Yoshikawa Yoshie, Emi Mitsuru, Nakano Takashi, Gaudino Giovanni
Department of Genetic, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
University of Hawai'i Cancer Center, Honolulu, HI, USA.
Transl Lung Cancer Res. 2020 Feb;9(Suppl 1):S67-S76. doi: 10.21037/tlcr.2019.11.15.
Malignant mesothelioma is associated with the exposure to asbestos fibers. Recent discovery of the cancer syndrome, a Mendelian disorder with high-penetrance autosomal dominant inheritance fostered the genotyping for nucleotide-level or larger structural alteration of germline DNA. Inherited heterozygous mutations of the gene increase the susceptibility to carcinogenic fibers, leading to a concept of gene x environment interaction (GxE) as a pathogenetic mechanism of mesothelioma. Several studies on cohorts of unselected patients with mesothelioma or on familial/early-onset cohorts of mesothelioma cases converged on as the more frequent germline mutated gene, followed by other genes involved in DNA repair and homologous recombination. Evidence has been emerging that patients with mesothelioma carrying germline mutations of and of other genes, such as those involved in DNA repair and tumor suppressor genes, have better prognosis and higher chemosensitivity when compared with patients with germline wildtype Bap1. We report here a germline genomic analysis targeted 22 genes in a cohort of 101 Japanese patients irrespective of asbestos exposure, age at diagnosis, or personal or family history of cancer. By comparing the results with the Human Genetic Variation Database (HGVD) and the Genome Aggregation Database (gnomAD) we selected rare germline variants with a Combined Annotation Dependent Depletion (CADD) >20. We show here that 31 of 101 subjects were carrying 25 rare variants in 14 genes, neither reported in the HGVD nor in the gnomAD database for 14/25 variants. Besides pathogenic variants of , rare missense variants were found in genes encoding lysine-specific histone methyltransferase and and genes encoding subunits of the mSWI/SNF chromatin remodeling complex. The complete scenario of the genetic background consisting of pathogenic germline variants required for the predisposition and GxE for pathogenesis of mesothelioma appears complex, and further large-scale studies are warranted.
恶性间皮瘤与接触石棉纤维有关。最近发现的一种癌症综合征，一种具有高外显率常染色体显性遗传的孟德尔疾病，促进了对种系DNA核苷酸水平或更大结构改变的基因分型。该基因的遗传性杂合突变增加了对致癌纤维的易感性，从而产生了基因与环境相互作用（GxE）作为间皮瘤发病机制的概念。几项针对未选择的间皮瘤患者队列或间皮瘤病例的家族性/早发性队列的研究都集中在作为更常见的种系突变基因上，其次是其他参与DNA修复和同源重组的基因。越来越多的证据表明，与种系野生型Bap1患者相比，携带该基因和其他基因（如参与DNA修复的基因和肿瘤抑制基因）种系突变的间皮瘤患者预后更好，化疗敏感性更高。我们在此报告了对101名日本患者队列中的22个基因进行的种系基因组分析，这些患者不论是否接触石棉、诊断时的年龄或个人或家族癌症病史。通过将结果与人类遗传变异数据库（HGVD）和基因组聚合数据库（gnomAD）进行比较，我们选择了综合注释依赖损耗（CADD）>20的罕见种系变异。我们在此表明，101名受试者中有31名在14个基因中携带25个罕见变异，其中14/25个变异在HGVD和gnomAD数据库中均未报告。除了该基因的致病变异外，在编码赖氨酸特异性组蛋白甲基转移酶和的基因以及编码mSWI/SNF染色质重塑复合体亚基的基因中还发现了罕见的错义变异。间皮瘤易感性所需的致病种系变异和发病机制的GxE组成的遗传背景的完整情况似乎很复杂，需要进一步的大规模研究。
