In:
Cancer Prevention Research, American Association for Cancer Research (AACR), Vol. 5, No. 11_Supplement ( 2012-11-01), p. A93-A93
Abstract:
Advanced age is arguably the most important risk factor for developing cancer. About 77% of all cancers are diagnosed in individuals 55 years of age and older. Aging is especially a dominant risk factor for colorectal cancer (CRC), with 91% of cases diagnosed in individuals 50 years of age and older. A number of genes and signaling pathways have been indicated in the aging process in model organisms including mammals, e.g. the insulin/IGF-1 signaling pathway, mTOR pathway and telomere and telomerase pathway. Recently, genome-wide association studies also identified several single nucleotide polymorphisms (SNPs) associated with longevity. Therefore, we hypothesized that genetic variations of the genes and pathways related to aging might be associated with CRC risk. We systematically identified 189 putative functional SNPs in 109 aging-related genes and 20 longevity-associated SNPs from GWAS. In the discovery phase, we genotyped these SNPs in 797 Caucasian CRC cases and 797 matched healthy control subjects. In main effect analysis, 10 SNPs were significantly associated with altered CRC risk. When evaluating combined effects of these SNPs, we found a significant gene dosage effect for increased CRC risk with increasing number of unfavorable genotypes. Compared with individuals carrying fewer than three unfavorable genotypes, individuals with six and more than six of these unfavorable genotypes exhibited a 2.06-fold (95% CI: 1.24-3.43, P = 0.006) and a 2.44-fold (95% CI: 1.76-3.38, P = 7.56×10−8) increased risk of CRC, respectively (P for trend 1.25×10−9). Higher order gene-gene interaction analysis also revealed potential relationships among SNPs in TP53, ERCC2, GPR133, PRKAG3, TEP1, TSC1 and LMNA that further defined risk groups for CRC. Our results suggest that genetic polymorphisms in aging-related genes and pathways may modify CRC susceptibility both individually and jointly. Replication is currently underway to validate these findings. Citation Format: Fanmao Zhang, Cathy Eng, Moubin Lin, Michelle A.T. Hildebrandt, Yonggang He, Jie Lin, Maosheng Huang, Jian Gu, Xifeng Wu. Genetic variations in aging-related genes/pathways and colorectal cancer risk. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr A93.
Type of Medium:
Online Resource
ISSN:
1940-6207
,
1940-6215
DOI:
10.1158/1940-6207.PREV-12-A93
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2012
detail.hit.zdb_id:
2422346-3
