Low-Frequency Mutational Heterogeneity of Invasive Ductal Carcinoma Subtypes: Information to Direct Precision Oncology

Meagan B Myers; Karen L McKim; Malathi Banda; Nysia I George; Barbara L Parsons

doi:10.3390/ijms20051011

Low-Frequency Mutational Heterogeneity of Invasive Ductal Carcinoma Subtypes: Information to Direct Precision Oncology

Int J Mol Sci. 2019 Feb 26;20(5):1011. doi: 10.3390/ijms20051011.

Authors

Meagan B Myers¹, Karen L McKim², Malathi Banda³, Nysia I George⁴, Barbara L Parsons⁵

Affiliations

¹ Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA. meagan.myers@fda.hhs.gov.
² Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA. karen.mckim@fda.hhs.gov.
³ Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA. malathi.banda@covance.com.
⁴ Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA. nysiainet@gmail.com.
⁵ Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA. barbara.parsons@fda.hhs.gov.

Abstract

Information regarding the role of low-frequency hotspot cancer-driver mutations (CDMs) in breast carcinogenesis and therapeutic response is limited. Using the sensitive and quantitative Allele-specific Competitor Blocker PCR (ACB-PCR) approach, mutant fractions (MFs) of six CDMs (PIK3CA H1047R and E545K, KRAS G12D and G12V, HRAS G12D, and BRAF V600E) were quantified in invasive ductal carcinomas (IDCs; including ~20 samples per subtype). Measurable levels (i.e., ≥ 1 × 10^-5, the lowest ACB-PCR standard employed) of the PIK3CA H1047R, PIK3CA E545K, KRAS G12D, KRAS G12V, HRAS G12D, and BRAF V600E mutations were observed in 34/81 (42%), 29/81 (36%), 51/81 (63%), 9/81 (11%), 70/81 (86%), and 48/81 (59%) of IDCs, respectively. Correlation analysis using available clinicopathological information revealed that PIK3CA H1047R and BRAF V600E MFs correlate positively with maximum tumor dimension. Analysis of IDC subtypes revealed minor mutant subpopulations of critical genes in the MAP kinase pathway (KRAS, HRAS, and BRAF) were prevalent across IDC subtypes. Few triple-negative breast cancers (TNBCs) had appreciable levels of PIK3CA mutation, suggesting that individuals with TNBC may be less responsive to inhibitors of the PI3K/AKT/mTOR pathway. These results suggest that low-frequency hotspot CDMs contribute significantly to the intertumoral and intratumoral genetic heterogeneity of IDCs, which has the potential to impact precision oncology approaches.

Keywords: PIK3CA; TNBC; breast cancer; cancer-driver; heterogeneity; invasive ductal carcinoma; mutation; subclonal; triple-negative breast cancer.

MeSH terms

Alleles
Breast Neoplasms / genetics*
Breast Neoplasms / pathology*
Carcinoma, Ductal, Breast / genetics*
Carcinoma, Ductal, Breast / pathology*
Female
Fluorescein / metabolism
Humans
Middle Aged
Mutation / genetics
Mutation Rate*
Neoplasm Invasiveness
Phosphatidylinositol 3-Kinases / genetics
Polymerase Chain Reaction
Precision Medicine*
Proto-Oncogene Proteins B-raf / genetics
Receptor, ErbB-2 / genetics
Receptor, ErbB-2 / metabolism

Substances

Phosphatidylinositol 3-Kinases
ERBB2 protein, human
Receptor, ErbB-2
Proto-Oncogene Proteins B-raf
Fluorescein