Synapse - Genomic characterization of tumor mutational burden-high breast carcinomas

Genomic characterization of tumor mutational burden-high breast carcinomas Journal Article

Authors:	Vougiouklakis, T.; Vanderbilt, C.; Rana, S.; Mohanty, A.; Pareja, F.; Brogi, E.; Schwartz, C.; Arcila, M. E.; Ladanyi, M.; Wen, H. Y.; Ross, D. S.
Article Title:	Genomic characterization of tumor mutational burden-high breast carcinomas
Abstract:	Tumor mutational burden (TMB) has emerged as a potential surrogate for neoantigen load and an indicator of immune checkpoint (IC)-blockade response; however, its precise significance in breast cancer (BC) is not fully understood. Here, we comprehensively characterized the genomic repertoire of BCs with a TMB ≥ 10 mut/Mb (TMB-high [n = 527]) to identify putative predictors of importance. The predominant mutational signature was apolipoprotein B mRNA-editing enzyme catalytic polypeptide (APOBEC) in 64.7% of tumors. TMB-high BCs were enriched in KMT2C, ARID1A, PTEN, NF1, and RB1 alterations, which are associated with APOBEC mutagenesis. Further identified were loss-of-function ARID1A and PTEN alterations, which are linked to immune cell exclusion. ESR1 p.E380Q prevailed among all ESR1 hotspot mutations, supporting APOBEC-mediated effects. Finally, mutations in DNA damage response and repair genes were seen at a higher frequency than in non-TMB-high BCs. These findings provide justification for exploring combined pharmacologic inhibition to improve IC-based efficacy. © 2025 Elsevier B.V., All rights reserved.
Keywords:	immunohistochemistry; adult; controlled study; human tissue; aged; gene mutation; major clinical study; missense mutation; gene; dna repair; cohort analysis; retrospective study; dna; messenger rna; breast carcinoma; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; dna damage response; mutagenesis; rb1 gene; retinoblastoma binding protein 2; nf1 gene; human; male; female; article; oncogenomics; apolipoprotein b mrna editing enzyme catalytic polypeptide like; tumor mutational burden; kmt2c gene
Journal Title:	npj Precision Oncology
Volume:	9
ISSN:	2397-768X
Publisher:	Springer Nature
Date Published:	2025-08-08
Start Page:	277
Language:	English
DOI:	10.1038/s41698-025-01045-x
PROVIDER:	scopus
PMCID:	PMC12331897
PUBMED:	40775459
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-105012768122&doi=10.1038%2Fs41698-025-01045-x&partnerID=40&md5=ff8757db788fc096538c8d1ef816d0d6
Notes:	Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Dara Ross -- Source: Scopus