TY - JOUR
T1 - Inherited Rare, Deleterious Variants in ATM Increase Lung Adenocarcinoma Risk
AU - Esai Selvan, Myvizhi
AU - Zauderer, Marjorie G.
AU - Rudin, Charles M.
AU - Jones, Siân
AU - Mukherjee, Semanti
AU - Offit, Kenneth
AU - Onel, Kenan
AU - Rennert, Gad
AU - Velculescu, Victor E.
AU - Lipkin, Steven M.
AU - Klein, Robert J.
AU - Gümüş, Zeynep H.
N1 - Funding Information:
This work was supported by grant to Dr. Gümüş from LUNGevity Foundation and the Lung Cancer Research Foundation , and in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. The authors thank Dr. Charles Powell for help with ISMMS Institutional Review Board protocol and Dr. Brendon Stiles for Weill Cornell Medical College samples. Drs. Esai Selvan, Klein, and Gümüş wrote the manuscript. Drs. Zauderer, Rudin, Lipkin, and Rennert recruited the patients. Drs. Velculescu and Jones led sample sequencing analyses. Drs. Klein and Gümüş performed germline sequence analysis (variant calling). Dr. Esai Selvan performed burden and other data analyses. Drs. Mukherjee and Offit analyzed the Integrated Mutation Profiling of Actionable Cancer Targets (IMPACT) cohort data. Dr. Onel interpreted the results. Dr. Gümüş conceived, designed, and supervised the study. All authors approved the final manuscript.
Funding Information:
This work was supported by grant to Dr. G?m?? from LUNGevity Foundation and the Lung Cancer Research Foundation, and in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. The authors thank Dr. Charles Powell for help with ISMMS Institutional Review Board protocol and Dr. Brendon Stiles for Weill Cornell Medical College samples. Drs. Esai Selvan, Klein, and G?m?? wrote the manuscript. Drs. Zauderer, Rudin, Lipkin, and Rennert recruited the patients. Drs. Velculescu and Jones led sample sequencing analyses. Drs. Klein and G?m?? performed germline sequence analysis (variant calling). Dr. Esai Selvan performed burden and other data analyses. Drs. Mukherjee and Offit analyzed the Integrated Mutation Profiling of Actionable Cancer Targets (IMPACT) cohort data. Dr. Onel interpreted the results. Dr. G?m?? conceived, designed, and supervised the study. All authors approved the final manuscript. Disclosure: Dr. Velculescu is a founder of Delfi Diagnostics and Personal Genome Diagnostics, serves on the Board of Directors and as a consultant for both organizations, and owns Delfi Diagnostics and Personal Genome Diagnostics stock, which are subject to certain restrictions under university policy. Additionally, Johns Hopkins University owns equity in Delfi Diagnostics and Personal Genome Diagnostics. Dr. Velculescu is an advisor to Bristol-Myers Squibb, Genentech, Merck, and Takeda Pharmaceuticals and has also been an advisor to Daiichi Sankyo, Janssen Diagnostics, and Ignyta, within the last five years. These arrangements have been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. Dr. Rudin reports personal fees from AbbVie, Amgen, Ascentage, AstraZeneca, Bicycle, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Jansen, Jazz, Lilly/Loxo, Pfizer, PharmaMar, Syros, Vavotek, Bridge Medicines, and Harpoon Therapeutics, outside the submitted work. Dr. Zauderer reports grants and personal fees from Glaxo Smith Kline and Epizyme; grants from Sellas Life Sciences, Department of Defense, National Cancer Institute, Polaris, BMS, Millenium, Curis, and Roche; and personal fees from Aldeyra Therapeutics, Novocure, Atara, Medical Learning Institute, and OncLive, outside the submitted work. The remaining authors declare no conflict of interest.
Funding Information:
Disclosure: Dr. Velculescu is a founder of Delfi Diagnostics and Personal Genome Diagnostics, serves on the Board of Directors and as a consultant for both organizations, and owns Delfi Diagnostics and Personal Genome Diagnostics stock, which are subject to certain restrictions under university policy. Additionally, Johns Hopkins University owns equity in Delfi Diagnostics and Personal Genome Diagnostics. Dr. Velculescu is an advisor to Bristol-Myers Squibb, Genentech, Merck, and Takeda Pharmaceuticals and has also been an advisor to Daiichi Sankyo, Janssen Diagnostics, and Ignyta, within the last five years. These arrangements have been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. Dr. Rudin reports personal fees from AbbVie, Amgen, Ascentage, AstraZeneca, Bicycle, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Jansen, Jazz, Lilly/Loxo, Pfizer, PharmaMar, Syros, Vavotek, Bridge Medicines, and Harpoon Therapeutics, outside the submitted work. Dr. Zauderer reports grants and personal fees from Glaxo Smith Kline and Epizyme; grants from Sellas Life Sciences, Department of Defense, National Cancer Institute, Polaris, BMS, Millenium, Curis, and Roche; and personal fees from Aldeyra Therapeutics, Novocure, Atara, Medical Learning Institute, and OncLive, outside the submitted work. The remaining authors declare no conflict of interest.
