Continuing advances in genotyping technologies and the inclusion of DNA collection in observational studies have resulted in an increasing number of genetic association studies.
To evaluate the overall progress and contribution of candidate gene association studies to current understanding of the genetic susceptibility to cancer.
We systematically examined the results of meta- and pooled analyses for genetic polymorphisms and cancer risk published through March 2008.
We identified 161 meta- and pooled analyses, encompassing 18 cancer sites and 99 genes. Analyses had to meet the following criteria: 1) at least 500 cases, 2) cancer risk as outcome, 3) not focused on HLA genetic markers, and 4) published in English.
Information on cancer site, gene name, variant, point estimate and 95% confidence interval, allelic frequency, number of studies and cases, tests of study heterogeneity and publication bias were extracted by one investigator and reviewed by other investigators.
These 161 analyses evaluated 344 gene-variant/cancer associations and included on average 7.3 studies and 3,551 cases (range: 508–19,729 cases) per investigated association. The summary OR for 98 (28%) statistically significant associations (p-value <0.05) were further evaluated by estimating the false-positive report probability (FPRP) at a given prior probability and statistical power. At a prior probability level of 0.001 and statistical power to detect an OR of 1.5, thirteen gene-variant/cancer associations remained noteworthy (FPRP<0.2). Assuming a very low prior probability of 0.000001, similar to a probability assumed for a randomly selected SNP in a genome-wide association study, and statistical power to detect an OR of 1.5, four associations were considered noteworthy as denoted by a FPRP value < 0.2: 1) GSTM1 null and bladder cancer (OR:1.5, 95% CI: 1.3–1.6, p-value=1.9×10−14), 2) NAT2 slow acetylator and bladder cancer (OR: 1.46, 95% CI:1.26–1.68, p-value=2.5×10−7), 3) MTHFR C677T and gastric cancer (OR: 1.52, 95% CI: 1.31–1.77, p-value=4.9×10−8), and 4) GSTM1 null and acute leukemia (OR: 1.20, 95% CI: 1.14–1.25, p-value=8.6×10−15). When the OR used to determine statistical power was lowered to 1.2, two of the four noteworthy associations remained so: GSTM1 null with bladder cancer and acute leukemia.
Phase II enzymes, which are key enzymes involved in the detoxification and excretion of carcinogens (and particularly deletion of GSTM1), were among the most consistent and highly significant associations.