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Title: The role of germline variants in multiple genes in inherited predisposition to colorectal adenoma formation
Author: Fearnhead, Nicola Shan
ISNI:       0000 0004 2720 6391
Awarding Body: Oxford University
Current Institution: University of Oxford
Date of Award: 2009
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Introduction: Around 20-30% of the population are thought to have some form of inherited predisposition to colorectal cancer outside of the genetic syndromes of familial adenomatous polyposis (FAP), MYH-associated polyposis (MAP) and hereditary non-polyposis colorectal cancer (HNPCC). Inherited susceptibility should be particularly suspected when colorectal cancer is diagnosed at young age, when a patient presents with synchronous or metachronous colorectal cancers or adenomas, or where there is a strong family history of colorectal cancer. The rare variant hypothesis of inherited susceptibility proposes that a number of low frequency variants in a variety of different genes, each conferring a moderate but detectable increase in relative risk of developing disease, may be responsible for non- syndromic predisposition to colorectal cancer. Rare variants may occur in many genes involved in colorectal tumorigenesis, including those with roles in Wnt signalling, transcriptional activation, mismatch repair, cell cycle regulatory mechanisms and cellular adhesion. Methods: DNA from 124 United Kingdom patients with between 3 and 100 adenomatous polyps was screened for germline variants in genes involved in Wnt signalling (APC, AXINI and CTNNBI), mismatch repair (hMLHI and hMSH2) and cell cycling (TP53). The APC variants II307K and EJ317Q were detected using amplification refractory mutation system (ARMS) polymerase chain reaction (PCR) and alkaline-mediated differential interaction (AMDI). For all other genes, PCR primers were designed to encompass the entire coding sequence of the gene and variant detection was carried out on the Transgenomic Wave" machine. Variants were sequenced and analysed using Sequencher" software. The findings in the sample population were compared with a population of 53 Korean patients with multiple adenomas, and with a panel of 483 healthy controls. Results: 30/124 (24.9%) of the U.K. multiple adenoma patients carried potentially pathogenic germline variants in the genes tested as compared to 55 (12%) of the controls. The overall association between the rare alleles at the loci tested and the formation of multiple adenomas, as compared to controls, was highly significant with an odds ratio of 2.2 (p = 0.0001). None of the variants identified in the U.K. patients was found in the Korean patients. Discussion: The difference in rare variants between cases and controls is highly significant, suggesting that many rare variants collectively contribute to inherited susceptibility to colorectal adenomas. Each variant would effect a subtle change in protein interaction or level of gene expression, resulting in only a marginal selective disadvantage but a clearly defined increase in relative risk. Such variants are likely to be population-specific, as in the cases of APC 1307K and E1317Q. Strategies for detection of multiple rare alleles include efficient variant detection and sequencing techniques in at-risk individuals, identification of candidate genes, large-scale population studies, careful selection of controls, and targeted statistical approaches. Each potential rare variant needs to be assessed for its functional consequences. These findings give support to the hypothesis that multiple rare alleles, predominantly missense, promoter and splice site variants, are collectively responsible for inherited susceptibility to colorectal cancer in the general population. It is probable that ultimately a large number of rare alleles will contribute more to the population burden of colorectal cancer than the classically inherited Mendelian syndromes associated with colorectal tumorigenesis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available