Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Nov;20(11):1626-1638.
doi: 10.1016/j.jtho.2025.06.005. Epub 2025 Jun 15.

Genomic Profiles of Pathogenic and Moderate-Penetrance Germline Variants Associated With Risk of Early-Onset Lung Adenocarcinoma

Hourin Cho  1 , Kouya Shiraishi  2 , Kuniko Sunami  1 , Yukihide Momozawa  3 , Tatsuya Yoshida  4 , Shingo Matsumoto  5 , Koichi Matsuda  6 , Motonobu Saito  7 , Akiteru Goto  8 , Takayuki Honda  9 , Akifumi Mochizuki  10 , Masahiro Torasawa  11 , Yataro Daigo  12 , Kimihiro Shimizu  13 , Hideo Kunitoh  14 , Yukihiro Yoshida  15 , Makoto Hirata  16 , Yoko Shimada  1 , Michiko Ueki  1 , Hanako Ono  17 , Masahiro Gotoh  17 , Yukiko Shimoda Igawa  11 , Akiko Tateishi  11 , Yoh Yamaguchi  11 , Ryoko Inaba Higashiyama  11 , Erika Machida  18 , Motoki Iwasaki  19 , Yosuke Kawai  20 , Hiroyuki Yasuda  21 , Junko Hamamoto  21 , Issei Imoto  22 , Hirokazu Matsushita  23 , Sadaaki Takata  3 , Tomomi Aoi  3 , Syuzo Kaneko  24 , Aya Kuchiba  25 , Akihiko Shimomura  26 , Maki Fukami  27 , Kotaro Hattori  28 , Kouichi Ozaki  29 , Yoshihiro Asano  30 ; NCBN Controls WGS Consortium  31 ; Biobank Japan Project  32 ; Atsushi Takano  33 , Masashi Kobayashi  34 , Yohei Miyagi  35 , Kazumi Tanaka  36 , Hiroyuki Suzuki  37 , Takumi Yamaura  37 , Teruhiko Yoshida  16 , Yasushi Goto  4 , Hidehito Horinouchi  4 , Yasunari Miyazaki  9 , Hidemi Ito  38 , Toshiteru Nagashima  36 , Yoichi Ohtaki  36 , Kazuhiro Imai  39 , Yoshihiro Minamiya  39 , Kenichi Okubo  34 , Johji Inazawa  40 , Yuichi Shiraishi  41 , Katsushi Tokunaga  42 , Yoichiro Kamatani  43 , Yasushi Yatabe  44 , Koichi Goto  5 , Masahiro Tsuboi  45 , Shun-Ichi Watanabe  15 , Yuichiro Ohe  4 , Yoshinori Murakami  46 , Keitaro Matsuo  47 , Ryuji Hamamoto  24 , Takahshi Kohno  1
Affiliations
Free article

Genomic Profiles of Pathogenic and Moderate-Penetrance Germline Variants Associated With Risk of Early-Onset Lung Adenocarcinoma

Hourin Cho et al. J Thorac Oncol. 2025 Nov.
Free article

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 evaluated by whole-exome and whole-genome sequencing of 348 early-onset LADC (aged ≤ 40 y) and 1425 later-onset LADC (aged ≥ 41 y) cases. A case-control study comprising 10,302 LADC cases and 7898 healthy controls was performed to identify moderate-risk genetic factors for the disease. Analysis of somatic mutations in 1278 patients with LADC, 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 exhibited a high incidence of concurrent TP53 somatic mutations. Patients with BRCA2 GPVs exhibited deficient homologous recombination in tumors by means of 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 exhibited a correlation between SBS4-related somatic mutations and the Brinkman index.

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

Keywords: ALKBH2; BRCA2; Early-onset; Hereditary; Lung adenocarcinoma; TP53.

