Identification of Novel Loci and New Risk Variant in Known Loci for Colorectal Cancer Risk in East Asians

Yingchang Lu¹, Sun-Seog Kweon^{2

3}, Qiuyin Cai¹, Chizu Tanikawa⁴, Xiao-Ou Shu¹, Wei-Hua Jia⁵, Yong-Bing Xiang⁶, Jeroen R Huyghe⁷, Tabitha A Harrison⁷, Jeongseon Kim⁸, Aesun Shin⁹, Dong-Hyun Kim¹⁰, Keitaro Matsuo^{11

12}, Sun Ha Jee¹³, Xingyi Guo¹, Wanqing Wen¹, Jiajun Shi¹, Bingshan Li¹⁴, Nan Wang¹⁵, Min-Ho Shin², Hong-Lan Li⁶, Zefang Ren¹⁶, Jae Hwan Oh¹⁷, Isao Oze¹⁰, Yoon-Ok Ahn¹⁸, Keum Ji Jung¹⁹, Jing Gao⁶, Yu-Tang Gao⁶, Zhi-Zhong Pan⁵, Yoichiro Kamatani^{20

21}, Andrew T Chan^{22

23

24

25}, Andrea Gsur²⁶, Jochen Hampe²⁷, Loic Le Marchand²⁸, Li Li²⁹, Annika Lindblom^{30

31}, Victor Moreno^{32

33

34}, Polly A Newcomb^{7

35}, Kenneth Offit^{36

37}, Paul D P Pharoah³⁸, Franzel J B van Duijnhoven³⁹, Bethany Van Guelpen⁴⁰, Pavel Vodicka^{41

42

43}, Stephanie J Weinstein⁴⁴, Alicja Wolk⁴⁵, Anna H Wu⁴⁶, Li Hsu^{7

47}, Yi-Xin Zeng⁵, Jirong Long¹, Ulrike Peters^{7

48}, Koichi Matsuda⁴⁹, Wei Zheng⁵⁰

Affiliations

¹ Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
² Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, South Korea.
³ Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, South Korea.
⁴ Laboratory of Genome Technology, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
⁵ State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
⁶ State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
⁷ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
⁸ Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Gyeonggi-do, South Korea.
⁹ Department of Preventive Medicine, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Korea.
¹⁰ Department of Social and Preventive Medicine, Hallym University College of Medicine, Okcheon-dong, Korea.
¹¹ Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Nagoya, Japan.
¹² Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
¹³ Department of Epidemiology and Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, Korea.
¹⁴ Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee.
¹⁵ General Surgery Department, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
¹⁶ School of Public Health, Sun Yat-sen University, Guangzhou, China.
¹⁷ Center for Colorectal Cancer, National Cancer Center Hospital, National Cancer Center, Gyeonggi-do, South Korea.
¹⁸ Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea.
¹⁹ Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, Korea.
²⁰ Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
²¹ Kyoto-McGill International Collaborative School in Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
²² Division of Gastroenterology, and Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
²³ Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
²⁴ Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
²⁵ Department of Epidemiology, and Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts.
²⁶ Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria.
²⁷ Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany.
²⁸ University of Hawaii Cancer Center, Honolulu, Hawaii.
²⁹ Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
³⁰ Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
³¹ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
³² Cancer Prevention and Control Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
³³ CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
³⁴ Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
³⁵ School of Public Health, University of Washington, Seattle, Washington.
³⁶ Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
³⁷ Department of Medicine, Weill Cornell Medical College, New York, New York.
³⁸ Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
³⁹ Division of Human Nutrition, Wageningen University and Research, Wageningen, the Netherlands.
⁴⁰ Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
⁴¹ Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic.
⁴² Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic.
⁴³ Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic.
⁴⁴ Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland.
⁴⁵ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁴⁶ University of Southern California, Preventative Medicine, Los Angeles, California.
⁴⁷ Department of Biostatistics, University of Washington, Seattle, Washington.
⁴⁸ Department of Epidemiology, University of Washington, Seattle, Washington.
⁴⁹ Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan.
⁵⁰ Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee. wei.zheng@vanderbilt.edu.

PMID: 31826910
PMCID: PMC7571256
DOI: 10.1158/1055-9965.EPI-19-0755

Identification of Novel Loci and New Risk Variant in Known Loci for Colorectal Cancer Risk in East Asians

Yingchang Lu et al. Cancer Epidemiol Biomarkers Prev. 2020 Feb.

. 2020 Feb;29(2):477-486.

doi: 10.1158/1055-9965.EPI-19-0755. Epub 2019 Dec 11.

