CarcSeq Measurement of Rat Mammary Cancer Driver Mutations and Relation to Spontaneous Mammary Neoplasia

McKim, Karen L.; Myers, Meagan B.; Harris, Kelly L.; Gong, Binsheng; Xu, Joshua; Parsons, Barbara L.

doi:10.1093/toxsci/kfab040

CarcSeq Measurement of Rat Mammary Cancer Driver Mutations and Relation to Spontaneous Mammary Neoplasia

Journal Article · Fri Apr 02 00:00:00 EDT 2021 · Toxicological Sciences

DOI:https://doi.org/10.1093/toxsci/kfab040· OSTI ID:1808361

McKim, Karen L. ^[1]; Myers, Meagan B. ^[1]; Harris, Kelly L. ^[1]; Gong, Binsheng ^[2]; Xu, Joshua ^[2]; ^[1]

Division of Genetic and Molecular Toxicology
Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas 72079, USA

Abstract

The ability to deduce carcinogenic potential from subchronic, repeat dose rodent studies would constitute a major advance in chemical safety assessment and drug development. This study investigated an error-corrected NGS method (CarcSeq) for quantifying cancer driver mutations (CDMs) and deriving a metric of clonal expansion predictive of future neoplastic potential. CarcSeq was designed to interrogate subsets of amplicons encompassing hotspot CDMs applicable to a variety of cancers. Previously, normal human breast DNA was analyzed by CarcSeq and metrics based on mammary-specific CDMs were correlated with tissue donor age, a surrogate of breast cancer risk. Here we report development of parallel methodologies for rat. The utility of the rat CarcSeq method for predicting neoplastic potential was investigated by analyzing mammary tissue of 16-week-old untreated rats with known differences in spontaneous mammary neoplasia (Fischer 344, Wistar Han, and Sprague Dawley). Hundreds of mutants with mutant fractions ≥ 10−4 were quantified in each strain, most were recurrent mutations, and 42.5% of the nonsynonymous mutations have human homologs. Mutants in the mammary-specific target of the most tumor-sensitive strain (Sprague Dawley) showed the greatest nonsynonymous/synonymous mutation ratio, indicative of positive selection consistent with clonal expansion. For the mammary-specific target (Hras, Pik3ca, and Tp53 amplicons), median absolute deviation correlated with percentages of rats that develop spontaneous mammary neoplasia at 104 weeks (Pearson r = 1.0000, 1-tailed p = .0010). Therefore, this study produced evidence CarcSeq analysis of spontaneously occurring CDMs can be used to derive an early metric of clonal expansion relatable to long-term neoplastic outcome.

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Sponsoring Organization:: USDOE

OSTI ID:: 1808361

Journal Information:: Toxicological Sciences, Journal Name: Toxicological Sciences Journal Issue: 1 Vol. 182; ISSN 1096-6080

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United States

Language:: English

References (36)