PubMed Disclaimer

Conflict of interest statement

Disclosure Dr. Cho reports receiving funding from the Japan Society for the Promotion of Science (JSPS) KAKENHI. Dr. Shiraishi reports receiving funding from the Japan Agency for Medical Research and Development and the National Cancer Center Research and Development Fund. Dr. Sunami reports receiving a grant from Sysmex, outside the current work. Dr. Momozawa reports receiving funding and a grant from the Japan Agency for Medical Research and Development. Dr. Tatsuya Yoshida reports receiving grants from Novartis, AbbVie, Amgen, Daiichi-Sankyo, AstraZeneca, MSD, Chugai Pharmaceutical Co., Astellas, Boehringer Ingelheim, BMS, Ono pharmaceutical and Merck Biopharma; and payment for lectures from Novartis, Daiichi-Sankyo, AstraZeneca, MSD, Chugai Pharmaceutical Co. Ltd., BMS, Ono, Takeda, Pfizer, Lilly, and Merck Biopharma; and reports advisory roles as a Board Member of Novartis, MSD, Amgen, Chugai Pharmaceutical Co. Ltd., Daiichi-Sankyo, Pfizer, and Boehringer Ingelheim, outside the current work. Dr. Matsumoto reports receiving grants from MSD and Janssen Pharmaceuticals, and payment for lectures from Eli Lilly and Chugai Pharmaceutical Co., outside the current work. Dr. Daigo reports receiving funding from the Japan Society for the Promotion of Science (JSPS). Dr. Kunitoh reports receiving consulting fees and payment for lectures from Daiichi-Sankyo, and payment for lectures from MSD and Johnson and Johnson, outside the current work. Dr. Yukihiro Yoshida reports receiving grants from Takahata Precision Co., Ltd., Astra Zeneca plc, and Chugai Pharmaceutical Co., Ltd. Outside the current work. Dr. Matsushita reports receiving funding and provision of study materials. Dr. Shimomura reports receiving grants from Daiichi-Sankyo, Astra Zeneca, Eisai, Pfizer, and Gilead Sciences, and payment for lectures from Astra Zeneca, Pfizer, MSD, Nihon Medi-physics, Exact Sciences, Daiichi-Sankyo, Eli Lilly, Chugai Pharmaceutical Co., and Taiho Pharmaceutical, outside the current work. Dr. Yasushi Goto reports receiving grants from IQVIA Services Japan, MSD, Astellas Pharma, AstraZeneca, AbbVie, Amgen, Syneos Health Clinical, Sysmex Corporation, CMIC, Novartis Pharma, Bayer Pharmaceuticals, Bristol-Myers Squibb, MedPace Japan, Janssen Pharma, Clinical Research Support Center Kyushu, SATOMI, Ono Pharmaceutical, Daiichi-Sankyo, Takeda Pharmaceutical, Chugai Pharmaceutical, NPO Thoracic Oncology Research Group, Eli Lilly Japan, Preferred Network, Eli Lilly, Pfizer, Novartis, Kyorin, and Guardant Health Inc.; and payment for lectures from Eli Lilly, Chugai, Taiho, Boehringer Ingelheim, Ono, Bristol-Myers Squibb, Pfizer, MSD, Novartis. Merck, and Thermo Fisher; and advisory fees from Astra Zeneca, Chugai, Boehringer Ingelheim, Eli Lilly, Glaxo Smith Kline, Taiho, Pfizer, Novartis, Kyorin, Guardant Health Inc., Illumina, Daiichi-Sankyo, Merck, MSD, Ono Pharmaceutical, and Janssen; and reports leadership roles as a Board Member of Cancer Net Japan, Japanese Association of Medical Technologists, outside the current work. Dr. Horinouchi reports receiving grants from MSD, AbbVie, Astra Zeneca, BMS, Ono Pharmaceutical, Daiichi-Sankyo, Janssen, and Chugai/Roche; and honoraria for lectures from Astra Zeneca, MSD, Ono Pharmaceutical, BMS, Chugai/Roche, Amgen, and AbbVie; and reports advisory roles as a Board