Genome-wide association study confirms lung cancer susceptibility loci on chromosomes 5p15 and 15q25 in an African-American population

Krista A Zanetti; Zhaoming Wang; Melinda Aldrich; Christopher I Amos; William J Blot; Elise D Bowman; Laurie Burdette; Qiuyin Cai; Neil Caporaso; Charles C Chung; Elizabeth M Gillanders; Christopher A Haiman; Helen M Hansen; Brian E Henderson; Laurence N Kolonel; Loic Le Marchand; Shengchao Li; Lorna Haughton McNeill; Bríd M Ryan; Ann G Schwartz; Jennette D Sison; Margaret R Spitz; Margaret Tucker; Angela S Wenzlaff; John K Wiencke; Lynne Wilkens; Margaret R Wrensch; Xifeng Wu; Wei Zheng; Weiyin Zhou; David Christiani; Julie R Palmer; Trevor M Penning; Alyssa G Rieber; Lynn Rosenberg; Edward A Ruiz-Narvaez; Li Su; Anil Vachani; Yongyue Wei; Alexander S Whitehead; Stephen J Chanock; Curtis C Harris

doi:10.1016/j.lungcan.2016.05.008

Genome-wide association study confirms lung cancer susceptibility loci on chromosomes 5p15 and 15q25 in an African-American population

Lung Cancer. 2016 Aug:98:33-42. doi: 10.1016/j.lungcan.2016.05.008. Epub 2016 May 13.

Authors

Krista A Zanetti¹, Zhaoming Wang², Melinda Aldrich³, Christopher I Amos⁴, William J Blot⁵, Elise D Bowman⁶, Laurie Burdette⁷, Qiuyin Cai⁸, Neil Caporaso⁹, Charles C Chung¹⁰, Elizabeth M Gillanders¹¹, Christopher A Haiman¹², Helen M Hansen¹³, Brian E Henderson¹⁴, Laurence N Kolonel¹⁵, Loic Le Marchand¹⁶, Shengchao Li¹⁷, Lorna Haughton McNeill¹⁸, Bríd M Ryan¹⁹, Ann G Schwartz²⁰, Jennette D Sison²¹, Margaret R Spitz²², Margaret Tucker²³, Angela S Wenzlaff²⁴, John K Wiencke²⁵, Lynne Wilkens²⁶, Margaret R Wrensch²⁷, Xifeng Wu²⁸, Wei Zheng²⁹, Weiyin Zhou³⁰, David Christiani³¹, Julie R Palmer³², Trevor M Penning³³, Alyssa G Rieber³⁴, Lynn Rosenberg³⁵, Edward A Ruiz-Narvaez³⁶, Li Su³⁷, Anil Vachani³⁸, Yongyue Wei³⁹, Alexander S Whitehead⁴⁰, Stephen J Chanock⁴¹, Curtis C Harris⁴²

