Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

Insights into oncogenesis derived from cancer susceptibility loci (SNP) hold the potential to facilitate better cancer management and treatment through precision oncology. However, therapeutic insights have thus far been limited by our current lack of understanding regarding both interactions of these loci with somatic cancer driver mutations and their influence on tumorigenesis. For example, although both germline and somatic genetic variation to the p53 tumor suppressor pathway are known to promote tumorigenesis, little is known about the extent to which such variants cooperate to alter pathway activity. Here we hypothesize that cancer risk-associated germline variants interact with somatic TP53 mutational status to modify cancer risk, progression, and response to therapy. Focusing on a cancer risk SNP (rs78378222) with a well-documented ability to directly influence p53 activity as well as integration of germline datasets relating to cancer susceptibility with tumor data capturing somatically-acquired genetic variation provided supportive evidence for this hypothesis. Integration of germline and somatic genetic data enabled identification of a novel entry point for therapeutic manipulation of p53 activities. A cluster of cancer risk SNPs resulted in increased expression of prosurvival p53 target gene KITLG and attenuation of p53-mediated responses to genotoxic therapies, which were reversed by pharmacologic inhibition of the prosurvival c-KIT signal. Together, our results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and identify novel combinatorial therapies. SIGNIFICANCE: These results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and present novel therapeutic targets.

Original publication

DOI

10.1158/0008-5472.can-20-0177

Type

Journal article

Journal

Cancer research

Publication Date

04/2021

Volume

81

Pages

1667 - 1680

Addresses

Ludwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical Medicine, Old Road Campus Research Building, Oxford, United Kingdom.

Keywords

Cell Line, Tumor, Animals, Mice, Inbred BALB C, Humans, Mice, Mice, Nude, Neoplasms, Disease Progression, Genetic Predisposition to Disease, Antineoplastic Agents, Prognosis, Treatment Outcome, Risk Factors, Case-Control Studies, Signal Transduction, Drug Resistance, Neoplasm, Germ-Line Mutation, Mutation, Missense, Polymorphism, Single Nucleotide, Female, Male, Tumor Suppressor Protein p53, Biomarkers, Pharmacological, Genome-Wide Association Study, Carcinogenesis