Search for low penetrance alleles for colorectal cancer through a scan of 1467 non-synonymous SNPs in 2575 cases and 2707 controls with validation by kin-cohort analysis of 14 704 first-degree relatives

Abstract

To identify low penetrance susceptibility alleles for colorectal cancer (CRC), we genotyped 1467 non-synonymous SNPs mapping to 871 candidate cancer genes in 2575 cases and 2707 controls. nsSNP selection was biased towards those predicted to be functionally deleterious. One SNP AKAP9 M463I remained significantly associated with CRC risk after stringent adjustment for multiple testing. Further SNPs associated with CRC risk included several previously reported to be associated with cancer risk including ATM F858L [OR=1.48; 95% confidence interval (CI): 1.06-2.07] and P1054R (OR=1.42; 95% CI: 1.14-1.77) and MTHFR A222V (OR=0.82; 95% CI: 0.69-0.97). To validate associations, we performed a kin-cohort analysis on the 14 704 first-degree relatives of cases for each SNP associated at the 5% level in the case-control analysis employing the marginal maximum likelihood method to infer genotypes of relatives. Our observations support the hypothesis that inherited predisposition to CRC is in part mediated through polymorphic variation and identify a number of SNPs defining inter-individual susceptibility. We have made data from this analysis publicly available at http://www.icr.ac.uk/research/research_sections/cancer_genetics/cancer_genetics_teams/molecular_and_population_genetics/software_and_databases/index.shtml in order to facilitate the identification of low penetrance CRC susceptibility alleles through pooled analyses.

Scan of 977 nonsynonymous SNPs in CLL4 trial patients for the identification of genetic variants influencing prognosis

“…As 10% to 15% of patients with CLL with progressive disease are thought to display deletions involving 17p, we examined this particular locus in detail. Genotypes for the p53 Arg72Pro (rs1042522 30 ) were obtained for 421 (99.1%) of the 425 patients, and the distribution of genotypes (239, 154, 28) was not significantly different to those we have previously documented in the United Kingdom population 31 (1471,1022,197; P ϭ .64).…”

“…Of the patients genotyped, approximately a third had been diagnosed with CLL before age 60 years, and approximately two-thirds had presented with stage B or C disease. The median follow-up time for patients was 32 months with follow-up to October, 31,2005. There were 27% deaths in the cohort.…”

Large-Scale Evaluation of Genetic Variants in Candidate Genes for Colorectal Cancer Risk in the Nurses' Health Study and the Health Professionals' Follow-up Study

“…Main-effects analysis identified the association of two nonsynonymous SNPs, MGMT Lys 178 Arg (''benign'' by polymorphism phenotyping, which combines a conservation score with additional properties to predict the functional importance of an amino acid alteration) and SAT2 Arg 126 Cys (''possibly damaging'' by polymorphism phenotyping), with colorectal cancer risk (17). In a recent evaluation of 1,041 nonsynonymous SNPs in 2,575 colorectal cancer cases and 2,707 controls colorectal cancer, these nonsynonymous SNPs were not significantly associated with colorectal cancer risk (18).…”

Genetics and molecular epidemiology of multiple myeloma: The rationale for the IMMEnSE consortium (Review)

“…MTHFR, which has been found associated with cancer risk (108,109), is one of the most important enzymes involved in the regulation of folate homeostasis. Two MTHFR missense SNPs, C677T (rs1801133) and A1298C (rs1801131), were investigated in relation to MM susceptibility in various reports with evidence for association (110)(111)(112) as well as for no association (113)(114)(115)(116)(117).…”