Fu Rui, Zhang Jia-Tao, Chen Rong-Rong, Li Hong, Tai Zai-Xian, Lin Hao-Xiang, Su Jian, Chu Xiang-Peng, Zhang Chao, Qiu Zhen-Bin, Chen Zi-Hao, Tang Wen-Fang, Dong Song, Yang Xue-Ning, Zhang Guo-Qing, Zhao Guo-Ping, Wu Yi-Long, Zhong Wen-Zhao
School of Medicine, South China University of Technology, Guangzhou, China.
Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Transl Lung Cancer Res. 2022 Apr;11(4):509-522. doi: 10.21037/tlcr-21-789.
In East Asia, the number of patients with adenocarcinoma, especially those presenting with ground-glass nodules (GGNs), is gradually increasing. Family aggregation of pulmonary GGNs is not uncommon; however, genetic predisposition in these patients remains poorly understood and identification of genes involved in the cause of these early-stage lung cancers might contribute to understanding of the underlying mechanisms and potential prevention strategies.
Fifty patients with early-stage lung adenocarcinoma (LUAD) presenting as GGNs and a first-degree family history of lung cancer (FHLC) from 34 independent families were enrolled into this study. Germline mutations of these patients were analyzed with whole exome sequencing (WES) and compared with age- and sex-matched 39 patients with sporadic lung cancer and 689 local healthy people. We used a stepwise variant filtering strategy, gene-based burden testing, and enrichment analysis to investigate rare but potentially pathogenic heritable mutations. Somatic tumor mutations were analyzed to consolidate germline findings.
In total, 1,571 single nucleotide variants (SNVs) and 238 frameshifts with a minor allele frequency (MAF) <0.01, which were rare, recurrent, and potentially damaging candidates, were finally identified through the filtering in the GGN cohort. Pathway analysis showed the extracellular matrix to be the top dysregulated pathway. Gene-based burden testing of these highly disruptive risk-conferring heritable variants showed that [odds ratio (OR), 9.28, 95% confidence interval (CI): 2.49-35.87], (OR, 8.11, 95% CI: 2.22-28.43), and (OR, 8.09, 95% CI: 2.68-24.92) were significantly enriched in our cohort (P<0.05). The number of rare damaging germline variants in non-smoking patients was significantly higher than that of smoking-affected patients (Spearman's ρ=-0.39, P=0.02).
Heritable, potentially deleterious, and rare candidate variants of , and were significantly associated with early-stage LUAD presenting with GGNs. Nonsmoking patients likely have a higher genetic predisposition to this type of cancer than smoking-affected patients. These results have extended our understanding of the underlying mechanisms of early-stage LUAD.
在东亚地区，腺癌患者的数量，尤其是那些表现为磨玻璃结节（GGN）的患者数量正在逐渐增加。肺部GGN的家族聚集现象并不罕见；然而，这些患者的遗传易感性仍知之甚少，识别与这些早期肺癌病因相关的基因可能有助于理解其潜在机制和潜在的预防策略。
本研究纳入了50例表现为GGN且有肺癌一级家族史（FHLC）的早期肺腺癌（LUAD）患者，这些患者来自34个独立家庭。采用全外显子组测序（WES）分析这些患者的胚系突变，并与年龄和性别匹配的39例散发性肺癌患者及689名当地健康人进行比较。我们使用逐步变异过滤策略、基于基因的负担测试和富集分析来研究罕见但可能致病的遗传性突变。分析体细胞肿瘤突变以巩固胚系研究结果。
通过对GGN队列的筛选，最终共鉴定出1571个单核苷酸变异（SNV）和238个移码突变，其次要等位基因频率（MAF）<0.01，这些都是罕见、复发性且可能具有损害性的候选变异。通路分析显示细胞外基质是失调最严重的通路。对这些具有高度破坏性的遗传性风险变异进行基于基因的负担测试表明，[优势比（OR），9.28，95%置信区间（CI）：2.49 - 35.87]，（OR，8.11，95% CI：2.22 - 28.43），以及（OR，8.09，95% CI：2.68 - 24.92）在我们的队列中显著富集（P<0.05）。非吸烟患者中罕见的有害胚系变异数量显著高于受吸烟影响的患者（斯皮尔曼相关系数ρ = -0.39，P = 0.02）。
、 和 的遗传性、潜在有害且罕见的候选变异与表现为GGN的早期LUAD显著相关。非吸烟患者可能比受吸烟影响的患者对此类癌症具有更高的遗传易感性。这些结果扩展了我们对早期LUAD潜在机制的理解。
