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Germline BAP1 mutations predispose to renal cell carcinomas

Tatiana Popova et al. Am J Hum Genet. .

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.

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Figures

Figure 1
Figure 1
Clinical and Biological Characterization of Family A (A) Pedigree and tumor spectrum of family A. Proven BAP1 mutation carriers are indicated with a red plus sign, obligate mutation carriers with a black plus sign, and proven wild-type individuals with a black minus sign. Abbreviations are as follows: RCC, renal cell carcinoma; Breast, breast carcinoma. Other cancers: I-1, esophagus carcinoma; II-6, head and neck carcinoma; II-7, esophagus carcinoma; III-1, cervix carcinoma; III-7, lung carcinoma; III-9, adenocarcinoma of unknown primitive tumor (ACUP). (B) Whole-genome tumor analysis by SNP array identified 3p21-containing BAP1 gene as the unique region of consistent loss of heterozygosity (LOH) and identical by descent (IBD) haplotype. The three lower tracks correspond to the three tumors analyzed in Affymetrix SNP6.0, using the number of consecutive probesets as coordinates. LOH is indicated by red boxes (IBD haplotype retained in the tumor) and black boxes (unshared haplotype retained in the tumor). Cumulative LOH is shown on the upper track with the location of BAP1. IBD is defined between III-1, III-3, and III-5 affected individuals. (C) BAP1 transcript detected in index case III-1. Three sequences are visible on the electropherogram: the wild-type cDNA, the cDNA with the missense c.277A>G mutation, and the abnormally spliced cDNA as a consequence of the new acceptor splicing site within exon 5. The alternative splicing is illustrated below the electropherogram. The cDNA sequence was amplified from a lymphoblastoid cell line derived from patient III-1. (D) Immunohistochemistry from a renal cell carcinoma affecting index case III-1. The left panel shows adjacent normal renal tissue of the tumor sample. The brown staining illustrates a significant normal nuclear immune-labeling of BAP1 protein. The right panel shows a subset of tumor cells with a blue counterstaining indicating a lack of BAP1 expression in tumors.
Figure 2
Figure 2
Pedigree of the Families with Members Carrying BAP1 Mutations (A) Venn diagram of familial tumor spectrum of the 60 families screened for BAP1 germline mutation. Numbers in black represent number of families with members carrying a given tumor association, and numbers in red represent number of these families with members carrying BAP1 mutation. (B) Pedigrees of families with members carrying a germline BAP1 mutation. Arrows indicate index cases. Proven BAP1 mutation carriers are indicated with a red plus sign, obligate mutation carriers indicated with a black plus sign, and proven wild-type individuals indicated with a black minus sign. Abbreviations are as follows: CM, cutaneous melanoma; MPM, malignant pleural mesothelioma; UM, uveal melanoma.

References

    1. Ferlay J., Parkin D.M., Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur. J. Cancer. 2010;46:765–781. - PubMed
    1. Pavlovich C.P., Schmidt L.S. Searching for the hereditary causes of renal-cell carcinoma. Nat. Rev. Cancer. 2004;4:381–393. - PubMed
    1. Axwijk P.H., Kluijt I., de Jong D., Gille H., Teertstra J., Horenblas S. Hereditary causes of kidney tumours. Eur. J. Clin. Invest. 2010;40:433–439. - PubMed
    1. Woodward E.R., Ricketts C., Killick P., Gad S., Morris M.R., Kavalier F., Hodgson S.V., Giraud S., Bressac-de Paillerets B., Chapman C. Familial non-VHL clear cell (conventional) renal cell carcinoma: clinical features, segregation analysis, and mutation analysis of FLCN. Clin. Cancer Res. 2008;14:5925–5930. - PubMed
    1. Li H., Handsaker B., Wysoker A., Fennell T., Ruan J., Homer N., Marth G., Abecasis G., Durbin R., 1000 Genome Project Data Processing Subgroup The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009;25:2078–2079. - PMC - PubMed

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