Genomic profiles of pathogenic and moderate-penetrance germline variants associated with risk of early-onset lung adenocarcinoma.

IF 21 1区医学 Q1 ONCOLOGY

Journal of Thoracic Oncology Pub Date : 2025-06-12 DOI:10.1016/j.jtho.2025.06.005

Hourin Cho, Kouya Shiraishi, Kuniko Sunami, Yukihide Momozawa, Tatsuya Yoshida, Shingo Matsumoto, Koichi Matsuda, Motonobu Saito, Akiteru Goto, Takayuki Honda, Akifumi Mochizuki, Masahiro Torasawa, Yataro Daigo, Kimihiro Shimizu, Hideo Kunitoh, Yukihiro Yoshida, Makoto Hirata, Yoko Shimada, Michiko Ueki, Hanako Ono, Masahiro Gotoh, Yukiko Shimoda Igawa, Akiko Tateishi, Yoh Yamaguchi, Ryoko Inaba Higashiyama, Erika Machida, Motoki Iwasaki, Yosuke Kawai, Hiroyuki Yasuda, Junko Hamamoto, Issei Imoto, Hirokazu Matsushita, Sadaaki Takata, Tomomi Aoi, Syuzo Kaneko, Aya Kuchiba, Akihiko Shimomura, Maki Fukami, Kotaro Hattori, Kouichi Ozaki, Yoshihiro Asano, Biobank Japan Project, Atsushi Takano, Masashi Kobayashi, Yohei Miyagi, Kazumi Tanaka, Hiroyuki Suzuki, Takumi Yamaura, Teruhiko Yoshida, Yasushi Goto, Hidehito Horinouchi, Yasunari Miyazaki, Hidemi Ito, Toshiteru Nagashima, Yoichi Ohtaki, Kazuhiro Imai, Yoshihiro Minamiya, Kenichi Okubo, Johji Inazawa, Yuichi Shiraishi, Katsushi Tokunaga, Yoichiro Kamatani, Yasushi Yatabe, Koichi Goto, Masahiro Tsuboi, Shun-Ichi Watanabe, Yuichiro Ohe, Yoshinori Murakami, Keitaro Matsuo, Ryuji Hamamoto, Takahshi Kohno

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引用次数: 0

Abstract

Introduction: Up to 54% of all lung adenocarcinoma (LADC) cases in Asian populations occur in never-smoking women, suggesting that the impact of smoking and other environmental factors on the risk of early-onset LADC is minimal. Genetic factors may play a crucial role in disease development.

Methods: The prevalence of germline pathogenic variants (GPVs) of 454 hereditary cancer and DNA repair genes was examined by whole-exome and whole-genome sequencing of 350 early-onset LADC (aged < 40 years) and 1,441 later-onset LADC (aged ≥ 41 years) cases. A case-control study comprising 10,672 LADC cases and 7,898 healthy controls was performed to identify moderate-risk genetic factors for the disease. Analysis of somatic mutations in 1,280 LADC patients, including 31 patients with GPVs, was also performed.

Results: The frequency of GPVs of TP53 and BRCA2 was significantly higher in those with early-onset LADC than in those with later-onset LADC. The detection rates for TP53 and BRCA2 GPVs were 2.9% and 1.7%, respectively, in patients with early-onset LADC, and 0.14% and 0.21%, respectively, in patients with later-onset LADC. Patients with BRCA1 GPVs showed a high incidence of concurrent TP53 somatic mutations. Patients with BRCA2 GPVs showed deficient homologous recombination in tumors via loss of the wild-type allele. A germline ALKBH2 variant, p.Glu35Alafs*54, was associated with the risk of early-onset LADC, and patients with a deleterious variant showed a correlation between SBS4-related somatic mutations and the Brinkman index.

Conclusions: TP53 and BRCA2 GPVs and the ALKBH2 novel variant are associated with early-onset LADC in Asians.

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与早发性肺腺癌风险相关的致病性和中等外显率种系变异的基因组谱

在亚洲人群中，高达54%的肺腺癌（LADC）病例发生在从不吸烟的女性中，这表明吸烟和其他环境因素对早发性LADC风险的影响很小。遗传因素可能在疾病发展中起着至关重要的作用。方法：对350例早发性LADC（年龄< 40岁）和1441例晚发性LADC（年龄≥41岁）患者进行全外显子组和全基因组测序，检测454种遗传性癌症和DNA修复基因的种系致病变异（GPVs）的流行情况。一项病例对照研究包括10,672例LADC病例和7,898例健康对照，以确定该疾病的中等风险遗传因素。对1,280例LADC患者（包括31例gpv患者）的体细胞突变进行了分析。结果：早发性LADC中TP53和BRCA2的gpv频率明显高于晚发性LADC。早发性LADC患者TP53和BRCA2 gpv检出率分别为2.9%和1.7%，晚发性LADC患者TP53和BRCA2 gpv检出率分别为0.14%和0.21%。BRCA1 GPVs患者并发TP53体细胞突变的发生率很高。BRCA2 gpv患者通过丢失野生型等位基因在肿瘤中显示同源重组缺陷。一种种系ALKBH2变体p.Glu35Alafs*54与早发性LADC的风险相关，一种有害变体的患者显示sbs4相关体细胞突变与Brinkman指数相关。结论：TP53和BRCA2 GPVs以及ALKBH2新变体与亚洲人早发性LADC相关。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Thoracic Oncology 医学-呼吸系统

CiteScore

36.00

自引率

3.90%

发文量

1406

审稿时长

13 days

期刊介绍： Journal of Thoracic Oncology (JTO), the official journal of the International Association for the Study of Lung Cancer,is the primary educational and informational publication for topics relevant to the prevention, detection, diagnosis, and treatment of all thoracic malignancies.The readship includes epidemiologists, medical oncologists, radiation oncologists, thoracic surgeons, pulmonologists, radiologists, pathologists, nuclear medicine physicians, and research scientists with a special interest in thoracic oncology.