Affiliations

¹ Division of Cancer Control and Population Sciences, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20892, USA. Electronic address: zanettik@mail.nih.gov.
² Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20892, USA. Electronic address: wangzha@mail.nih.gov.
³ Division of Epidemiology, Vanderbilt University Medical Center, 1161 21st Avenue South, D-3100 Medical Center North, Nashville, TN 37232, USA; Department of Thoracic Surgery, Vanderbilt University Medical Center, 609 Oxford House, 1313 21st Ave South, Nashville, TN 37232-4682, USA. Electronic address: melinda.aldrich@Vanderbilt.Edu.
⁴ Department of Biomedical Data Science, Geisel School of Medicine, 1 Rope Ferry Road, Dartmouth, Lebanon, NH 03755-1404, USA. Electronic address: Christopher.I.Amos@Dartmouth.edu.
⁵ Division of Epidemiology, Vanderbilt University Medical Center, 1161 21st Avenue South, D-3100 Medical Center North, Nashville, TN 37232, USA. Electronic address: blotw@iei.us.
⁶ Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Building 37, Room 3068A, Bethesda, MD 20892, USA. Electronic address: bowmane@intra.nci.nih.gov.
⁷ Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20892, USA. Electronic address: burdettl@mail.nih.gov.
⁸ Division of Epidemiology, Vanderbilt University Medical Center, 1161 21st Avenue South, D-3100 Medical Center North, Nashville, TN 37232, USA. Electronic address: qiuyin.cai@Vanderbilt.Edu.
⁹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20892, USA. Electronic address: caporasn@mail.nih.gov.
¹⁰ Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20892, USA. Electronic address: chungcc@mail.nih.gov.
¹¹ Division of Cancer Control and Population Sciences, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20892, USA. Electronic address: lgilland@mail.nih.gov.
¹² Department of Preventive Medicine, Keck School of Medicine, University of Southern California and Norris Comprehensive Cancer Center, 1975 Zonal Avenue, Los Angeles, CA 90033, USA. Electronic address: haiman@usc.edu.
¹³ Department of Neurological Surgery, University of California, 505 Parnassus Ave., Room 779 M, San Francisco, San Francisco, CA 94143-00112, USA. Electronic address: helen.hansen@ucsf.edu.
¹⁴ Department of Preventive Medicine, Keck School of Medicine, University of Southern California and Norris Comprehensive Cancer Center, 1975 Zonal Avenue, Los Angeles, CA 90033, USA.
¹⁵ Epidemiology Program, Cancer Research Center, University of Hawaii, 701 Ilalo Street, Honolulu, HI 96813, USA. Electronic address: lkolonel@cc.hawaii.edu.
¹⁶ Epidemiology Program, Cancer Research Center, University of Hawaii, 701 Ilalo Street, Honolulu, HI 96813, USA. Electronic address: Loic@cc.hawaii.edu.
¹⁷ Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20892, USA. Electronic address: shengchao.li@nih.gov.
¹⁸ Department of Health Disparities Research, Division of OVP, Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 91, Houston, TX 77030, USA. Electronic address: lmcneill@mdanderson.org.
¹⁹ Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Building 37, Room 3068A, Bethesda, MD 20892, USA. Electronic address: ryanb@mail.nih.gov.
²⁰ Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R, Detroit, MI 48201, USA. Electronic address: schwarta@karmanos.org.
²¹ Department of Neurological Surgery, University of California, 505 Parnassus Ave., Room 779 M, San Francisco, San Francisco, CA 94143-00112, USA. Electronic address: jennette.sison@ucsf.edu.
²² Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Mail Stop BCM225, Houston, TX 77030, USA. Electronic address: spitz@bcm.edu.
²³ Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20892, USA. Electronic address: tuckerp@mail.nih.gov.
²⁴ Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R, Detroit, MI 48201, USA. Electronic address: wenzlaff@karmanos.org.
²⁵ Department of Neurological Surgery, University of California, 505 Parnassus Ave., Room 779 M, San Francisco, San Francisco, CA 94143-00112, USA. Electronic address: john.wiencke@ucsf.edu.
²⁶ Epidemiology Program, Cancer Research Center, University of Hawaii, 701 Ilalo Street, Honolulu, HI 96813, USA. Electronic address: lynne@cc.hawaii.edu.
²⁷ Department of Neurological Surgery, University of California, 505 Parnassus Ave., Room 779 M, San Francisco, San Francisco, CA 94143-00112, USA. Electronic address: Margaret.Wrensch@ucsf.edu.
²⁸ Department of Epidemiology, Division of OVP, Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Unit 1340, PO Box 301439, Houston, TX 77230-1439, USA. Electronic address: xwu@mdanderson.org.
²⁹ Division of Epidemiology, Vanderbilt University Medical Center, 1161 21st Avenue South, D-3100 Medical Center North, Nashville, TN 37232, USA. Electronic address: wei.zheng@vanderbilt.edu.
³⁰ Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20892, USA. Electronic address: zhouw@mail.nih.gov.
³¹ Harvard School of Public Health, Massachusetts General Hospital/Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA. Electronic address: dchris@hsph.harvard.edu.
³² Slone Epidemiology Cancer Center at Boston University, 1010 Commonwealth Avenue, 4th Floor, Boston, MA 02215, USA. Electronic address: jpalmer@bu.edu.
³³ Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania, 3535 Market Street, Mezzanine, Philadelphia PA 19104, USA; Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, 3535 Market Street, Mezzanine, Philadelphia PA 19104, USA. Electronic address: PENNING@UPENN.EDU.
³⁴ Department of General Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. Electronic address: arieber@mdanderson.org.
³⁵ Slone Epidemiology Cancer Center at Boston University, 1010 Commonwealth Avenue, 4th Floor, Boston, MA 02215, USA. Electronic address: lrosenbe@bu.edu.
³⁶ Slone Epidemiology Cancer Center at Boston University, 1010 Commonwealth Avenue, 4th Floor, Boston, MA 02215, USA. Electronic address: eruiznar@bu.edu.
³⁷ Harvard School of Public Health, Massachusetts General Hospital/Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA. Electronic address: lisu@hsph.harvard.edu.
³⁸ Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania, 3535 Market Street, Mezzanine, Philadelphia PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, 3535 Market Street, Mezzanine, Philadelphia, PA 19104, USA. Electronic address: avachani@mail.med.upenn.edu.
³⁹ Harvard School of Public Health, Massachusetts General Hospital/Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA. Electronic address: ywei@hsph.harvard.edu.
⁴⁰ Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania, 3535 Market Street, Mezzanine, Philadelphia PA 19104, USA; Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, 3535 Market Street, Mezzanine, Philadelphia PA 19104, USA. Electronic address: aswhiteh@mail.med.upenn.edu.
⁴¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20892, USA. Electronic address: chanocks@mail.nih.gov.
⁴² Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Building 37, Room 3068A, Bethesda, MD 20892, USA. Electronic address: Curtis_Harris@nih.gov.