Member of Astra Zeneca, Chugai/Roche, Ono Pharmaceutical, BMS, and AbbVie, outside the current work. Dr. Miyazaki reports receiving payment for lectures from Astra Zeneca, outside of the current work. Dr. Inazawa reports receiving funding from research funding from Japan Agency for Medical Research and Development (AMED), Japan for the current work; and consulting fees from BML Inc., outside of the current work. Dr. Kamatani reports receiving honoraria from Illumina Japan, outside the current work. Dr. Yatabe reports receiving grants from Merk Biopharma, Chugai-pharma, Konica-Minolta REALM, Optieum Biotechnologies, and Eizai; and consulting fees from Astra Zeneca, MSD, AbbVie, Novartis, Amgen, Daiichi-Sankyo, Janssen Pharma, and Konica-Minolta REALM; and honorarium for lectures from MSD, Chugai-pharma, Astra Zeneca, Merk Biopharma, Novartis, Amgen, Daiichi-Sankyo, and Thermo Fisher Scientific, outside the current work. Dr. Koichi Goto reports receiving grants from Amgen, Astra Zeneca, AbbVie, AnHeart Therapeutics, AccuraGen, Bayer Yakuhin, Nippon Boehringer Ingelheim, Bristol-Myers Squibb, Blueprint Medicines Corporation., BillionToOne, Chugai Pharmaceutical, Craif, Daiichi-Sankyo, Eisai, Eli Lilly Japan, Guardant Health AMEA, Haihe Biopharma, Ignyta, Janssen Pharmaceutical, Kyowa Kirin, Lunit, Loxo Oncology, Medical and Biological Laboratories, Merus N.V. MSD, Nippon Kayaku, Novartis Pharma, Ono Pharmaceutical, Pfizer Japan, RIKEN Genesis, Sumitomo Pharma, Spectrum Pharmaceuticals; and consulting fees from Nippon Boehringer Ingelheim., GlaxoSmithKline, and Pfizer.; and honorarium for lectures from Amgen, Amoy Diagnostics, Astra Zeneca, ArriVent Biopharma, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi-Sankyo, Eisai, Eli Lilly Japan, Janssen Pharmaceutical, Thermo Fisher Scientific, Merck Biopharma, Nippon Kayaku, Novartis Pharma, Ono Pharmaceutical, Sysmex Corporation, Taiho Pharmaceutical, Takeda Pharmaceutical; and reports advisory roles as Board Members from Amgen Inc., Amgen, ArriVent Biopharma, Bayer HealthCare Pharmaceuticals, Nippon Boehringer Ingelheim., Bristol-Myers Squibb., Boehringer Ingelheim Taiwan, Daiichi-Sankyo, Eli Lilly Japan, Guardant Health Japan Corp., Haihe Biopharma, iTeos Therapeutics, Novartis Pharma, Pharma Mar, S.A., Sysmex Corporation., Taiho Pharmaceutical, outside the current work. Dr. Ohe reports receiving grants from Astra Zeneca, Chugai, Eli Lilly, LOXO Kirin, Sumitomo, Pfizer, Taiho, Novartis, Takeda, Kissei, Daiichi-Sankyo, and Janssen; and payment for lectures from Astra Zeneca, Chugai, Eli Lilly, ONO, BMS, Boehringer Ingelheim, Bayer, Pfizer, MSD, Taiho, Nippon Kayaku, Kyowa Hakko Kirin, Eisai and Daiichi-Sankyo; and payment for expert testimony from AstraZeneca, Chugai, ONO, BMS, Kyorin, Celltrion, Amgen, Nippon Kayaku, Boehringer Ingelheim, AnHeart Therapeutics Inc. and PharmaMar, outside the current work. Mr. R. Hamamoto reports receiving funding from Japan Science and Technology Agency (JST) Core Research for Evolutionary Science and Technology (CREST), JST Artificial Intelligence, Big Data, IoT, Cyber Security Integration Project (AIP) Public/Private R&D Investment Strategic Expansion Program (PRISM), and Programs for Bridging the gap between R&D and the IDeal society (Society 5.0) and Generating Economic and Social Value (BRIDGE). The remaining authors declare no conflict of interest.