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. |
| 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 |
| Issue: | 1 |
| ISSN: | 2397768X |
| Publisher: | Elsevier B.V. |
| Date Published: | 2025-01-01 |
| Start Page: | 277 |
| Language: | English |
| DOI: | 10.1038/s41698-025-01045-x |
| PROVIDER: | scopus |
| PMCID: | PMC12331897 |
| PUBMED: | 40775459 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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