Liu Mengyuan, Liu Xinyi, Suo Peisu, Gong Yuan, Qu Baolin, Peng Xiumei, Xiao Wenhua, Li Yuemin, Chen Yan, Zeng Zhen, Lu Yinying, Huang Tanxiao, Zhao Yingshen, Liu Ming, Li Lifeng, Chen Yaru, Zhou Yanqing, Liu Guifeng, Yao Jianfei, Chen Shifu, Song Lele
HaploX Biotechnology, Co., Ltd., Shenzhen 518057, China.
The Second Medical Center of the Chinese PLA General Hospital, Beijing 100853, China.
Transl Lung Cancer Res. 2020 Jun;9(3):646-658. doi: 10.21037/tlcr-19-403.
Germline variations may contribute to lung cancer susceptibility besides environmental factors. The influence of germline mutations on lung cancer susceptibility and their correlation with somatic mutations has not been systematically investigated.
In this study, germline mutations from 1,026 non-small cell lung cancer (NSCLC) patients were analyzed with a 58-gene next-generation sequencing (NGS) panel containing known hereditary cancer-related genes, and were categorized based on American College of Medical Genetics and Genomics (ACMG) guidelines in pathogenicity, and the corresponding somatic mutations were analyzed using a 605-gene NGS panel containing known cancer-related genes.
Plausible genetic susceptibility was found in 4.7% of lung cancer patients, in which 14 patients with pathogenic mutations (P group) and 34 patients with likely-pathogenic mutations (LP group) were identified. The ratio of the first degree relatives with lung cancer history of the P groups was significantly higher than the Non-P group (P=0.009). The ratio of lung cancer patients with history of other cancers was higher in P (P=0.0007) or LP (P=0.017) group than the Non-P group. Pathogenic mutations fell most commonly in , followed by and . Likely-pathogenic mutations fell most commonly in and followed by and . These genes are involved in DNA repair, cell cycle regulation and tumor suppression. By comparing the germline mutation frequency from this study with that from the whole population or East Asian population (gnomAD database), we found that the overall odds ratio (OR) for P or LP group was 17.93 and 15.86, respectively, when compared with the whole population, and was 2.88 and 3.80, respectively, when compared with the East Asian population, suggesting the germline mutations of the P and LP groups were risk factors for lung cancer. Somatic mutation analysis revealed no significant difference in tumor mutation burden (TMB) among the groups, although a trend of lower TMB in the pathogenic group was found. The SNV/INDEL mutation frequency of TP53 in the P group was significantly lower than the other two groups, and the copy number variation (CNV) mutation frequency of and was significantly higher than the Non-P group. Pathway enrichment analysis found no significant difference in aberrant pathways among the three groups.
A proportion of 4.7% of patients carrying germline variants may be potentially linked to increased susceptibility to lung cancer. Patients with pathogenic germline mutations exhibited stronger family history and higher lung cancer risk.
除环境因素外，种系变异可能会导致肺癌易感性。种系突变对肺癌易感性的影响及其与体细胞突变的相关性尚未得到系统研究。
在本研究中，使用包含已知遗传性癌症相关基因的58基因二代测序（NGS）面板分析了1026例非小细胞肺癌（NSCLC）患者的种系突变，并根据美国医学遗传学与基因组学学会（ACMG）的致病性指南进行分类，同时使用包含已知癌症相关基因的605基因NGS面板分析相应的体细胞突变。
在4.7%的肺癌患者中发现了合理的遗传易感性，其中鉴定出14例具有致病性突变的患者（P组）和34例具有可能致病性突变的患者（LP组）。P组中有肺癌家族史的一级亲属比例显著高于非P组（P = 0.009）。P组（P = 0.0007）或LP组（P = 0.017）中有其他癌症病史的肺癌患者比例高于非P组。致病性突变最常见于 ，其次是 和 。可能致病性突变最常见于 和 ，其次是 和 。这些基因参与DNA修复、细胞周期调控和肿瘤抑制。通过将本研究中的种系突变频率与全人群或东亚人群（gnomAD数据库）的频率进行比较，我们发现与全人群相比，P组或LP组的总体优势比（OR）分别为17.93和15.86，与东亚人群相比，分别为2.88和3.80，这表明P组和LP组的种系突变是肺癌的危险因素。体细胞突变分析显示，各组之间的肿瘤突变负荷（TMB）没有显著差异，尽管在致病性组中发现了TMB较低的趋势。P组中TP53的单核苷酸变异/插入缺失（SNV/INDEL）突变频率显著低于其他两组， 和 的拷贝数变异（CNV）突变频率显著高于非P组。通路富集分析发现三组之间异常通路没有显著差异。
4.7%携带种系变异的患者可能与肺癌易感性增加潜在相关。具有致病性种系突变的患者表现出更强的家族史和更高的肺癌风险。