Oncomutations as biomarkers of cancer risk Parsons, Barbara L.; Myers, Meagan B.; Meng, Fanxue Environmental and Molecular Mutagenesis, Vol. 51, Issue 8-9 https://doi.org/10.1002/em.20600	journal	August 2010
Mechanisms of DNA damage, repair, and mutagenesis: DNA Damage and Repair Chatterjee, Nimrat; Walker, Graham C. Environmental and Molecular Mutagenesis, Vol. 58, Issue 5 https://doi.org/10.1002/em.22087	journal	May 2017
Variation in organ-specific PIK3CA and KRAS mutant levels in normal human tissues correlates with mutation prevalence in corresponding carcinomas: Tissue-Specific Properties of Hotspot Cancer-Driver Mutations Parsons, Barbara L.; McKim, Karen L.; Myers, Meagan B. Environmental and Molecular Mutagenesis, Vol. 58, Issue 7 https://doi.org/10.1002/em.22110	journal	July 2017
Rationale and Roadmap for Developing Panels of Hotspot Cancer Driver Gene Mutations as Biomarkers of Cancer Risk Harris, Kelly L.; Myers, Meagan B.; McKim, Karen L. Environmental and Molecular Mutagenesis, Vol. 61, Issue 1 https://doi.org/10.1002/em.22326	journal	October 2019
Next‐Generation Genotoxicology: Using Modern Sequencing Technologies to Assess Somatic Mutagenesis and Cancer Risk Salk, Jesse J.; Kennedy, Scott R. Environmental and Molecular Mutagenesis, Vol. 61, Issue 1 https://doi.org/10.1002/em.22342	journal	November 2019
Quantification of cancer driver mutations in human breast and lung DNA using targeted, error‐corrected CarcSeq Harris, Kelly L.; Walia, Vijay; Gong, Binsheng Environmental and Molecular Mutagenesis, Vol. 61, Issue 9 https://doi.org/10.1002/em.22409	journal	September 2020
A subset of papillary thyroid carcinomas contain KRAS mutant subpopulations at levels above normal thyroid: KRAS MUTANT FRACTION IN PAPILLARY THYROID TUMORS Myers, Meagan B.; McKim, Karen L.; Parsons, Barbara L. Molecular Carcinogenesis, Vol. 53, Issue 2 https://doi.org/10.1002/mc.21953	journal	August 2012
Prospects for applying genotypic selection of somatic oncomutation to chemical risk assessment McKinzie, P. Mutation Research/Reviews in Mutation Research, Vol. 489, Issue 1 https://doi.org/10.1016/S1383-5742(01)00063-1	journal	October 2001
Universal Patterns of Selection in Cancer and Somatic Tissues Martincorena, Iñigo; Raine, Keiran M.; Gerstung, Moritz Cell, Vol. 171, Issue 5 https://doi.org/10.1016/j.cell.2017.09.042	journal	November 2017
Clonal Expansion and Diversification of Cancer-Associated Mutations in Endometriosis and Normal Endometrium Suda, Kazuaki; Nakaoka, Hirofumi; Yoshihara, Kosuke Cell Reports, Vol. 24, Issue 7 https://doi.org/10.1016/j.celrep.2018.07.037	journal	August 2018
Ultra-Sensitive TP53 Sequencing for Cancer Detection Reveals Progressive Clonal Selection in Normal Tissue over a Century of Human Lifespan Salk, Jesse J.; Loubet-Senear, Kaitlyn; Maritschnegg, Elisabeth Cell Reports, Vol. 28, Issue 1 https://doi.org/10.1016/j.celrep.2019.05.109	journal	July 2019
Changing the field of carcinogenicity testing of human pharmaceuticals by emphasizing mode of action van der Laan, Jan Willem; Duijndam, Britt; van den Hoorn, Tineke Current Opinion in Toxicology, Vol. 3 https://doi.org/10.1016/j.cotox.2017.06.004	journal	April 2017
Breast Cancer Heterogeneity Examined by High-Sensitivity Quantification of PIK3CA, KRAS, HRAS, and BRAF Mutations in Normal Breast and Ductal Carcinomas Myers, Meagan B.; Banda, Malathi; McKim, Karen L. Neoplasia, Vol. 18, Issue 4 https://doi.org/10.1016/j.neo.2016.03.002	journal	April 2016
MATH, a novel measure of intratumor genetic heterogeneity, is high in poor-outcome classes of head and neck squamous cell carcinoma Mroz, Edmund A.; Rocco, James W. Oral Oncology, Vol. 49, Issue 3 https://doi.org/10.1016/j.oraloncology.2012.09.007	journal	March 2013
The stability of historical control data for common neoplasms in laboratory rats: adrenal gland (medulla), mammary gland, liver, endocrine pancreas, and pituitary gland Tennekes, Henk; Gembardt, Christian; Dammann, Martina Regulatory Toxicology and Pharmacology, Vol. 40, Issue 1 https://doi.org/10.1016/j.yrtph.2004.04.003	journal	August 2004
Evaluation of carcinogenicity studies of medicinal products for human use authorised via the European centralised procedure (1995–2009) Friedrich, Anita; Olejniczak, Klaus Regulatory Toxicology and Pharmacology, Vol. 60, Issue 2 https://doi.org/10.1016/j.yrtph.2011.04.001	journal	July 2011
A cross-sector call to improve carcinogenicity risk assessment through use of genomic methodologies Yauk, Carole L.; Harrill, Alison H.; Ellinger-Ziegelbauer, Heidrun Regulatory Toxicology and Pharmacology, Vol. 110 https://doi.org/10.1016/j.yrtph.2019.104526	journal	February 2020
Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults Young, Andrew L.; Challen, Grant A.; Birmann, Brenda M. Nature Communications, Vol. 7, Issue 1 https://doi.org/10.1038/ncomms12484	journal	August 2016
Detecting ultralow-frequency mutations by Duplex Sequencing Kennedy, Scott R.; Schmitt, Michael W.; Fox, Edward J. Nature Protocols, Vol. 9, Issue 11 https://doi.org/10.1038/nprot.2014.170	journal	October 2014
Enhancing the accuracy of next-generation sequencing for detecting rare and subclonal mutations Salk, Jesse J.; Schmitt, Michael W.; Loeb, Lawrence A. Nature Reviews Genetics, Vol. 19, Issue 5 https://doi.org/10.1038/nrg.2017.117	journal	March 2018
The COSMIC Cancer Gene Census: describing genetic dysfunction across all human cancers Sondka, Zbyslaw; Bamford, Sally; Cole, Charlotte G. Nature Reviews Cancer, Vol. 18, Issue 11 https://doi.org/10.1038/s41568-018-0060-1	journal	October 2018
Age-related remodelling of oesophageal epithelia by mutated cancer drivers Yokoyama, Akira; Kakiuchi, Nobuyuki; Yoshizato, Tetsuichi Nature, Vol. 565, Issue 7739 https://doi.org/10.1038/s41586-018-0811-x	journal	January 2019
The mutational landscape of normal human endometrial epithelium Moore, Luiza; Leongamornlert, Daniel; Coorens, Tim H. H. Nature, Vol. 580, Issue 7805 https://doi.org/10.1038/s41586-020-2214-z	journal	April 2020
The mutational signature profile of known and suspected human carcinogens in mice Riva, Laura; Pandiri, Arun R.; Li, Yun Rose Nature Genetics, Vol. 52, Issue 11 https://doi.org/10.1038/s41588-020-0692-4	journal	September 2020
Only three driver gene mutations are required for the development of lung and colorectal cancers Tomasetti, Cristian; Marchionni, Luigi; Nowak, Martin A. Proceedings of the National Academy of Sciences, Vol. 112, Issue 1 https://doi.org/10.1073/pnas.1421839112	journal	December 2014
N-nitroso-N-methylurea-induced rat mammary tumors arise from cells with preexisting oncogenic Hras1 gene mutations. Cha, R. S.; Thilly, W. G.; Zarbl, H. Proceedings of the National Academy of Sciences, Vol. 91, Issue 9 https://doi.org/10.1073/pnas.91.9.3749	journal	April 1994
ACB-PCR Quantification of K- RAS Codon 12 GAT and GTT Mutant Fraction in Colon Tumor and Non-Tumor Tissue Parsons, Barbara L.; Marchant-Miros, Kathryn E.; Delongchamp, Robert R. Cancer Investigation, Vol. 28, Issue 4 https://doi.org/10.1080/07357901003630975	journal	April 2010
Temporal Changes in K-ras Mutant Fraction in Lung Tissue of Big Blue B6C3F1 Mice Exposed to Ethylene Oxide Parsons, Barbara L.; Manjanatha, Mugimane G.; Myers, Meagan B. Toxicological Sciences, Vol. 136, Issue 1 https://doi.org/10.1093/toxsci/kft190	journal	September 2013
High burden and pervasive positive selection of somatic mutations in normal human skin Martincorena, I.; Roshan, A.; Gerstung, M. Science, Vol. 348, Issue 6237 https://doi.org/10.1126/science.aaa6806	journal	May 2015
Somatic mutation in cancer and normal cells Martincorena, I.; Campbell, P. J. Science, Vol. 349, Issue 6255 https://doi.org/10.1126/science.aab4082	journal	September 2015
Somatic mutant clones colonize the human esophagus with age Martincorena, Iñigo; Fowler, Joanna C.; Wabik, Agnieszka Science, Vol. 362, Issue 6417 https://doi.org/10.1126/science.aau3879	journal	October 2018
Comparison of NTP Historical Control Tumor Incidence Rates in Female Harlan Sprague Dawley and Fischer 344/N Rats Dinse, Gregg E.; Peddada, Shyamal D.; Harris, Shawn F. Toxicologic Pathology, Vol. 38, Issue 5 https://doi.org/10.1177/0192623310373777	journal	July 2010
A Critical Review of the Effectiveness of Rodent Pharmaceutical Carcinogenesis Testing in Predicting for Human Risk Alden, C. L.; Lynn, A.; Bourdeau, A. Veterinary Pathology, Vol. 48, Issue 3 https://doi.org/10.1177/0300985811400445	journal	March 2011
Low-frequency KRAS mutations are prevalent in lung adenocarcinomas Myers, Meagan B.; McKim, Karen L.; Meng, Fanxue Personalized Medicine, Vol. 12, Issue 2 https://doi.org/10.2217/pme.14.69	journal	March 2015
Selective Pressures on Human Cancer Genes along the Evolution of Mammals Vicens, Alberto; Posada, David Genes, Vol. 9, Issue 12 https://doi.org/10.3390/genes9120582	journal	November 2018
Low-Frequency Mutational Heterogeneity of Invasive Ductal Carcinoma Subtypes: Information to Direct Precision Oncology Myers, Meagan; McKim, Karen; Banda, Malathi International Journal of Molecular Sciences, Vol. 20, Issue 5 https://doi.org/10.3390/ijms20051011	journal	February 2019

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