Identification of telomere maintenance gene variations related to lung adenocarcinoma risk by genome-wide association and whole genome sequencing analyses

Kouya Shiraishi^{1

2}, Atsushi Takahashi^{3

4}, Yukihide Momozawa⁵, Yataro Daigo^{6

7}, Syuzo Kaneko⁸, Takahisa Kawaguchi⁹, Hideo Kunitoh¹⁰, Shingo Matsumoto¹¹, Hidehito Horinouchi¹², Akiteru Goto¹³, Takayuki Honda¹⁴, Kimihiro Shimizu^{15

16}, Masahiro Torasawa^{1

12}, Daisuke Takayanagi¹, Motonobu Saito¹⁷, Akira Saito¹⁸, Yuichiro Ohe¹², Shun-Ichi Watanabe¹⁹, Koichi Goto¹¹, Masahiro Tsuboi²⁰, Katsuya Tsuchihara²¹, Sadaaki Takata⁵, Tomomi Aoi⁵, Atsushi Takano⁶, Masashi Kobayashi²², Yohei Miyagi²³, Kazumi Tanaka¹⁶, Hiroyuki Suzuki²⁴, Daichi Maeda¹³, Takumi Yamaura²⁴, Maiko Matsuda¹, Yoko Shimada¹, Takaaki Mizuno^{1

12}, Hiromi Sakamoto²⁵, Teruhiko Yoshida²⁶, Yasushi Goto¹², Tatsuya Yoshida¹², Taiki Yamaji²⁷, Makoto Sonobe²⁸, Shinichi Toyooka²⁹, Kazue Yoneda³⁰, Katsuhiro Masago³¹, Fumihiro Tanaka³⁰, Megumi Hara³², Nobuo Fuse³³, Satoshi S Nishizuka³⁴, Noriko Motoi³⁵, Norie Sawada²⁷, Yuichiro Nishida³², Kazuki Kumada³³, Kenji Takeuchi³⁶, Kozo Tanno³⁴, Yasushi Yatabe³⁵, Kuniko Sunami¹, Tomoyuki Hishida^{20

37}, Yasunari Miyazaki¹⁴, Hidemi Ito³⁸, Mitsuhiro Amemiya¹⁸, Hirohiko Totsuka¹⁸, Haruhiko Nakayama³⁹, Tomoyuki Yokose⁴⁰, Kazuyoshi Ishigaki³, Toshiteru Nagashima¹⁶, Yoichi Ohtaki¹⁶, Kazuhiro Imai⁴¹, Ken Takasawa⁸, Yoshihiro Minamiya⁴¹, Kazuma Kobayashi⁸, Kenichi Okubo²², Kenji Wakai³⁶, Atsushi Shimizu³⁴, Masayuki Yamamoto³³, Motoki Iwasaki^{27

42}, Koichi Matsuda⁴³, Johji Inazawa⁴⁴, Yuichi Shiraishi⁴⁵, Hiroyoshi Nishikawa⁴⁶, Yoshinori Murakami⁴⁷, Michiaki Kubo⁵, Fumihiko Matsuda⁹, Yoichiro Kamatani³, Ryuji Hamamoto⁸, Keitaro Matsuo⁴⁸, Takashi Kohno¹

