Dataset Information

Novel Common Genetic Susceptibility Loci for Colorectal Cancer.

ABSTRACT:

Background

Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.

Methods

We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.

Results

The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.

Conclusions

This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

SUBMITTER: Schmit SL

PROVIDER: S-EPMC6555904 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Publications

Novel Common Genetic Susceptibility Loci for Colorectal Cancer.

Schmit Stephanie L SL Edlund Christopher K CK Schumacher Fredrick R FR Gong Jian J Harrison Tabitha A TA Huyghe Jeroen R JR Qu Chenxu C Melas Marilena M Van Den Berg David J DJ Wang Hansong H Tring Stephanie S Plummer Sarah J SJ Albanes Demetrius D Alonso M Henar MH Amos Christopher I CI Anton Kristen K Aragaki Aaron K AK Arndt Volker V Barry Elizabeth L EL Berndt Sonja I SI Bezieau Stéphane S Bien Stephanie S Bloomer Amanda A Boehm Juergen J Boutron-Ruault Marie-Christine MC Brenner Hermann H Brezina Stefanie S Buchanan Daniel D DD Butterbach Katja K Caan Bette J BJ Campbell Peter T PT Carlson Christopher S CS Castelao Jose E JE Chan Andrew T AT Chang-Claude Jenny J Chanock Stephen J SJ Cheng Iona I Cheng Ya-Wen YW Chin Lee Soo LS Church James M JM Church Timothy T Coetzee Gerhard A GA Cotterchio Michelle M Cruz Correa Marcia M Curtis Keith R KR Duggan David D Easton Douglas F DF English Dallas D Feskens Edith J M EJM Fischer Rocky R FitzGerald Liesel M LM Fortini Barbara K BK Fritsche Lars G LG Fuchs Charles S CS Gago-Dominguez Manuela M Gala Manish M Gallinger Steven J SJ Gauderman W James WJ Giles Graham G GG Giovannucci Edward L EL Gogarten Stephanie M SM Gonzalez-Villalpando Clicerio C Gonzalez-Villalpando Elena M EM Grady William M WM Greenson Joel K JK Gsur Andrea A Gunter Marc M Haiman Christopher A CA Hampe Jochen J Harlid Sophia S Harju John F JF Hayes Richard B RB Hofer Philipp P Hoffmeister Michael M Hopper John L JL Huang Shu-Chen SC Huerta Jose Maria JM Hudson Thomas J TJ Hunter David J DJ Idos Gregory E GE Iwasaki Motoki M Jackson Rebecca D RD Jacobs Eric J EJ Jee Sun Ha SH Jenkins Mark A MA Jia Wei-Hua WH Jiao Shuo S Joshi Amit D AD Kolonel Laurence N LN Kono Suminori S Kooperberg Charles C Krogh Vittorio V Kuehn Tilman T Küry Sébastien S LaCroix Andrea A Laurie Cecelia A CA Lejbkowicz Flavio F Lemire Mathieu M Lenz Heinz-Josef HJ Levine David D Li Christopher I CI Li Li L Lieb Wolfgang W Lin Yi Y Lindor Noralane M NM Liu Yun-Ru YR Loupakis Fotios F Lu Yingchang Y Luh Frank F Ma Jing J Mancao Christoph C Manion Frank J FJ Markowitz Sanford D SD Martin Vicente V Matsuda Koichi K Matsuo Keitaro K McDonnell Kevin J KJ McNeil Caroline E CE Milne Roger R Molina Antonio J AJ Mukherjee Bhramar B Murphy Neil N Newcomb Polly A PA Offit Kenneth K Omichessan Hanane H Palli Domenico D Cotoré Jesus P Paredes JPP Pérez-Mayoral Julyann J Pharoah Paul D PD Potter John D JD Qu Conghui C Raskin Leon L Rennert Gad G Rennert Hedy S HS Riggs Bridget M BM Schafmayer Clemens C Schoen Robert E RE Sellers Thomas A TA Seminara Daniela D Severi Gianluca G Shi Wei W Shibata David D Shu Xiao-Ou XO Siegel Erin M EM Slattery Martha L ML Southey Melissa M Stadler Zsofia K ZK Stern Mariana C MC Stintzing Sebastian S Taverna Darin D Thibodeau Stephen N SN Thomas Duncan C DC Trichopoulou Antonia A Tsugane Shoichiro S Ulrich Cornelia M CM van Duijnhoven Franzel J B FJB van Guelpan Bethany B Vijai Joseph J Virtamo Jarmo J Weinstein Stephanie J SJ White Emily E Win Aung Ko AK Wolk Alicja A Woods Michael M Wu Anna H AH Wu Kana K Xiang Yong-Bing YB Yen Yun Y Zanke Brent W BW Zeng Yi-Xin YX Zhang Ben B Zubair Niha N Kweon Sun-Seog SS Figueiredo Jane C JC Zheng Wei W Marchand Loic Le LL Lindblom Annika A Moreno Victor V Peters Ulrike U Casey Graham G Hsu Li L Conti David V DV Gruber Stephen B SB

