Comparative analysis of distinct genomic landscapes in young-onset gBRCA1/2 breast cancer

Q: What was the main goal of the study?

To define pretreatment genomic landscapes in young-onset gBRCA-associated breast cancer and compare differences between gBRCA1 and gBRCA2 tumors with potential therapeutic implications.

Q: How were tumors analyzed in the study?

Whole-exome sequencing was used to evaluate somatic variation, allele-specific loss of heterozygosity (asLOH), homologous recombination deficiency (HRD), and single-base substitution (SBS) signatures.

Q: What key genomic differences were observed between gBRCA1 and gBRCA2 tumors?

Both showed high asLOH rates, but gBRCA1 and gBRCA2 differed significantly in average HRD scores and in the median SBS composition across signatures SBS1, SBS18, and SBS3.

Sep 22, 2026

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Carriers of germline BRCA1/2 pathogenic variants (gBRCA1/2 PVs) face elevated young-onset breast cancer risk. To characterize pretreatment genomic landscapes, 136 treatment-naive young-onset gBRCA-associated tumors from the prospective POSH study were compared with 66 noncarriers from The Cancer Genome Atlas. Whole-exome sequencing assessed somatic variation, asLOH, HRD, and SBS signatures. gBRCA1 and gBRCA2 cancers differed in HRD scores and SBS composition, with gBRCA1 asLOH tumors enriched for ROS, DNA repair, and EMT pathways, and ER+ HER2- tumors showing alterations linked to CDK4/6 inhibitor resistance, supporting trials contrasting gBRCA1 vs gBRCA2 and PARPi vs CDK4/6i.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Introduction

Background on BRCA1/2 and young-onset risk

Prior genomic differences and limitations

Therapeutic relevance of PARP and CDK4/6 inhibitors

RESE AR CH ARTICLE Copyright: © 2026, Akamandisa et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. Submitted: December 8, 2025 Accepted: April 21, 2026 Published: April 28, 2026 Reference information: JCI Insight. 2026;11(12):e203005 . [https://doi.org/10.1172/jci](https://doi.org/10.1172/jci). insight.203005 . Comparative analysis of distinct genomic landscapes in young-onset gBRCA1/2 breast cancer Mwangala P. Akamandisa,1,2 Mingyi Xia,1 Wilson Cheah,3 Bradley Wubbenhorst,1 Kurt P. D’Andrea,1 Mengyao Fan,1 Jake S. Shilan,1 Dana Pueschl,1 Anupma Nayak,4 Hayley McKenzie,3 William Tapper,3 Ellen R. Copson,3 Ramsey I. Cutress,3 Susan M. Domchek,2,5,6 Diana M. Eccles,3 and Katherine L. Nathanson1,2,6 1Division of Translational Medicine and Human Genetics and 2Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 3University of Southampton, Southampton, United Kingdom. 4Department of Pathology and Laboratory Medicine, 5Division of Hematology and Oncology, and 6Basser Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Carriers of germline BRCA1/2 pathogenic variants (gBRCA1/2 PVs) have elevated young-onset breast cancer risk. To define the pretreatment genomic landscapes of young-onset gBRCAassociated 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 wholeexome 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 (ROSassociated), and SBS3 (HRD-associated). Compared with gBRCA2 tumors, gBRCA1 tumors with asLOH were significantly enriched for alterations in hallmark ROS, DNA repair, and epithelialmesenchymal transition pathways. In ER-positive, HER2-negative tumors from gBRCA1/2 carriers compared with noncarriers, we found significant enrichment of RB1, TP53, FAT1, and MYC singlenucleotide variants, indels, and copy number variants associated with CDK4/6 inhibitor (CDK4/6i) resistance. Together, these findings demonstrate significant differences between gBRCA1-and gBRCA2-associated breast cancers, and preexisting CDK4/6i resistance mechanisms, supporting prospective trials comparing individualized therapy for gBRCA1 versus gBRCA2 carriers and comparing poly(ADP-ribose) polymerase inhibitors versus CDK4/6i for ER-positive gBRCA1/2-associated breast cancer. Introduction Approximately 12% of young-onset breast cancer patients (first diagnosis at age ≤40 years) and 30% of veryyoung-onset breast cancer patients (first diagnosis at age ≤30 years) carry germline BRCA1 or BRCA2 pathogenic variants (gBRCA1/2 PV) (1–4) . gBRCA1/2 PV carriers have an elevated lifetime breast cancer risk of 60%–80%(5–9) . The Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer (POSH) is a prospective cohort study investigating differences in outcomes between hereditary (gBRCA1/2-associated) and sporadic young-onset breast cancer (10) . Enrollment of more than 2,700 women diagnosed with breast cancer at age ≤40 (<50 if a known gBRCA1/2 PV carrier) was performed in the United Kingdom between 2000 and 2008. The study demonstrated a 5-year survival advantage but no survival difference by year 8 after diagnosis for women with estrogen receptor–positive (ER-positive) breast cancer compared with those with ER-negative disease and similar overall survival (OS) between young-onset female breast cancer patients with and without gBRCA1/2 PVs (3, 11) . Genomic features such as allele-specific loss of heterozygosity (asLOH) w

FAQs

What was the main goal of the study?

To define pretreatment genomic landscapes in young-onset gBRCA-associated breast cancer and compare differences between gBRCA1 and gBRCA2 tumors with potential therapeutic implications.

How were tumors analyzed in the study?

Whole-exome sequencing was used to evaluate somatic variation, allele-specific loss of heterozygosity (asLOH), homologous recombination deficiency (HRD), and single-base substitution (SBS) signatures.

What key genomic differences were observed between gBRCA1 and gBRCA2 tumors?

Both showed high asLOH rates, but gBRCA1 and gBRCA2 differed significantly in average HRD scores and in the median SBS composition across signatures SBS1, SBS18, and SBS3.

Sep 22, 2026

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