Abstract 5147: Characterization of the tissue-specific properties of cancer driver mutations suggests spontaneous mutation in normal tissues drives tumor susceptibility

Cancer driver mutations (CDMs) are being developed as theranostic biomarkers. This study used high-sensitivity quantification by ACB-PCR, with a sensitivity of 10−5, to elucidate the tissue-specific properties of CDMs. We employed the paradigm of comparing levels of specific hotspot CDMs in normal human tissues and tumors. Specifically, we measured KRAS G12D, KRAS G12V, PIK3CA E545K, and PIK3CA H1047R mutant fractions (MFs) in normal breast, colon, lung, and thyroid and quantified the same mutations in mammary ductal carcinomas (DCs), colonic adenocarcinomas, lung adenocarcinomas, and papillary thyroid carcinomas. Three major findings were: 1) these mutations occur in normal human tissues at relatively high frequencies, 2) there is considerable variability in CDM MFs in normal tissues across individuals, and 3) tumors frequently carry CDMs at levels greater than that present in normal tissue, but below that detected by standard DNA sequencing. Understanding the prevalence of mutant subpopulations is important because they can drive resistance to molecularly-targeted therapies. The PIK3CA H1047R profile for normal breast and DC were similar, with large mutant subpopulations present in both tissue types. Because the PIK3CA H1047R mutation is the most prevalent point mutation reported in breast cancer, we conclude that it can drive breast carcinogenesis as a subpopulation, potentially through a paracrine mechanism, and may be a useful biomarker of breast cancer susceptibility. Other properties of CDMs elucidated were gender differences, the accumulation of mutation with donor age, and the correlation between MF and maximum tumor dimension (MTD). Male lung had significantly greater PIK3CA H1047R MFs than female lung. The PIK3CA H1047R MF in normal breast was positively correlated with donor age, and the mutation in DCs was positively correlated with MTD. By contrast, KRAS MFs showed non-significant decreases in normal lung with increasing donor age. For colorectal adenocarcinomas, KRAS G12V MF was negatively correlated with MTD, consistent with previous findings that KRAS G12V MF decreases during adenoma to adenocarcinoma progression. This suggests that the selective advantage provided by KRAS G12V mutation is context-dependent and can be either positive or negative. Across the four mutational targets and four tissue types, a significant positive correlation was observed between the variability (Log10 standard deviation) of MF measured in normal tissues and the prevalence with which the mutation reportedly occurs in tumors, as per The Cancer Genome Atlas database. This suggests that level and inter-individual variation in CDMs can be used to identify promising tissue-specific, mutational biomarkers of cancer susceptibility. This is not a formal dissemination of information by FDA and does not represent agency position or policy. Citation Format: Barbara L. Parsons, Meagan B. Myers, Karen L. McKim, Malathi Banda. Characterization of the tissue-specific properties of cancer driver mutations suggests spontaneous mutation in normal tissues drives tumor susceptibility. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5147.