FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2808820107> ?p ?o ?g. }

• W2808820107 abstract "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." @default.
• W2808820107 created "2018-06-29" @default.
• W2808820107 creator A5062830106 @default.
• W2808820107 date "2017-01-01" @default.
• W2808820107 modified "2023-09-23" @default.
• W2808820107 title "Germline determinants of colorectal cancer risk and outcome" @default.
• W2808820107 hasPublicationYear "2017" @default.
• W2808820107 type Work @default.
• W2808820107 sameAs 2808820107 @default.
• W2808820107 citedByCount "0" @default.
• W2808820107 crossrefType "dissertation" @default.
• W2808820107 hasAuthorship W2808820107A5062830106 @default.
• W2808820107 hasConcept C104317684 @default.
• W2808820107 hasConcept C106208931 @default.
• W2808820107 hasConcept C109825262 @default.
• W2808820107 hasConcept C121608353 @default.
• W2808820107 hasConcept C13514818 @default.
• W2808820107 hasConcept C135763542 @default.
• W2808820107 hasConcept C143998085 @default.
• W2808820107 hasConcept C153209595 @default.
• W2808820107 hasConcept C180754005 @default.
• W2808820107 hasConcept C197754878 @default.
• W2808820107 hasConcept C501734568 @default.
• W2808820107 hasConcept C526805850 @default.
• W2808820107 hasConcept C54355233 @default.
• W2808820107 hasConcept C71924100 @default.
• W2808820107 hasConcept C84597430 @default.
• W2808820107 hasConcept C86803240 @default.
• W2808820107 hasConceptScore W2808820107C104317684 @default.
• W2808820107 hasConceptScore W2808820107C106208931 @default.
• W2808820107 hasConceptScore W2808820107C109825262 @default.
• W2808820107 hasConceptScore W2808820107C121608353 @default.
• W2808820107 hasConceptScore W2808820107C13514818 @default.
• W2808820107 hasConceptScore W2808820107C135763542 @default.
• W2808820107 hasConceptScore W2808820107C143998085 @default.
• W2808820107 hasConceptScore W2808820107C153209595 @default.
• W2808820107 hasConceptScore W2808820107C180754005 @default.
• W2808820107 hasConceptScore W2808820107C197754878 @default.
• W2808820107 hasConceptScore W2808820107C501734568 @default.
• W2808820107 hasConceptScore W2808820107C526805850 @default.
• W2808820107 hasConceptScore W2808820107C54355233 @default.
• W2808820107 hasConceptScore W2808820107C71924100 @default.
• W2808820107 hasConceptScore W2808820107C84597430 @default.
• W2808820107 hasConceptScore W2808820107C86803240 @default.
• W2808820107 hasLocation W28088201071 @default.
• W2808820107 hasOpenAccess W2808820107 @default.
• W2808820107 hasPrimaryLocation W28088201071 @default.
• W2808820107 hasRelatedWork W1577731455 @default.
• W2808820107 hasRelatedWork W1965913932 @default.
• W2808820107 hasRelatedWork W2011454310 @default.
• W2808820107 hasRelatedWork W2036450891 @default.
• W2808820107 hasRelatedWork W2051537173 @default.
• W2808820107 hasRelatedWork W2064867939 @default.
• W2808820107 hasRelatedWork W2102707853 @default.
• W2808820107 hasRelatedWork W2549599763 @default.
• W2808820107 hasRelatedWork W2550445135 @default.
• W2808820107 hasRelatedWork W2556663537 @default.
• W2808820107 hasRelatedWork W2751116833 @default.
• W2808820107 hasRelatedWork W2769654894 @default.
• W2808820107 hasRelatedWork W2771077434 @default.
• W2808820107 hasRelatedWork W2911108032 @default.
• W2808820107 hasRelatedWork W2949786246 @default.
• W2808820107 hasRelatedWork W2994781997 @default.
• W2808820107 hasRelatedWork W3083496133 @default.
• W2808820107 hasRelatedWork W3083538759 @default.
• W2808820107 hasRelatedWork W3153633985 @default.
• W2808820107 hasRelatedWork W3159670789 @default.
• W2808820107 isParatext "false" @default.
• W2808820107 isRetracted "false" @default.
• W2808820107 magId "2808820107" @default.
• W2808820107 workType "dissertation" @default.