Common, germline genetic variations in the novel tumor suppressor BAP1 and risk of developing different types of cancer

Our plain-English summary of Common, germline genetic variations in the novel tumor suppressor BAP1 and risk of developing different types of cancer, by M. Lin, L. Zhang, M.A.T. Hildebrandt, et al (Oncotarget, 2017).

The study

• Authors: M. Lin, L. Zhang, M.A.T. Hildebrandt, M. Huang, X. Wu, Y. Ye
• Journal: Oncotarget
• Published: 2017;8(43):74936-74946
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

BRCA1 associated protein-1 (BAP1) is a novel tumor suppressor that has recently been shown to be somatically mutated in several cancers. The BAP1 gene also carries rare germline mutations in families with a high incidence of several types of cancers, such as mesothelioma, uveal melanoma, lung adenocarcinoma, melanocytic neoplasms, and renal cell carcinoma. To test the hypothesis that common, germline genetic variants in BAP1 may also contribute to the risk of developing different types of cancer, we genotyped germline single nucleotide polymorphisms (SNPs) for BAP1 in a large population of patients with cancer, including 2,340 with colorectal cancer, 1,436 with bladder cancer, 3,313 with lung cancer, 1,325 with renal cell carcinoma, and 1,162 with esophageal cancer. We identified significant association of rs11708581 (P = 0.0034) and rs390802 (P = 0.015) with risk of renal cell carcinoma and rs12163565 (P = 0.038) with risk of lung cancer. Expression quantitative trait loci analysis in renal cell carcinoma using publicly available data from TCGA showed that the proxy SNPs for rs11708581 and rs390802 were negatively associated with the expression level of BAP1. Our study indicate that common germline genetic variants of BAP1 play a role in mediating the risk of developing renal cell carcinoma and lung cancer.

In plain English

This case-control study from the University of Texas MD Anderson Cancer Center asked whether common inherited variations in and near the BAP1 gene were linked to risk of five cancers. It included 9,576 white patients with bladder, lung, kidney (renal cell carcinoma), esophageal or colorectal cancer, and 4,945 healthy controls. It did not study mesothelioma or asbestos exposure. Mesothelioma appears only in descriptions of earlier studies. Carriers of the rs11708581 variant had lower odds of renal cell carcinoma (odds ratio 0.74, 95% confidence interval 0.61-0.91). This was the only cancer-risk association that stayed significant after multiple-testing correction. Carriers of rs390802 also had lower odds of renal cell carcinoma (0.80, 0.67-0.96). Carriers of rs12163565 had higher odds of lung cancer (1.11, 1.01-1.24). These three variants lie in the neighboring DNAH1 gene. No variant was significantly linked to esophageal or colorectal cancer. In public kidney tumor data, some stand-ins for the two kidney-linked variants were associated with lower BAP1 expression. The authors concluded that the results support a role for common BAP1 variants in renal cell carcinoma and lung cancer risk.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Case-control genetic association study (candidate gene approach) covering five cancer types, with an additional expression (eQTL) analysis of public tumor data
• Who was studied: 9,576 self-reported white cancer patients and 4,945 healthy controls. The cases were 1,436 bladder, 2,340 colorectal, 1,162 esophageal, 1,325 renal cell carcinoma and 3,313 lung cancer. Cases were recruited from the University of Texas MD Anderson Cancer Center, with additional colorectal cases from the TexGen Consortium. Controls came through random digit dialing and Kelsey-Seybold Clinics in Houston, Texas. Recruitment dates are not given. No mesothelioma patients were studied.
• Exposure: No asbestos or other environmental exposure was studied. The study examined inherited single nucleotide variants (SNPs) within 10 kb of the BAP1 gene: four tagging SNPs plus two chosen for possible function. One of these, rs56238158, was not polymorphic and was excluded, leaving five analyzed. Smoking status was used as an adjustment and stratification factor.
• Main results:
  • Renal cell carcinoma: carriers of one or two copies of the rs11708581 variant had a 26% lower risk (odds ratio 0.74, 95% CI 0.61-0.91, P=0.0034)
  • Renal cell carcinoma: carriers of rs390802 variant alleles had reduced risk (OR 0.80, 95% CI 0.67-0.96, P=0.015)
  • Lung cancer: carriers of rs12163565 variant alleles had increased risk (OR 1.11, 95% CI 1.01-1.24, P=0.038)
  • The two renal-cell-carcinoma-linked variants are located in the neighboring DNAH1 gene
  • The lung-cancer-linked variant rs12163565 is also a variant of DNAH1, located within 10 kb of BAP1
  • Bladder cancer: rs12163565 showed an increased risk that was not statistically significant (OR 1.17, 95% CI 0.99-1.39, P=0.070)
  • No variant was significantly associated with esophageal or colorectal cancer
  • Among the cancer-risk associations, only rs11708581 with renal cell carcinoma remained significant after Bonferroni correction for multiple comparisons
  • In analyses stratified by age, smoking status and sex, none of the interactions between the three SNPs and these factors was significant
  • In TCGA renal clear cell carcinoma data, two proxy SNPs for rs11708581 and one for rs390802 were negatively associated with BAP1 expression level
  • In the expression analysis, the association of proxy SNP rs17052053 with BAP1 expression remained significant after Bonferroni correction
• The authors' conclusion: The authors concluded that their results support the idea that common germline variants in BAP1 play a role in the risk of developing renal cell carcinoma and lung cancer.
• Limitations the authors state:
  • For the lung-cancer-associated variant rs12163565, which lies in the neighboring DNAH1 gene, the authors state that its functional effect on BAP1 remains unknown

Topics

Medical terms in this study, explained in our Lexicon: BAP1, Germline Mutation, Mesothelioma, Lung Adenocarcinoma, Neoplasm, Carcinoma, Colorectal Cancer, Lung Cancer.

Related studies

• Bap1 Is a Bona Fide Tumor Suppressor: Genetic Evidence from Mouse Models Carrying Heterozygous Germline Bap1 Mutations — Y. Kadariya, M. Cheung, et al. (2016)
• Spontaneous Mesotheliomas in Germline Bap1 Heterozygous Mice from Different Genetic Backgrounds — Y. Kadariya, L. Zhang, et al. (2025)
• The Influence of Genetic Variability on the Risk of Developing Malignant Mesothelioma — A. Franko, N. Kotnik, et al. (2018)
• Different prognostic roles of tumor suppressor gene BAP1 in cancer: A systematic review with meta-analysis — C. Luchini, N. Veronese, et al. (2016)
• Functional differences between wild-type and mutant-type BRCA1-associated protein 1 tumor suppressor against malignant mesothelioma cells — S. Hakiri, H. Osada, et al. (2015)
• Identification of novel candidate oncogenes and tumor suppressors in malignant pleural mesothelioma using large-scale transcriptional profiling — G.J. Gordon, G.N. Rockwell, et al. (2005)

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