Affiliations

¹ Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
² Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan.
³ Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
⁴ Department of Genomic Medicine, Research Institute, National Cerebral and Cardiovascular Center, Osaka, Japan.
⁵ Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
⁶ Center for Antibody and Vaccine Therapy, Research Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁷ Department of Medical Oncology and Cancer Center, and Center for Advanced Medicine against Cancer, Shiga University of Medical Science, Otsu, Japan.
⁸ Division of Medical AI Research and Development, National Cancer Center Research Institute, Tokyo, Japan.
⁹ Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
¹⁰ Department of Medical Oncology, Japanese Red Cross Medical Center, Tokyo, Japan.
¹¹ Department of Thoracic Oncology, National Cancer Center Hospital East, Japan.
¹² Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
¹³ Department of Cellular and Organ Pathology, Graduate School of Medicine, Akita University, Akita, Japan.
¹⁴ Department of Respiratory Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
¹⁵ Division of General Thoracic Surgery, Department of Surgery, Shinshu University School of Medicine, Matsumoto, Nagano, Japan.
¹⁶ Department of General Surgical Science, Division of General Thoracic Surgery, Gunma University Graduate School of Medicine, Integrative Center of General Surgery, Gunma University Hospital, Gunma, Japan.
¹⁷ Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan.
¹⁸ StaGen Co., Ltd, Tokyo, Japan.
¹⁹ Division of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan.
²⁰ Department of Thoracic Surgery, National Cancer Center Hospital East, Chiba, Japan.
²¹ Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Chiba, Japan.
²² Department of Thoracic Surgery, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
²³ Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Kanagawa, Japan.
²⁴ Department of Chest Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan.
²⁵ Fundamental Innovative Oncology Core Center, National Cancer Center Research Institute, Tokyo, Japan.
²⁶ Department of Genetic Medicine and Services, National Cancer Center Hospital, Tokyo, Japan.
²⁷ Division of Epidemiology, National Cancer Center Institute for Cancer Control, Tokyo, Japan.
²⁸ Department of Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan.
²⁹ Departments of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
³⁰ Second Department of Surgery, University of Occupational and Environmental Health, Kitakyushu, Japan.
³¹ Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan.
³² Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan.
³³ Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
³⁴ Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan.
³⁵ Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.
³⁶ Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
³⁷ Division of Thoracic Surgery, Department of Surgery, Keio University School of Medicine, Tokyo, Japan.
³⁸ Division of Cancer Information and Control, Aichi Cancer Center Research Institute, Nagoya, Japan.
³⁹ Department of Thoracic Surgery, Kanagawa Cancer Center, Kanagawa, Japan.
⁴⁰ Department of Pathology, Kanagawa Cancer Center, Yokohama, Japan.
⁴¹ Department of Thoracic Surgery, Graduate School of Medicine, Akita University, Akita, Japan.
⁴² Division of Cohort Research, National Cancer Center Institute for Cancer Control, Tokyo, Japan.
⁴³ Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Science, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
⁴⁴ Department of Molecular Cytogenetics, Medical Research Institute and Bioresource Research Center, Tokyo Medical and Dental University, Tokyo, Japan.
⁴⁵ Division of Genome Analysis Platform Development, National Cancer Center Research Institute, Tokyo, Japan.
⁴⁶ Division of Cancer Immunology, Research Institute, National Cancer Center, Tokyo, Japan.
⁴⁷ Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁴⁸ Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Nagoya, Japan.

PMID: 37882647
PMCID: PMC10876189
DOI: 10.1002/cac2.12498

Identification of telomere maintenance gene variations related to lung adenocarcinoma risk by genome-wide association and whole genome sequencing analyses

Kouya Shiraishi et al. Cancer Commun (Lond). 2024 Feb.

. 2024 Feb;44(2):287-293.

doi: 10.1002/cac2.12498. Epub 2023 Oct 26.

