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Title: Germline determinants of colorectal cancer risk and outcome
Author: Freeman-Mills, Luke
ISNI:       0000 0004 6501 071X
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2017
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Colorectal cancer (CRC) is the third most common global cancer. Approximately one fifth of phenotypic variance in CRC is attributable to additive genetic inputs: the disease risk is heritable. The nature and location of these genetic inputs has been the preoccupation of association studies over the last decade. Variation at some 30 genomic loci influences sporadic CRC risk. However, in Mendelian disorders this risk is almost absolute. Such cancer syndromes include Lynch syndrome, caused by defective DNA mismatch repair, and serrated polyposis syndrome, which has no confirmed genetic cause. The aim of this thesis was to continue exploring how common and rare germline genetics influence CRC liability. A reexamination of the chromosome 15 GREM1 locus in seven imputed UK case-control cohorts revealed a new, genome-wide significant risk polymorphism at rs17816465, independent of previously reported associations. This polymorphism lies near to conserved regulatory elements within the FMN1 gene and had allele-specific luciferase activity. Similar fine-mapping at the POLD3 locus showed a large haplotype carrying CRC risk, making further refinement of the signal difficult. A risk score incorporating a correlate of this haplotype and all other independently CRC-associated polymorphisms was significantly higher in cases than in controls, but did not predict patient survival. Instead, the risk score anticorrelated with tumour driver mutation burden in publically available colorectal cancer data. This thesis also reports the mapping and calling of the whole-genome sequences of 299 UK CRC and adenoma patients. Rare variants within this cohort were shown to be shared beyond expectation in geographic clines not visible to principal component analysis. Future rare variant association studies will need to correct for cryptic population structure using other statistical tools. In contravention of recruitment criteria, known polyposis syndrome genes were often deleteriously mutant within the genomes. Also, filtering on phenotype or gene subsets revealed potentially pathogenic variants in either whole-genome or whole-exome sequences in EXO1, RPA4, and LNX1. One individual displayed homozygous mutation of the mismatch repair gene MSH3. This was the second account of a germline MSH3 change causing tetranucleotide-unstable CRC. Lastly, a family suffering serrated polyposis was shown to carry a heterozygous RNF43 frameshift that segregated with the disease. This thesis improves our account of both sporadic and Mendelian CRC risk. It identifies a new genome-wide significant association with sporadic CRC at the GREM1 locus and provides a haplotypic account of risk at POLD3. It also describes two rare germline causes of Mendelian CRC: MSH3 and RNF43 loss of function.
Supervisor: Tomlinson, Ian Sponsor: Nuffield Department of Medicine
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available