Multiple rare variants in different genes account for multifactorial inherited susceptibility to colorectal adenomas

Abstract

Clear-cut inherited Mendelian traits, such as familial adenomatous polyposis or hereditary nonpolyposis colorectal cancer, account for <4% of colorectal cancers. Another 20% of all colorectal cancers are thought to occur in individuals with a significant inherited multifactorial susceptibility to colorectal cancer that is not obviously familial. Incompletely penetrant, comparatively rare missense variants in the adenomatous polyposis coli gene, which is responsible for familial adenomatous polyposis, have been described in patients with multiple colorectal adenomas. These variants represent a category of variation that has been suggested, quite generally, to account for a substantial fraction of such multifactorial inherited susceptibility. The aim of this study was to explore this rare variant hypothesis for multifactorial inheritance by using multiple colorectal adenomas as the model. Patients with multiple adenomas were screened for germ-line variants in a panel of candidate genes. Germ-line DNA was obtained from 124 patients with between 3 and 100 histologically proven synchronous or metachronous adenomatous polyps. All patients were tested for the adenomatous polyposis coli variants I1307K and E1317Q, and variants were also sought in AXIN1 (axin), CTNNB1 (␤-catenin), and the mismatch repair genes hMLH1 and hMSH2. The control group consisted of 483 random controls. Thirty of 124 (24.9%) patients carried potentially pathogenic germ-line variants as compared with 55 (Ϸ12%) of the controls. This overall difference is highly significant, suggesting that many rare variants collectively contribute to the inherited susceptibility to colorectal adenomas. polyposis ͉ cancer ͉ subpolymorphic ͉ mismatch repair ͉ founder

The role of phospholipases A2 in schizophrenia

“…87,107 The alternative common disease, rare variant (CDRV) hypothesis proposes that there a large pool of rare (minor allele frequency < 10%) or even unique risk variants. [108][109][110] Interestingly, association between a common variant and a disease can be due to LD with high penetrance rare variants present in only a few of the total study population. 111 It is likely that both paradigms contribute, as a spectrum of common and rare deleterious variants has been seen in both Mendelian and complex disorders.…”

Cyclin D1 rare variants in UK multiple adenoma and early-onset colorectal cancer patients

“…The UK patient group consisted of 112 individuals with 3-100 histologically proven synchronous or metachronous adenomatous polyps, 18 and 44 individuals with colorectal cancer diagnosed before 50 years of age. A total of 38 individuals with early-onset disease were obtained through the VICTOR clinical trial, a Phase III double-blind placebo controlled study of rofecoxib in Dukes stage B or C colorectal cancer patients following potentially curative therapy, whereas the remaining six were recruited through the John Radcliffe and Churchill hospitals' gastrointestinal clinics.…”

“…No patient fulfilled the criteria for familial adenomatous polyposis, autosomal recessive MYH-associated polyposis or hereditary nonpolyposis colorectal cancer on clinical grounds. 18 Some of these patients had already been screened for germline mutations in the APC and MYH genes during previous studies. 20,21 In addition, we collected samples from 131 French patients, 75 with multiple adenomas and 56 with early-onset colorectal cancer, who were recruited in the Department of Digestive Surgery at the Hôpital Saint-Antoine in Paris.…”

“…15,16 Given the low odds ratios (OR) associated with common variants, such as rs9344, we have argued that genetic risk factors underlying complex diseases are more likely to be due to functionally relevant rare variants with moderate penetrance that will considerably increase susceptibility and will, therefore, sometimes justify prophylactic interventions. [17][18][19] We defined rare variants as those having higher frequencies than rare severe effect, clearly familial, mutations but lower frequencies than polymorphisms. Thus, rare variants will generally be in the frequency range between 0.1 and 1%.…”

Evaluating rare variants under two-stage design

“…However, some studies have suggested that the genetic variants for common diseases could have a wide spectrum of frequencies, ranging from rare to common, and that rare variants could exhibit a relatively large genetic effect (for example, odds ratio greater than 2). [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] For example, in 2008, Stefansson et al 10 found that three rare deletions were associated with schizophrenia with the odds ratios of 2.7, 11.5 and 14.8, respectively. Some authors have proposed novel methods to detect associations with multiple rare variants for common diseases.…”