Authors

Affiliations

¹ Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
² Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan.
³ Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
⁴ Department of Genomic Medicine, Research Institute, National Cerebral and Cardiovascular Center, Osaka, Japan.
⁵ Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
⁶ Center for Antibody and Vaccine Therapy, Research Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁷ Department of Medical Oncology and Cancer Center, and Center for Advanced Medicine against Cancer, Shiga University of Medical Science, Otsu, Japan.
⁸ Division of Medical AI Research and Development, National Cancer Center Research Institute, Tokyo, Japan.
⁹ Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
¹⁰ Department of Medical Oncology, Japanese Red Cross Medical Center, Tokyo, Japan.
¹¹ Department of Thoracic Oncology, National Cancer Center Hospital East, Japan.
¹² Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
¹³ Department of Cellular and Organ Pathology, Graduate School of Medicine, Akita University, Akita, Japan.
¹⁴ Department of Respiratory Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
¹⁵ Division of General Thoracic Surgery, Department of Surgery, Shinshu University School of Medicine, Matsumoto, Nagano, Japan.
¹⁶ Department of General Surgical Science, Division of General Thoracic Surgery, Gunma University Graduate School of Medicine, Integrative Center of General Surgery, Gunma University Hospital, Gunma, Japan.
¹⁷ Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan.
¹⁸ StaGen Co., Ltd, Tokyo, Japan.
¹⁹ Division of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan.
²⁰ Department of Thoracic Surgery, National Cancer Center Hospital East, Chiba, Japan.
²¹ Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Chiba, Japan.
²² Department of Thoracic Surgery, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
²³ Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Kanagawa, Japan.
²⁴ Department of Chest Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan.
²⁵ Fundamental Innovative Oncology Core Center, National Cancer Center Research Institute, Tokyo, Japan.
²⁶ Department of Genetic Medicine and Services, National Cancer Center Hospital, Tokyo, Japan.
²⁷ Division of Epidemiology, National Cancer Center Institute for Cancer Control, Tokyo, Japan.
²⁸ Department of Thoracic Surgery, Kyoto University Hospital, Kyoto, Japan.
²⁹ Departments of General Thoracic Surgery and Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
³⁰ Second Department of Surgery, University of Occupational and Environmental Health, Kitakyushu, Japan.
³¹ Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan.
³² Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan.
³³ Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
³⁴ Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan.
³⁵ Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.
³⁶ Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
³⁷ Division of Thoracic Surgery, Department of Surgery, Keio University School of Medicine, Tokyo, Japan.
³⁸ Division of Cancer Information and Control, Aichi Cancer Center Research Institute, Nagoya, Japan.
³⁹ Department of Thoracic Surgery, Kanagawa Cancer Center, Kanagawa, Japan.
⁴⁰ Department of Pathology, Kanagawa Cancer Center, Yokohama, Japan.
⁴¹ Department of Thoracic Surgery, Graduate School of Medicine, Akita University, Akita, Japan.
⁴² Division of Cohort Research, National Cancer Center Institute for Cancer Control, Tokyo, Japan.
⁴³ Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Science, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
⁴⁴ Department of Molecular Cytogenetics, Medical Research Institute and Bioresource Research Center, Tokyo Medical and Dental University, Tokyo, Japan.
⁴⁵ Division of Genome Analysis Platform Development, National Cancer Center Research Institute, Tokyo, Japan.
⁴⁶ Division of Cancer Immunology, Research Institute, National Cancer Center, Tokyo, Japan.
⁴⁷ Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁴⁸ Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Nagoya, Japan.

PMID: 37882647
PMCID: PMC10876189
DOI: 10.1002/cac2.12498

No abstract available

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

**FIGURE 1**
Association of novel susceptibility loci with risk for lung adenocarcinoma according to *EGFR* mutation types and association between genotype and leukocyte telomere length. (A) A Forest plot showing associations between 19 SNPs and the presence or absence of *EGFR* mutations. Odds ratios were adjusted for age, sex, smoking status (never vs. ever smoking), and the top five principal components. Combined meta‐analysis was performed using a fixed‐effects model. P‐values of SNPs that differed significantly between patients with LADC with and without *EGFR* mutations in case‐case analysis are shown. (B) Association between *TERC, TERT*, and *POT1* genotypes and LTL. (C) Association between LADC risk and LTL in 19 LADC risk‐associated SNPs. (D) Association between SNPs in telomere maintenance genes and LTL in our cohort (X‐axis) and in GWAS catalog data (Y‐axis). **Abbreviations**: *EGFR*, epithelial growth factor receptor; Ctrl, control; KGP p3, 1000 genomes project phase 3; RSQR, imputation quality; LADC, lung adenocarcinoma; LTL, leukocyte telomere length; *TERC*, telomerase RNA component; *TERT*, telomerase reverse transcriptase; *POT1*, protection of telomeres 1; TL, telomere length; SNP, single nucleotide polymorphism; *TINF2*, TERF1 interacting nuclear factor 2; *OBFC1*, OB‐fold‐containing 1.

See this image and copyright information in PMC

References

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Identification of telomere maintenance gene variations related to lung adenocarcinoma risk by genome-wide association and whole genome sequencing analyses

Affiliations

Identification of telomere maintenance gene variations related to lung adenocarcinoma risk by genome-wide association and whole genome sequencing analyses

Authors

Affiliations

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical