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Title: Genetics and pharmacogenetics of colorectal cancer
Author: Smith, Christopher G.
ISNI:       0000 0004 2751 7237
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2011
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We aimed to identify genetic factors that alter colorectal cancer (CRC) risk, patient survival and response to treatment. Using a cohort of 2,186 advanced CRC (aCRC) cases and 2,176 healthy controls, we validated a role for loci at 18q21, 8q23, 15q13 and 8q24 in CRC susceptibility. We also identified a variant in OGG1 that may act as a novel low penetrance risk allele. We identified four germline SNPs from 14 genome wide associated CRC risk loci that independently altered patient survival (rs16892766 at 8q23, HR 1.28, 95% CI 1.13-1.45, P<0.001 rs9929218 at 16q22, HR 1.46, 95% CI 1.23-1.74, P=0.002 rs10411210 at 19q13, HR 1.23, 95% CI 1.08-1.39, P=0.001 and, rs10795668 at 10p14, HR 0.71, 95% CI 0.59-0.86, P=0.001). We found that somatic mutations of the KRAS (HR 1.34, 95% CI 1.18-1.52 P<0.001) and BRAF (HR 2.00, 95% CI 1.61-2.50, P<0.001) oncogenes altered patient survival independent of treatment. Through the COIN trial, we found no evidence for improved response to cetuximab in patients' wild-type for KRAS (OS HR 1.04, 95% CI 0.87-1.23, P=0.67) or all wild-type for KRAS, BRAF and NRAS (OS HR 1.02, 95% CI 0.83-1.24, P=0.86). Similarly, PIK3CA mutation status did not correlate with response (OS 1.03, 95% CI 0.86-1.24, P=0.89). However, we identified a 'most responsive' cohort (patients wild-type for KRAS, BRAF and NRAS, with £1 metastatic sites and that received OxFU) that showed improved response (PFS HR 0.55, 95% CI 0.35-0.87, P=0.01). Analysis of individual somatic variants revealed no significant associations with response. We found that rs9929218 altered response to (OR 0.48, 95% CI 0.31-0.75, P=0.001) and side effects from (OR 4.68, 95% CI 1.84- 11.9, P=0.001) standard chemotherapy and response to cetuximab in a KRAS, BRAF and NRAS mutant dependent manner (OR 1.69, 95% CI 0.61-4.74, P for interaction 0.004). We elucidated the underlying mechanisms at the 8q23 and 16q22 loci. These data may help to tailor future therapies for patients with aCRC.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available