OP-IJEJ150184 1..20

Background: Low penetrance genetic variants, primarily single nucleotide polymorphisms, have substantial influence on colorectal cancer (CRC) susceptibility. Most CRCs develop from colorectal adenomas (CRA). Here we report the first comprehensive field synopsis that catalogues all genetic association studies on CRA, with a parallel online database [http://www.chs.med.ed.ac.uk/CRAgene/]. Methods: We performed a systematic review, reviewing 9750 titles, and then extracted data from 130 publications reporting on 181 polymorphisms in 74 genes. We conducted meta-analyses to derive summary effect estimates for 37 polymorphisms in 26 genes. We applied the Venice criteria and Bayesian False Discovery Probability (BFDP) to assess the levels of the credibility of associations. Results: We considered the association with the rs6983267 variant at 8q24 as ‘highly credible’, reaching genome-wide statistical significance in at least one meta-analysis model. We identified ‘less credible’ associations (higher heterogeneity, lower statistical power, BFDP > 0.02) with a further four variants of four independent genes: MTHFR c.677C>T p.A222V VC The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association 1 International Journal of Epidemiology, 2015, 1–20 doi: 10.1093/ije/dyv185 Original article Int. J. Epidemiol. Advance Access published October 7, 2015 at Srials R ecosSerials on O cber 4, 2015 http://ijerdjournals.org/ D ow nladed from (rs1801133), TP53 c.215C>G p.R72P (rs1042522), NQO1 c.559C>T p.P187S (rs1800566), and NAT1 alleles imputed as fast acetylator genotypes. For the remaining 32 variants of 22 genes for which positive associations with CRA risk have been previously reported, the meta-analyses revealed no credible evidence to support these as true associations. Conclusions: The limited number of credible associations between low penetrance genetic variants and CRA reflects the lower volume of evidence and associated lack of statistical power to detect associations of the magnitude typically observed for genetic variants and chronic diseases. The CRA gene database provides context for CRA genetic association data and will help inform future research directions. INTRODUCTION Colorectal cancer (CRC) constitutes a major public health challenge, with over 1.3 million cases estimated to have been newly diagnosed in 2012, and almost 700 000 deaths from the disease. Most CRCs develop from preneoplastic asymptomatic lesions known as adenomatous polyps. The malignant potential of colorectal adenomas (CRAs) depends on their size, histological characteristics, degree of dysplasia and multiplicity. In addition, serrated lesions, particularly sessile serrated adenomas/polyps (SSA/P), previously thought not to have malignant potential, are also associated with an increased risk of CRC. Several risk factors have been reported to be associated with risk of developing CRAs. These include an increased risk associated with cigarette smoking, alcohol consumption and obesity and a decreased risk associated with regular aspirin intake. Improving our understanding of these adenoma risk factors may help inform the development of new strategies for the prevention of CRC. Although the majority of CRCs arise sporadically, the disease has a clear genetic component as shown by segregation of highly penetrant mutations in genes such as APC in families affected by the familial adenomatous polyposis (FAP) syndrome, and mutations in DNA mismatch repair Key Messages What is already known about this subject? • Most colorectal cancers (CRC) develop from preneoplastic asymptomatic lesions known as colorectal adenomas (CRA). • A recent original study found that eight common SNPs associated with CRC, identified through genome-wide association studies (GWAS), also increase the risk of CRA. • We have previously summarized the associations between common genetic variants and CRC in a field synopsis of genetic association and GWAS, but the genetic basis of CRA is less well documented. What are the new findings? • We present here the first synthesis of all published genetic association data for CRAs and the results of metaanalyses to summarize risk estimates. • Five variants out of 37 meta-analysed SNPs (approximately 14%) are likely to be associated with CRA. • For the 32 variants of 22 genes for which positive associations with CRA risk have been previously reported, the meta-analyses revealed no credible evidence to support these as true associations. How might it impact on clinical practice in the foreseeable future? • The identification of genetic variants for which there is robust evidence of influence on CRA risk may provide new insights into the fundamental biological mechanisms involved in early CRC development. • Improving our understanding of CRA risk factors may help inform the development of improved strategies for prevention of CRC. • Findings from this study should help focus further clinical research on understanding the role of gene-gene and gene-environment interactions in the development of colorectal neoplasia. 