Authors

Affiliations

¹ Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
² Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, South Korea.
³ Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, South Korea.
⁴ Laboratory of Genome Technology, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
⁵ State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
⁶ State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
⁷ Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
⁸ Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Gyeonggi-do, South Korea.
⁹ Department of Preventive Medicine, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Korea.
¹⁰ Department of Social and Preventive Medicine, Hallym University College of Medicine, Okcheon-dong, Korea.
¹¹ Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Nagoya, Japan.
¹² Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
¹³ Department of Epidemiology and Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, Korea.
¹⁴ Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee.
¹⁵ General Surgery Department, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
¹⁶ School of Public Health, Sun Yat-sen University, Guangzhou, China.
¹⁷ Center for Colorectal Cancer, National Cancer Center Hospital, National Cancer Center, Gyeonggi-do, South Korea.
¹⁸ Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea.
¹⁹ Institute for Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, Korea.
²⁰ Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
²¹ Kyoto-McGill International Collaborative School in Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
²² Division of Gastroenterology, and Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
²³ Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
²⁴ Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
²⁵ Department of Epidemiology, and Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts.
²⁶ Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria.
²⁷ Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany.
²⁸ University of Hawaii Cancer Center, Honolulu, Hawaii.
²⁹ Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
³⁰ Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
³¹ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
³² Cancer Prevention and Control Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
³³ CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
³⁴ Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
³⁵ School of Public Health, University of Washington, Seattle, Washington.
³⁶ Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
³⁷ Department of Medicine, Weill Cornell Medical College, New York, New York.
³⁸ Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
³⁹ Division of Human Nutrition, Wageningen University and Research, Wageningen, the Netherlands.
⁴⁰ Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
⁴¹ Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic.
⁴² Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic.
⁴³ Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic.
⁴⁴ Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland.
⁴⁵ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
⁴⁶ University of Southern California, Preventative Medicine, Los Angeles, California.
⁴⁷ Department of Biostatistics, University of Washington, Seattle, Washington.
⁴⁸ Department of Epidemiology, University of Washington, Seattle, Washington.
⁴⁹ Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo, Japan.
⁵⁰ Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee. wei.zheng@vanderbilt.edu.

PMID: 31826910
PMCID: PMC7571256
DOI: 10.1158/1055-9965.EPI-19-0755

Abstract

Background: Risk variants identified so far for colorectal cancer explain only a small proportion of familial risk of this cancer, particularly in Asians.

Methods: We performed a genome-wide association study (GWAS) of colorectal cancer in East Asians, including 23,572 colorectal cancer cases and 48,700 controls. To identify novel risk loci, we selected 60 promising risk variants for replication using data from 58,131 colorectal cancer cases and 67,347 controls of European descent. To identify additional risk variants in known colorectal cancer loci, we performed conditional analyses in East Asians.

Results: An indel variant, rs67052019 at 1p13.3, was found to be associated with colorectal cancer risk at P = 3.9 × 10^-8 in Asians (OR per allele deletion = 1.13, 95% confidence interval = 1.08-1.18). This association was replicated in European descendants using a variant (rs2938616) in complete linkage disequilibrium with rs67052019 (P = 7.7 × 10^-3). Of the remaining 59 variants, 12 showed an association at P < 0.05 in the European-ancestry study, including rs11108175 and rs9634162 at P < 5 × 10^-8 and two variants with an association near the genome-wide significance level (rs60911071, P = 5.8 × 10^-8; rs62558833, P = 7.5 × 10^-8) in the combined analyses of Asian- and European-ancestry data. In addition, using data from East Asians, we identified 13 new risk variants at 11 loci reported from previous GWAS.

Conclusions: In this large GWAS, we identified three novel risk loci and two highly suggestive loci for colorectal cancer risk and provided evidence for potential roles of multiple genes and pathways in the etiology of colorectal cancer. In addition, we showed that additional risk variants exist in many colorectal cancer risk loci identified previously.

Impact: Our study provides novel data to improve the understanding of the genetic basis for colorectal cancer risk.

PubMed Disclaimer

Conflict of interest statement

Disclosure of Potential Conflicts of Interest

Y. Kamatani reports receiving speakers bureau honoraria from Illumina Japan. No potential conflicts of interest were disclosed by the other authors.

Figures

**Figure 1.**
Regional association plots of five colorectal cancer risk loci in Asian descendants (A, rs67052019; B, rs60911071; C, rs62558833; D, rs11108175; and E, rs9634162). Each dot represents the P value (on a log₁₀ scale) of an SNP with colorectal cancer risk based on the meta-analysis results in East Asians only and is presented according to its genomic position (NCBI Build 37). The most significantly associated SNP in the combined meta-analyses is represented by purple. The color of all other SNPs indicates the level of LD with the lead SNP (estimated by ASN r² from the 1000 Genome Project data). Recombination rates were also estimated from 1000 Genomes Project data, and gene annotations within the 2 Mb regions that are centered on the newly identified risk variants were obtained from the UCSC Genome Browser.

See this image and copyright information in PMC

References

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Identification of Novel Loci and New Risk Variant in Known Loci for Colorectal Cancer Risk in East Asians

Affiliations

Identification of Novel Loci and New Risk Variant in Known Loci for Colorectal Cancer Risk in East Asians

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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