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To define the pretreatment genomic landscapes of young-onset g\n                    <jats:italic>BRCA<\/jats:italic>\n                    -associated breast cancer, we evaluated 136 treatment-naive tumors diagnosed before age 50 in the prospective POSH study and 66 noncarriers from The Cancer Genome Atlas. Using whole-exome sequencing, we analyzed somatic variation, allele-specific loss of heterozygosity (asLOH), homologous recombination deficiency (HRD), and single-base substitution (SBS) signatures. gBRCA1 and gBRCA2 breast cancers had high rates of asLOH but differed significantly in average HRD scores and median SBS composition of signatures SBS1 (aging-associated), SBS18 (ROS-associated), and SBS3 (HRD-associated). Compared with g\n                    <jats:italic>BRCA2<\/jats:italic>\n                    tumors, g\n                    <jats:italic>BRCA1<\/jats:italic>\n                    tumors with asLOH were significantly enriched for alterations in hallmark ROS, DNA repair, and epithelial-mesenchymal transition pathways. In ER-positive, HER2-negative tumors from g\n                    <jats:italic>BRCA1\/2<\/jats:italic>\n                    carriers compared with noncarriers, we found significant enrichment of\n                    <jats:italic>RB1<\/jats:italic>\n                    ,\n                    <jats:italic>TP53<\/jats:italic>\n                    ,\n                    <jats:italic>FAT1<\/jats:italic>\n                    , and\n                    <jats:italic>MYC<\/jats:italic>\n                    single-nucleotide variants, indels, and copy number variants associated with CDK4\/6 inhibitor (CDK4\/6i) resistance. Together, these findings demonstrate significant differences between g\n                    <jats:italic>BRCA1<\/jats:italic>\n                    - and g\n                    <jats:italic>BRCA2<\/jats:italic>\n                    -associated breast cancers, and preexisting CDK4\/6i resistance mechanisms, supporting prospective trials comparing individualized therapy for g\n                    <jats:italic>BRCA1<\/jats:italic>\n                    versus g\n                    <jats:italic>BRCA2<\/jats:italic>\n                    carriers and comparing poly(ADP-ribose) polymerase inhibitors versus CDK4\/6i for ER-positive g\n                    <jats:italic>BRCA1\/2<\/jats:italic>\n                    -associated breast cancer.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.203005","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T16:00:42Z","timestamp":1777392042000},"source":"Crossref","is-referenced-by-count":1,"title":["Comparative 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