FUNCTIONAL CHARACTERISATION OF COLORECTAL CANCER P.. (CRCINTERMPHEN)
FUNCTIONAL CHARACTERISATION OF COLORECTAL CANCER PREDISPOSITION GENES AND DEVELOPMENT OF INTERMEDIATE BIOMARKERS OF DISEASE RISK
Start date: Oct 26, 2012,
End date: Oct 25, 2014
"Colorectal cancer (CRC) is one of the most common cancers in both men and women in the EU. Recent advances in CRC genetics, largely through genome-wide association studies (GWAS), have identified 17 common polymorphisms (SNPs) associated with increased CRC risk in the general population. The SNPs only account for a minority of the genetic variation in CRC and genotyping these SNPs alone is not a sufficiently powerful risk predictor to be used in clinical practice. However, whilst the nature of the functional variation correlated with these SNPs is largely unknown, the CRC GWAS have provided excellent evidence for some of the important molecular pathways that influence disease risk, including bone morphogenetic protein (BMP) signalling and telomere length. These discoveries raise the important possibility that we can use intermediate molecular phenotypes as surrogate markers of genetic variation, thus allowing much better prediction of CRC risk. For example, although we would not know all the polymorphisms or mutations that impacted on an individual’s BMP signalling, by measuring that pathway’s activity, we could sum the effects of those genetic variants and provide a clinically-useful means of assessing CRC risk. In this proposal, I shall determine whether candidate molecular pathways can be used as intermediate phenotypes to predict CRC risk. I shall study not only BMP signalling and telomere length, but also candidate phenotypes such as stem cell markers, apoptosis/senescence markers and Wnt pathway activity. The national bowel cancer screening programme in the UK allows normal colorectal mucosa to be obtained readily, so as to build up a bank of tissue from patients with and without CRC. For each molecular phenotype, I shall (a) develop assays, (b) assess each patient and (c) test for associations with known CRC risk SNPs and overall disease risk. The finding of strong risk predictors would allow preventive measures to be targeted to those at highest risk of CRC."
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