Journal
GASTROENTEROLOGY
Volume 144, Issue 4, Pages 799-+Publisher
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2012.12.020
Keywords
Colon Cancer; Genetics; Risk Factors; SNP
Categories
Funding
- National Cancer Institute, National Institutes of Health
- US Department of Health and Human Services [U01 CA137088, R01 CA059045]
- Japanese Ministry of Education, Culture, Sports, Science and Technology [17015018, 221S0001]
- Hospital Clinical Research Program (PHRC)
- Regional Council of Pays de la Loire
- Groupement des Entreprises Francaises dans la Lutte Contre le Cancer
- Association Anne de Bretagne Genetique
- Ligue Regionale Contre le Cancer
- National Institutes of Health [U01 CA074783, R01 CA60987, RFA CA-95-011, R37CA070867, R01CA082729, R01CA124558, R01CA148667, R01CA122364, P50CA95103, R01CA121060, K05 CA154337]
- Ontario Research Fund
- Canadian Institutes of Health Research
- Cancer Risk Evaluation Program grant from the Canadian Cancer Society Research Institute
- Ontario Institute for Cancer Research
- National Cancer Institute, National Institutes of Health [U01 CA122839]
- Vanderbilt University School of Medicine
- Vanderbilt-Ingram Cancer Center [P30 CA 68485]
- National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]
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BACKGROUND & AIMS: Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis. METHODS: We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent. RESULTS: Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 X 10(-8): an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 X 10(-8)). We also found evidence for 3 additional loci with P values less than 5.0 X 10(-7): a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 X 10(-8)), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 X 10(-8)), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 X 10(-7)). CONCLUSIONS: In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to beta-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.
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