Influence of inherited genetic variants on risk, biology and prognosis of common cancers

Thesis

Cancer is a complex disease affected by both inherited risk variants and somatic alterations. Recent studies showed that inherited genetic variants and somatic driver mutations converge in cancer hallmark pathways, and that inherited genetic variants were associated with specific somatic driver mutations in tumours. However, it is unclear whether common inherited genetic variants interact with somatic driver mutations to influence cancer risk and prognosis.

In this study, I analyse multi-cancer datasets to investigate germline by somatic interaction in cancer and to evaluate the role of inherited genetic variants on risk, prognosis, nearby gene expression, response to anti-cancer therapy and adaptive immune response in common cancers. I describe how the p53 poly(A) SNP, rs78378222 (17p13.1; TP53), interacts with p53 mutational status in tumours to influence cancer risk, response to therapy and prognosis in common cancers. I find that a known colorectal cancer risk locus at 10p14 (rs10795668; ATP5C1) interacts with KRAS mutational status in tumours to associate with colorectal cancer risk. I identify two loci at 15q26.2 (rs72767781; NR2F2-AS1) and 15q22.2 (rs11447843; VPS13C) associated with prognosis in early-stage colorectal cancer at genome-wide significance, together with numerous suggestive loci. In particular, rs184423256 (8q22.3; RRM2B) and rs114887409 (4p16.1; ABLIM2) interact with KRAS mutational status in colorectal cancer to associate with clinical outcomes. Furthermore, I identify 22 loci associated with infiltrating CD8+ T cell density in colorectal cancer, which are used to infer the causal relationship between adaptive immune trait and prognosis in early-stage colorectal cancer.

In summary, this study constitutes an integrative analysis of germline by somatic interaction on risk, biology, and prognosis of common cancers. The findings provide supportive evidence that inherited genetic variants can play an active role during tumour development, thus offering insight into the genetic basis of cancer susceptibility and practical guidance for personalised disease prediction.

Authors: Xiong, L

• Alternative title: Influence of inherited genetic variants in common cancers
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: stratified GWAS; cancer prognosis; somatic driver mutations; cancer risk; p53 tumour suppressor; germline by somatic interaction; KRAS oncoprotein; adaptive immune response; inherited genetic variants
• Subjects: Bioinformatics; Biology; Genetics; Cancer; Epidemiology