{"doi":"10.1002/em.70027","title":"Tissue and Sex‐Specific Performance of a Cancer Driver Based Biomarker in <scp>rasH2</scp> ‐Tg Mice","abstract":"The ability to predict rodent lifetime tumor responses from short-term exposures and a scientific basis for rodent to human extrapolation are unmet needs in cancer risk assessment. To address these needs, quantitation of cancer driver mutations (CDMs) was integrated with an error-corrected, next generation sequencing (NGS) approach. The method developed, CarcSeq, involves performing multiple, high-fidelity PCR reactions to amplify hotspot CDM-containing target sequences, tagging amplicons with 9 base unique identifier sequences, and constructing libraries from the pooled amplicons. Single-strand consensus sequences were constructed for error correction. A metric of variability in CDM levels, median absolute deviation in mutant fraction (MAD), is being developed as a biomarker of clonal expansion. This study leveraged the sex-related difference in spontaneous lung tumor development in the rasH2-Tg mouse model to validate and refine the CarcSeq approach for assessing clonal expansion. Significantly greater MAD was observed in male as compared to female rasH2-Tg mice, along with more recurrent mutations and a higher proportion of mutations conferring a potentially selectable phenotype in males, consistent with the greater propensity for spontaneous lung tumorigenesis in males. In the analysis of MAD, use of a sex-specific median and classification of lung-specific drivers based on a COSMIC-reported mutation frequency ≥ 5% performed better than use of the overall median MF and classification based on COSMIC's top ranked lung neoplasia genes. Thus, this study provides further validation of the CarcSeq/MAD biomarker approach and technical insight into best practices in evaluating clonal expansion based on measurement of cancer driver gene mutations.","journal":"Environmental and Molecular Mutagenesis","year":2025,"id":528649,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9598,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1091947,"name":"Jennifer Faske","orcid":null,"position":1,"is_corresponding":false},{"id":377043,"name":"Binsheng Gong","orcid":"0000-0002-8724-5435","position":2,"is_corresponding":false},{"id":655698,"name":"Barbara L. Parsons","orcid":"0000-0002-3005-2552","position":3,"is_corresponding":false},{"id":680203,"name":"Kelly L. Harris","orcid":"0000-0002-5134-4829","position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-19T02:50:48.492873Z","pmid":"40799151","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}