Abstract

Objectives: Genome-wide association studies (GWAS) of lung cancer have identified regions of common genetic variation with lung cancer risk in Europeans who smoke and never-smoking Asian women. This study aimed to conduct a GWAS in African Americans, who have higher rates of lung cancer despite smoking fewer cigarettes per day when compared with Caucasians. This population provides a different genetic architecture based on underlying African ancestry allowing the identification of new regions and exploration of known regions for finer mapping.

Materials and methods: We genotyped 1,024,001 SNPs in 1737 cases and 3602 controls in stage 1, followed by a replication phase of 20 SNPs (p<1.51×10(-5)) in an independent set of 866 cases and 796 controls in stage 2.

Results and conclusion: In the combined analysis, we confirmed two loci to be associated with lung cancer that achieved the threshold of genome-wide significance: 15q25.1 marked by rs2036527 (p=1.3×10(-9); OR=1.32; 95% CI=1.20-1.44) near CHRNA5, and 5p15.33 marked by rs2853677 (p=2.8×10(-9); OR=1.28; 95% CI=1.18-1.39) near TERT. The association with rs2853677 is driven by the adenocarcinoma subtype of lung cancer (p=1.3×10(-8); OR=1.37; 95% CI=1.23-1.54). No SNPs reached genome-wide significance for either of the main effect models examining smoking - cigarettes per day and current or former smoker. Our study was powered to identify strong risk loci for lung cancer in African Americans; we confirmed results previously reported in African Americans and other populations for two loci near plausible candidate genes, CHRNA5 and TERT, on 15q25.1 and 5p15.33 respectively, are associated with lung cancer. Additional work is required to map and understand the biological underpinnings of the strong association of these loci with lung cancer risk in African Americans.

Keywords: African Americans; Genome-wide association study; Lung neoplasms; Receptors, Cholinergic; Smoking; Telomerase.

Published by Elsevier Ireland Ltd.

Publication types

Research Support, N.I.H., Intramural
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

MeSH terms

Black or African American / genetics*
Case-Control Studies
Chromosomes, Human, Pair 15*
Chromosomes, Human, Pair 5*
Genetic Predisposition to Disease*
Genome-Wide Association Study*
Humans
Lung Neoplasms / epidemiology*
Lung Neoplasms / genetics*
Polymorphism, Single Nucleotide
Population Surveillance
Quantitative Trait Loci*

Abstract

Publication types

MeSH terms

Grants and funding