Department of Health Sciences, University of Piemonte Orientale, Novara, Italy.
Department of Translational Medicine, Unit of Cancer Epidemiology, CPO-Piemonte, University of Piemonte Orientale, Novara, Italy.
Genes Chromosomes Cancer. 2018 Nov;57(11):573-583. doi: 10.1002/gcc.22670.
Pathogenic germline variants in the BAP1 tumor suppressor gene can cause a cancer syndrome called BAP1 tumor predisposition syndrome (BAP1-TPDS), which is characterized by predisposition to mesothelioma, melanoma, renal cell carcinoma, basal cell carcinoma, and other tumors. Other genes that may predispose to mesothelioma are CDKN2A and DNA repair genes. Asbestos exposure has often been reported in patients with malignant pleural mesothelioma (MPM) and germline variants in BAP1, but this exposure has never been quantified. We aimed to search for germline variants in BAP1 among 25 new Italian probands with suspected BAP1-TPDS, summarize the prevalence of these variants in 39 Italian patients with familial MPM and other tumors recruited over a 5-year period, and compare cumulative asbestos exposure in 14 patients with MPM and pathogenic germline variants in BAP1, CDKN2A, or DNA repair genes with that of 67 patients without germline variants in 94 cancer-predisposing genes. We report here a new pathogenic germline variant in BAP1: c.783 + 2 T > C. The prevalence of pathogenic germline variants in BAP1 was 7.7% among patients with familial MPM (3/39). Patients with pathogenic germline variants in BAP1, CDKN2A, or DNA repair genes showed lower cumulative asbestos exposure than patients without germline variants in 94 cancer-predisposing genes (P = .00002). This suggests an interaction between genetic risk factors and asbestos in the development of mesothelioma.
BAP1 肿瘤抑制基因中的致病变异体可能导致一种称为 BAP1 肿瘤易感性综合征（BAP1-TPDS）的癌症综合征，其特征是易患间皮瘤、黑色素瘤、肾细胞癌、基底细胞癌和其他肿瘤。可能易患间皮瘤的其他基因是 CDKN2A 和 DNA 修复基因。恶性胸膜间皮瘤（MPM）患者和 BAP1 中的致病变异体经常报道石棉暴露，但这种暴露从未被量化。我们旨在 25 名新的疑似 BAP1-TPDS 的意大利先证者中寻找 BAP1 中的致病变异体，总结在 5 年内招募的 39 名意大利家族性 MPM 和其他肿瘤患者中这些变体的流行率，并比较 14 名 MPM 患者和 BAP1、CDKN2A 或 DNA 修复基因中致病变异体的累积石棉暴露与 94 个癌症易感基因中无致病变异体的 67 名患者的累积石棉暴露。我们在这里报告了 BAP1 中的一个新的致病变异体：c.783 + 2 T > C。在家族性 MPM 患者中，BAP1 中的致病变异体的流行率为 7.7%（3/39）。与 94 个癌症易感基因中无致病变异体的患者相比，BAP1、CDKN2A 或 DNA 修复基因中有致病变异体的患者的累积石棉暴露量较低（P = .00002）。这表明遗传风险因素和石棉在间皮瘤的发展中存在相互作用。
