinoma and other cancers [3][4][5][6][7][8][9][10][11][12][13][14][15][16]. As of March 2016, forty-six families with multiple cases of MM have been analyzed for BAP1 germline alterations.…”