Publisher Copyright:
© 2020 International Association for the Study of Lung Cancer
PY - 2020/12
Y1 - 2020/12
N2 - Introduction: Lung cancer is the leading cause of cancer deaths in the world, and lung adenocarcinoma (LUAD) is its most prevalent subtype. Symptoms are often found in advanced disease in which treatment options are limited. Identifying genetic risk factors will enable better identification of high-risk individuals. Methods: To identify LUAD risk genes, we performed a case-control association study for gene-level burden of rare, deleterious variants (RDVs) in germline whole-exome sequencing data of 1083 patients with LUAD and 7650 controls, split into discovery and validation cohorts. Of these, we performed whole-exome sequencing on 97 patients and acquired the rest from multiple public databases. We annotated all rare variants for pathogenicity conservatively, using the guidelines of the American College of Medical Genetics and Genomics and ClinVar curation, and investigated gene-level RDV burden using penalized logistic regression. All statistical tests were two-sided. Results: We discovered and replicated the finding that the burden of germline ATM RDVs was significantly higher in patients with LUAD versus controls (combined cohort OR = 4.6; p = 1.7e−04; 95% confidence interval = 2.2–9.5; 1.21% of cases; 0.24% of controls). Germline ATM RDVs were also enriched in an independent clinical cohort of 1594 patients from the MSK-IMPACT study (0.63%). In addition, we observed that an Ashkenazi Jewish (AJ) founder ATM variant, rs56009889, was statistically significantly more frequent in AJ cases versus AJ controls in our cohort (combined AJ cohort OR = 2.7, p = 6.9e−03, 95% confidence interval = 1.3–5.3). Conclusions: Our results indicate that ATM is a moderate-penetrance LUAD risk gene and that LUAD may be a part of the ATM-related cancer syndrome spectrum. Individuals with ATM RDVs are at an elevated LUAD risk and can benefit from increased surveillance (particularly computed tomography scanning), early detection, and chemoprevention programs, improving prognosis.
AB - Introduction: Lung cancer is the leading cause of cancer deaths in the world, and lung adenocarcinoma (LUAD) is its most prevalent subtype. Symptoms are often found in advanced disease in which treatment options are limited. Identifying genetic risk factors will enable better identification of high-risk individuals. Methods: To identify LUAD risk genes, we performed a case-control association study for gene-level burden of rare, deleterious variants (RDVs) in germline whole-exome sequencing data of 1083 patients with LUAD and 7650 controls, split into discovery and validation cohorts. Of these, we performed whole-exome sequencing on 97 patients and acquired the rest from multiple public databases. We annotated all rare variants for pathogenicity conservatively, using the guidelines of the American College of Medical Genetics and Genomics and ClinVar curation, and investigated gene-level RDV burden using penalized logistic regression. All statistical tests were two-sided. Results: We discovered and replicated the finding that the burden of germline ATM RDVs was significantly higher in patients with LUAD versus controls (combined cohort OR = 4.6; p = 1.7e−04; 95% confidence interval = 2.2–9.5; 1.21% of cases; 0.24% of controls). Germline ATM RDVs were also enriched in an independent clinical cohort of 1594 patients from the MSK-IMPACT study (0.63%). In addition, we observed that an Ashkenazi Jewish (AJ) founder ATM variant, rs56009889, was statistically significantly more frequent in AJ cases versus AJ controls in our cohort (combined AJ cohort OR = 2.7, p = 6.9e−03, 95% confidence interval = 1.3–5.3). Conclusions: Our results indicate that ATM is a moderate-penetrance LUAD risk gene and that LUAD may be a part of the ATM-related cancer syndrome spectrum. Individuals with ATM RDVs are at an elevated LUAD risk and can benefit from increased surveillance (particularly computed tomography scanning), early detection, and chemoprevention programs, improving prognosis.
KW - Burden analysis
KW - Germline risk
KW - Lung adenocarcinoma
KW - Whole-exome sequencing
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U2 - 10.1016/j.jtho.2020.08.017
DO - 10.1016/j.jtho.2020.08.017
M3 - Article
C2 - 32866655
AN - SCOPUS:85091218577
SN - 1556-0864
VL - 15
SP - 1871
EP - 1879
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
IS - 12
ER -