Germline and somatic genetic variants in the p53 pathway interact to affect cancer risk, progression and drug response

Abstract

46Insights into oncogenesis derived from cancer susceptibility loci could facilitate 47 better cancer management and treatment through precision oncology. However, 48 therapeutic applications have thus far been limited by our current lack of 49 understanding regarding both their interactions with somatic cancer driver mutations 50 and their influence on tumorigenesis. Here, by integrating germline datasets relating 51 to cancer susceptibility with tumour data capturing somatically-acquired genetic 52 variation, we provide evidence that single nucleotide polymorphism (SNPs) and 53 somatic mutations in the p53 tumor suppressor pathway can interact to influence 54 cancer development, progression and treatment response. We go on to provide human 55 genetic evidence of a tumor-promoting role for the pro-survival activities of p53, 56 which supports the development of more effective therapy combinations through their 57 inhibition in cancers retaining wild-type p53. 58 59Significance 60 We describe significant interactions between heritable and somatic genetic variants 61 in the p53 pathway that affect cancer susceptibility, progression and treatment 62 response. Our results offer evidence of how cancer susceptibility SNPs can interact 63 with cancer driver genes to affect cancer progression and identify novel therapeutic 64 targets. 65 affect p53's ability to bind to DNA in a sequence-specific manner and regulate 99 transcription of its target genes. Some of these same TP53 mutations when found 100 constitutionally result in Li-Fraumeni Syndrome: a syndrome comprising dramatic 101 increase in cancer risk in many tissues types. Although targeting driver mutations in 102 tumor suppressors has been challenging, the high abundance of p53 mutations in 103 cancer has motivated the development of small molecules that aim to reactivate 104 mutant p53 to increase sensitivities to DNA-damaging therapies or inhibit gain-of 105 function activities (15). 106Somatic driver mutations in other p53 pathway genes are also current drug 107 targets. In a sub-set of p53 wild-type cancers, p53 signaling can be attenuated through 108 somatic driver events that alter key p53 regulators. For example, the MDM2 109 oncogene is amplified in a variety of cancers. Its amplification results in decreased 110 p53-mediated tumor suppression, increased cancer susceptibility, and the reduction of 111 selection pressures for somatic p53 mutations (16). Moreover, cancer cells with 112 amplified MDM2 and wild-type p53 have an attenuated p53-mediated DNA damage 113 response (17). Thus, amplification of MDM2 is a promising target for treatment, in 114 combination with DNA-damaging therapies (15,18). 115Most studies have separately examined the consequences of somatic and 116 germline variation affecting p53 activity to understand their roles in disease risk, 117 progression or response to therapy. Here we hypothesize that cancer-associated 118 germline variants (single nucleotide polymorphisms, SNPs) interact with p53 somatic 119 driver mutations to modify c...

The Landscape of the Heritable Cancer Genome

“…Although most SNPs have only subtle effects, there is mounting evidence suggesting that they still contribute to the risk of developing cancer (13). Recently, we have shown that low-penetrant germline mutations in p53 pathway genes can directly control cancer related processes, including p53 activity and response to chemotherapies (14). Moreover, the Pan-Cancer Analysis of Whole Genomes (PCAWG) study found that 17% of all patients have rare germline variants associated with cancer (15).…”

Oncogenic alterations in the p53 pathway abolish oscillatory competence

“…Second, a loss of p53, due to inherited cancer risk polymorphisms, truncating mutations or allelic deletion in TP53, decreases the production rate of p53 (lowering α (Donehower et al, 2019; Livingstone et al, 1992; Macedo et al, 2016; Venkatachalam, 1998; X. Wang & Sun, 2017; P. Zhang et al, 2019)), dropping the system out of the Hopf subspace (Fig. 3C).…”

Genomic hallmarks of cellular dormancy in cancer and therapeutic implications

“…TP53 functional status was assessed based on somatic mutation and copy number alterations as described in Zhang et al 90 . TP53 mutation and copy number for the TCGA tumours were downloaded from cBioPortal (http://www.cbioportal.org).…”