Variation in organ-specific PIK3CA and KRAS mutant levels in normal human tissues correlates with mutation prevalence in corresponding carcinomas.

Barbara L Parsons,Karen L Mckim,Meagan B Myers

doi:10.1002/em.22110

Abstract

Large‐scale sequencing efforts have described the mutational complexity of individual cancers and identified mutations prevalent in different cancers. As a complementary approach, allele‐specific competitive blocker PCR (ACB‐PCR) is being used to quantify levels of hotspot cancer driver mutations (CDMs) with high sensitivity, to elucidate the tissue‐specific properties of CDMs, their occurrence as tumor cell subpopulations, and their occurrence in normal tissues. Here we report measurements of PIK3CA H1047R mutant fraction (MF) in normal colonic mucosa, normal lung, colonic adenomas, colonic adenocarcinomas, and lung adenocarcinomas. We report PIK3CA E545K MF measurements in those tissues, as well as in normal breast, normal thyroid, mammary ductal carcinomas, and papillary thyroid carcinomas. We report KRAS G12D and G12V MF measurements in normal colon. These MF measurements were integrated with previously published ACB‐PCR data on KRAS G12D, KRAS G12V, and PIK3CA H1047R. Analysis of these data revealed a correlation between the degree of interindividual variability in these mutations (as log10 MF standard deviation) in normal tissues and the frequencies with which the mutations are detected in carcinomas of the corresponding organs in the COSMIC database. This novel observation has important implications. It suggests that interindividual variability in mutation levels of normal tissues may be used as a metric to identify mutations with critical early roles in tissue‐specific carcinogenesis. Additionally, it raises the possibility that personalized cancer therapeutics, developed to target specifically activated oncogenic products, might be repurposed as prophylactic therapies to reduce the accumulation of cells carrying CDMs and, thereby, reduce future cancer risk. Environ. Mol. Mutagen. 58:466–476, 2017. © 2017 This article is a U.S. Government work and is in the public domain in the USA. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society

Highlights

Large-scale cancer genome sequencing projects have been valuable in terms of identifying the prevalent cancer driver mutations (CDMs) associated with particular types of cancers [Ciriello et al, 2013; Kandoth et al, 2013; Watson et al, 2013; Stover and Wagle, 2015]
Levels of PIK3CA E545K mutation were measured in normal breast, colonic mucosa, lung, and thyroid DNA samples, as well as in DNA isolated from ductal carcinomas, colonic adenomas, colonic adenocarcinomas, lung adenocarcinomas, and papillary thyroid carcinomas
Each unknown was quantified in three independent experiments (276 PIK3CA H1047R mutant fraction (MF) measurements)

Summary

Introduction

Large-scale cancer genome sequencing projects have been valuable in terms of identifying the prevalent cancer driver mutations (CDMs) associated with particular types of cancers [Ciriello et al, 2013; Kandoth et al, 2013; Watson et al, 2013; Stover and Wagle, 2015]. Cancer “drivers” have been defined as genetic events associated with tumor initiation or progression [Alizadeh et al, 2015] and as somatic mutations that increase the fitness of a cell [Fisher et al, 2013]. A cancer driver is “a cell autonomous or non-cell autonomous alteration that contributes to the tumor evolution at any stage—including initiation, progression, metastasis, and resistance to therapy—by promoting a variety of functions including proliferation, survival, invasion, or immune evasion” [Alizadeh et al, 2015]. Some of the most impactful cancer drivers are hotspot point mutations. Hotspot point mutations merit investigation because of their high prevalence in cancer, their established roles as. Additional Supporting Information may be found in the online version of this article

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