2 International Journal of Epidemiology, 2015, Vol. 0, No. 0 at Srials R ecosSerials on O cber 4, 2015 http://ijerdjournals.org/ D ow nladed from genes (MLH1, MSH2, MSH6 and PMS2) in families affected by Lynch syndrome (Hereditary Non Polyposis Colorectal Cancer—HNPCC). However, whereas highly penetrant mutations account for less than 10% of CRC susceptibility, an expanding number of low penetrance genetic variants have been increasingly recognized to influence the risk of colorectal neoplasia. We summarized the contribution of these alleles in a field synopsis of genetic association and genome-wide association studies (GWAS) in CRC. The genetic basis of CRA is less well documented. The risk of colorectal neoplasia in first-degree relatives of a patient with adenomas [relative risk (RR) for advanced adenoma 1.68, 95% confidence interval (CI) 1.29-2.18] compared with controls is reported to be of a similar magnitude to the risk of CRC in first-degree relatives of patients with CRC. In addition, a recent study investigated whether CRC single nucleotide polymorphisms (SNPs) identified through GWAS also increased the CRA risk, and found that 8 of 18 known CRC-associated SNPs (rs10936599, rs6983267, rs10795668, rs3802842, rs4444235, rs1957636, rs4939827 and rs961253) were over-represented in CRC-free patients with adenomas, compared with controls. The main objective of the present study was to identify and interpret associations between common genetic variants and CRA risk. The identification of genetic variants for which there is robust evidence of influence on CRA risk may provide new insights into the fundamental biological mechanisms involved in early CRC development and help to inform future research. Further, identification of CRA risk-associated variants may also show utility in contributing to future risk scores for accurate population risk stratification, which could be of potential value in targeting primary prevention and CRC screening modalities. We have previously undertaken a comprehensive review of genetic factors associated with CRC using published guidelines for the assessment of cumulative evidence on genetic association studies following a format similar to published overview meta-analyses and utilizing an inference framework to aid transparent and objective interpretation of data. We now report the results of a similar exercise for CRA. This represents the first attempt to synthesize all published genetic association data for CRAs and conduct meta-analyses to summarize risk estimates. The search strategy and the results of meta-analyses are publicly available on a regularly updated internet database (CRAgene; http://www.chs.med.ed.ac.uk/CRAgene/). METHODS Literature search and data collection We undertook a comprehensive systematic review of published data on genetics and colorectal polyps using the Medline database via the Ovid gateway. The search strategy is shown in Supplementary Box 1 (available as Supplementary data at IJE online). We cross-checked these findings against those listed in the HuGENet phenopedia TM . Review articles and meta-analyses on genetic associations of colorectal polyps were also considered so that the references they used could be screened for eligibility, in case they had been missed in the Medline search. The abstracts and if necessary the full texts were screened for eligibility using the following inclusion and exclusion criteria. The paper must have evaluated the association between a polymorphic genetic variant (one with a MAF 0.01 in the general population based on the data on the reference panel of the 1000 Genomes; Table 1) and sporadic colorectal polyps. Papers studying only CRCs were not included. All studies needed to relate to human participants. Case-control, cohort and GWA studies were included. The study had to be published in English (one Chinese and one Spanish study were also included) in a peer-reviewed journal before 31 March 2014. Any research that had only been reported in abstracts, eg presented in scientific conferences but not yet fully published, was excluded and 14 family-based studies were also excluded. A list with all variants to be summarized using metaanalysis was generated. A second list with all variants with two or more studies was compared with a list of variants that were included in two GWAS (CORGI and APC). If a variant was found to be included in either of these GWAS, then genotype counts were included in the metaanalysis of this variant. Descriptions of the CORGI and APC GWAS are presented in Supplementary Box 2 (available as Supplementary data at IJE online). Data entry, management and abstraction Once the search was completed, the references of the papers in the search were entered into a web-based database, ‘RefWorks’ [http://www.refworks.com/]. Data from all studies that met