Journal of the National Cancer Institute 20190201 2

<h4>Background</h4>Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.<h4>Methods</h4>We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). I ...[more]

PMID: 29917119

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Project description:Background & aimsRisk for colorectal cancer (CRC) can be greatly reduced through screening. To aid in the development of screening strategies, we refined models designed to determine risk of CRC by incorporating information from common genetic susceptibility loci.MethodsBy using data collected from more than 12,000 participants in 6 studies performed from 1990 through 2011 in the United States and Germany, we developed risk determination models based on sex, age, family history, genetic risk score (number of risk alleles carried at 27 validated common CRC susceptibility loci), and history of endoscopic examinations. The model was validated using data collected from approximately 1800 participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, conducted from 1993 through 2001 in the United States.ResultsWe identified a CRC genetic risk score that independently predicted which patients in the training set would develop CRC. Compared with determination of risk based only on family history, adding the genetic risk score increased the discriminatory accuracy from 0.51 to 0.59 (P = .0028) for men and from 0.52 to 0.56 (P = .14) for women. We calculated age- and sex-specific 10-year CRC absolute risk estimates based on the number of risk alleles, family history, and history of endoscopic examinations. A model that included a genetic risk score better determined the recommended starting age for screening in subjects with and without family histories of CRC. The starting age for high-risk men (family history of CRC and genetic risk score, 90%) was 42 years, and for low-risk men (no family history of CRC and genetic risk score, 10%) was 52 years. For men with no family history and a high genetic risk score (90%), the starting age would be 47 years; this is an intermediate value that is 5 years earlier than it would be for men with a genetic risk score of 10%. Similar trends were observed in women.ConclusionsBy incorporating information on CRC risk alleles, we created a model to determine the risk for CRC more accurately. This model might be used to develop screening and prevention strategies.

Project description:Background & aimsKnown genetic factors explain only a small fraction of genetic variation in colorectal cancer (CRC). We conducted a genome-wide association study to identify risk loci for CRC.MethodsThis discovery stage included 8027 cases and 22,577 controls of East-Asian ancestry. Promising variants were evaluated in studies including as many as 11,044 cases and 12,047 controls. Tumor-adjacent normal tissues from 188 patients were analyzed to evaluate correlations of risk variants with expression levels of nearby genes. Potential functionality of risk variants were evaluated using public genomic and epigenomic databases.ResultsWe identified 4 loci associated with CRC risk; P values for the most significant variant in each locus ranged from 3.92 × 10(-8) to 1.24 × 10(-12): 6p21.1 (rs4711689), 8q23.3 (rs2450115, rs6469656), 10q24.3 (rs4919687), and 12p13.3 (rs11064437). We also identified 2 risk variants at loci previously associated with CRC: 10q25.2 (rs10506868) and 20q13.3 (rs6061231). These risk variants, conferring an approximate 10%-18% increase in risk per allele, are located either inside or near protein-coding genes that include transcription factor EB (lysosome biogenesis and autophagy), eukaryotic translation initiation factor 3, subunit H (initiation of translation), cytochrome P450, family 17, subfamily A, polypeptide 1 (steroidogenesis), splA/ryanodine receptor domain and SOCS box containing 2 (proteasome degradation), and ribosomal protein S2 (ribosome biogenesis). Gene expression analyses showed a significant association (P < .05) for rs4711689 with transcription factor EB, rs6469656 with eukaryotic translation initiation factor 3, subunit H, rs11064437 with splA/ryanodine receptor domain and SOCS box containing 2, and rs6061231 with ribosomal protein S2.ConclusionsWe identified susceptibility loci and genes associated with CRC risk, linking CRC predisposition to steroid hormone, protein synthesis and degradation, and autophagy pathways and providing added insight into the mechanism of CRC pathogenesis.

Dataset Information

Novel Common Genetic Susceptibility Loci for Colorectal Cancer.

Background

Methods

Results

Conclusions

Publications

Novel Common Genetic Susceptibility Loci for Colorectal Cancer.

Similar Datasets

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