Title: Assessment of Clonal Expansion Using CarcSeq Measurement of Lung Cancer Driver Mutations and Correlation With Mouse Strain- and Sex-Related Incidence of Spontaneous Lung Neoplasia

Abstract

Abstract Quantification of variation in levels of spontaneously occurring cancer driver mutations (CDMs) was developed to assess clonal expansion and predict future risk of neoplasm development. Specifically, an error-corrected next-generation sequencing method, CarcSeq, and a mouse CarcSeq panel (analogous to human and rat panels) were developed and used to quantify low-frequency mutations in a panel of amplicons enriched in hotspot CDMs. Mutations in a subset of panel amplicons, Braf, Egfr, Kras, Stk11, and Tp53, were related to incidence of lung neoplasms at 2 years. This was achieved by correlating median absolute deviation (MAD) from the overall median mutant fraction (MF) measured in the lung DNA of 16-week-old male and female, B6C3F1 and CD-1 mice (10 mice/sex/strain) with percentages of spontaneous alveolar/bronchioloalveolar adenomas and carcinomas reported in bioassay control groups. A total of 1586 mouse lung mutants with MFs >1 × 10−4 were recovered. The ratio of nonsynonymous to synonymous mutations was used to assess the proportion of recovered mutations conferring a positive selective advantage. The greatest ratio was observed in what is considered the most lung tumor-sensitive model examined, male B6C3F1 mice. Of the recurrent, nonsynonymous mouse mutations recovered, 55.5% have been reported in human tumors, with many located inmore » or around the mouse equivalent of human cancer hotspot codons. MAD for the same subset of amplicons measured in normal human lung DNA samples showed a correlation of moderate strength and borderline significance with age (a cancer risk factor), as well as age-related cumulative lung cancer risk, suggesting MAD may inform species extrapolation.« less

Authors:

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

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+ Show Author Affiliations

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

Publication Date:

Mon Aug 09 00:00:00 EDT 2021

Sponsoring Org.:

USDOE

OSTI Identifier:

1814548

Resource Type:

Publisher's Accepted Manuscript

Journal Name:

Toxicological Sciences

Additional Journal Information:

Journal Name: Toxicological Sciences; Journal ID: ISSN 1096-6080

Publisher:

Oxford University Press

Country of Publication:

United States

Language:

English