Low-Frequency Mutational Heterogeneity of Invasive Ductal Carcinoma Subtypes: Information to Direct Precision Oncology
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 potentialmore »
- Authors:
-
- U.S. Food and Drug Administration (FDA),Jefferson, AR (United States). Division of Genetic and Molecular Toxicology, National Center for Toxicological Research
- U.S. Food and Drug Administration (FDA),Jefferson, AR (United States). Div. of Bioinformatics and Biostatistics, National Center for Toxicological Research
- Publication Date:
- Research Org.:
- Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)
- Sponsoring Org.:
- USDOE; US Food and Drug Administration
- OSTI Identifier:
- 1628383
- Grant/Contract Number:
- SC0014664
- Resource Type:
- Accepted Manuscript
- Journal Name:
- International Journal of Molecular Sciences (Online)
- Additional Journal Information:
- Journal Name: International Journal of Molecular Sciences (Online); Journal Volume: 20; Journal Issue: 5; Journal ID: ISSN 1422-0067
- Publisher:
- MDPI
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Biochemistry & Molecular Biology; Chemistry; invasive ductal carcinoma; breast cancer; mutation; cancer-driver; triple-negative breast cancer; TNBC; heterogeneity; PIK3CA; subclonal
Citation Formats
Myers, Meagan, McKim, Karen, Banda, Malathi, George, Nysia, and Parsons, Barbara. Low-Frequency Mutational Heterogeneity of Invasive Ductal Carcinoma Subtypes: Information to Direct Precision Oncology. United States: N. p., 2019.
Web. doi:10.3390/ijms20051011.
Myers, Meagan, McKim, Karen, Banda, Malathi, George, Nysia, & Parsons, Barbara. Low-Frequency Mutational Heterogeneity of Invasive Ductal Carcinoma Subtypes: Information to Direct Precision Oncology. United States. https://doi.org/10.3390/ijms20051011
Myers, Meagan, McKim, Karen, Banda, Malathi, George, Nysia, and Parsons, Barbara. Tue .
"Low-Frequency Mutational Heterogeneity of Invasive Ductal Carcinoma Subtypes: Information to Direct Precision Oncology". United States. https://doi.org/10.3390/ijms20051011. https://www.osti.gov/servlets/purl/1628383.
@article{osti_1628383,
title = {Low-Frequency Mutational Heterogeneity of Invasive Ductal Carcinoma Subtypes: Information to Direct Precision Oncology},
author = {Myers, Meagan and McKim, Karen and Banda, Malathi and George, Nysia and Parsons, Barbara},
abstractNote = {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.},
doi = {10.3390/ijms20051011},
journal = {International Journal of Molecular Sciences (Online)},
number = 5,
volume = 20,
place = {United States},
year = {Tue Feb 26 00:00:00 EST 2019},
month = {Tue Feb 26 00:00:00 EST 2019}
}
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Figure 1: Representative images of the fluorescein-labeled ACB-PCR products on a polyacrylamide gel are shown for PIK3CA codon 1047 CAT!CGT (H1047R) (a). The pixel intensities of the bands produced from the standards were quantified and used to construct a standard curve relating pixel intensity to MF (b). The standard curvemore »
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Works referencing / citing this record:
Rationale and Roadmap for Developing Panels of Hotspot Cancer Driver Gene Mutations as Biomarkers of Cancer Risk
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