@article{da9d5907e0d749d2b5fa6af99224822f,
title = "Germline and somatic genetic variants in the p53 pathway interact to affect cancer risk, progression, and drug response",
abstract = "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 welldocumented 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.",
author = "Ping Zhang and Isaac Kitchen-Smith and Lingyun Xiong and Giovanni Stracquadanio and Katherine Brown and Richter, {Philipp Harald} and Wallace, {Marsha D} and Elisabeth Bond and Natasha Sahgal and Samantha Moore and Svanhild Nornes and {De Val}, Sarah and Mirvat Surakhy and David Sims and Xuting Wang and Bell, {Douglas A} and Jorge Zeron-Medina and Yanyan Jiang and Ryan, {Anderson J} and Selfe, {Joanna L} and Janet Shipley and Siddhartha Kar and Pharoah, {Paul D P} and Chey Loveday and Rick Jansen and Grochola, {Lukasz F} and Claire Palles and Andrew Protheroe and Val Millar and Ebner, {Daniel V} and Meghana Pagadala and Blagden, {Sarah P} and Maughan, {Timothy Stanley} and Enric Domingo and Ian Tomlinson and Clare Turnbull and Hannah Carter and Bond, {Gareth L}",
note = "Funding Information: PsiOxus outside the submitted work; and has a patent for patent pending. H. Carter reports grants from NIH, The Mark Foundation for Cancer Research, and Harry J. Lloyd Charitable Trust during the conduct of the study. No other disclosures were reported by the other authors. Funding Information: J. Zeron-Medina reports employment with AstraZeneca. S.P. Blagden reports grants from Nucana PLC and other funding from Redx, Sierra Oncology, Astex, Incyte, Octimet, and Tesaro outside the submitted work. T.S. Maughan reports grants from AstraZeneca, Merck Serono, and PsiOxus; personal fees from AstraZeneca and Pierre Fabre; and nonfinancial support from AstraZeneca, Merck Serono, and Funding Information: This work was funded in part by the Ludwig Institute for Cancer Research, the Nuffield Department of Medicine, the Development Fund, Oxford Cancer Research Centre, University of Oxford, UK, by the Intramural Research Program of the National Institute of Environmental Health Sciences-National Institutes of Health (Z01-ES100475), and NIH grant (DP5-OD017937), US, and by the S-CORT Consortium from the Medical Research Council and Cancer Research UK. Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2021",
month = apr,
doi = "https://doi.org/10.1158/0008-5472.CAN-20-0177",
language = "English",
volume = "81",
pages = "1667--1680",
journal = "Cancer research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "7",
}