Early Detection Research Network

Novel Common Genetic Susceptibility Loci for Colorectal Cancer.

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.

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.

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.

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

Albanes D, Alonso MH, Amos CI, Anton K, Aragaki AK, Arndt V, Barry EL, Berndt SI, Bezieau S, Bien S, Bloomer A, Boehm J, Boutron-Ruault MC, Brenner H, Brezina S, Buchanan DD, Butterbach K, Caan BJ, Campbell PT, Carlson CS, Casey G, Castelao JE, Chan AT, Chang-Claude J, Chanock SJ, Cheng I, Cheng YW, Chin LS, Church JM, Church T, Coetzee GA, Conti DV, Cotoré JPP, Cotterchio M, Cruz Correa M, Curtis KR, Duggan D, Easton DF, Edlund CK, English D, Feskens EJM, Figueiredo JC, Fischer R, FitzGerald LM, Fortini BK, Fritsche LG, Fuchs CS, Gago-Dominguez M, Gala M, Gallinger SJ, Gauderman WJ, Giles GG, Giovannucci EL, Gogarten SM, Gong J, Gonzalez-Villalpando C, Gonzalez-Villalpando EM, Grady WM, Greenson JK, Gruber SB, Gsur A, Gunter M, Haiman CA, Hampe J, Harju JF, Harlid S, Harrison TA, Hayes RB, Hofer P, Hoffmeister M, Hopper JL, Hsu L, Huang SC, Hudson TJ, Huerta JM, Hunter DJ, Huyghe JR, Idos GE, Iwasaki M, Jackson RD, Jacobs EJ, Jee SH, Jenkins MA, Jia WH, Jiao S, Joshi AD, Kolonel LN, Kono S, Kooperberg C, Krogh V, Kuehn T, Kweon SS, Küry S, LaCroix A, Laurie CA, Lejbkowicz F, Lemire M, Lenz HJ, Levine D, Li CI, Li L, Lieb W, Lin Y, Lindblom A, Lindor NM, Liu YR, Loupakis F, Lu Y, Luh F, Ma J, Mancao C, Manion FJ, Marchand LL, Markowitz SD, Martin V, Matsuda K, Matsuo K, McDonnell KJ, McNeil CE, Melas M, Milne R, Molina AJ, Moreno V, Mukherjee B, Murphy N, Newcomb PA, Offit K, Omichessan H, Palli D, Peters U, Pharoah PD, Plummer SJ, Potter JD, Pérez-Mayoral J, Qu C, Qu C, Raskin L, Rennert G, Rennert HS, Riggs BM, Schafmayer C, Schmit SL, Schoen RE, Schumacher FR, Sellers TA, Seminara D, Severi G, Shi W, Shibata D, Shu XO, Siegel EM, Slattery ML, Southey M, Stadler ZK, Stern MC, Stintzing S, Taverna D, Thibodeau SN, Thomas DC, Trichopoulou A, Tring S, Tsugane S, Ulrich CM, Van Den Berg DJ, Vijai J, Virtamo J, Wang H, Weinstein SJ, White E, Win AK, Wolk A, Woods M, Wu AH, Wu K, Xiang YB, Yen Y, Zanke BW, Zeng YX, Zhang B, Zheng W, Zubair N, van Duijnhoven FJB, van Guelpan B

29917119

J. Natl. Cancer Inst., 2019, 111 (2)

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