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Article

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

1
Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA
2
Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA
*
Author to whom correspondence should be addressed.
Current affiliation: Covance Inc., Indianapolis, IN 46214, USA.
Int. J. Mol. Sci. 2019, 20(5), 1011; https://doi.org/10.3390/ijms20051011
Received: 5 February 2019 / Revised: 19 February 2019 / Accepted: 20 February 2019 / Published: 26 February 2019
(This article belongs to the Special Issue Molecular Biology and Pathology of Breast Cancer)
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. View Full-Text
Keywords: invasive ductal carcinoma; breast cancer; mutation; cancer-driver; triple-negative breast cancer; TNBC; heterogeneity; PIK3CA; subclonal invasive ductal carcinoma; breast cancer; mutation; cancer-driver; triple-negative breast cancer; TNBC; heterogeneity; PIK3CA; subclonal
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MDPI and ACS Style

Myers, M.B.; McKim, K.L.; Banda, M.; George, N.I.; Parsons, B.L. Low-Frequency Mutational Heterogeneity of Invasive Ductal Carcinoma Subtypes: Information to Direct Precision Oncology. Int. J. Mol. Sci. 2019, 20, 1011. https://doi.org/10.3390/ijms20051011

AMA Style

Myers MB, McKim KL, Banda M, George NI, Parsons BL. Low-Frequency Mutational Heterogeneity of Invasive Ductal Carcinoma Subtypes: Information to Direct Precision Oncology. International Journal of Molecular Sciences. 2019; 20(5):1011. https://doi.org/10.3390/ijms20051011

Chicago/Turabian Style

Myers, Meagan B., Karen L. McKim, Malathi Banda, Nysia I. George, and Barbara L. Parsons 2019. "Low-Frequency Mutational Heterogeneity of Invasive Ductal Carcinoma Subtypes: Information to Direct Precision Oncology" International Journal of Molecular Sciences 20, no. 5: 1011. https://doi.org/10.3390/ijms20051011

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