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<p>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 [<i>n</i> = 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 <i>KMT2C</i>, <i>ARID1A</i>, <i>PTEN</i>, <i>NF1</i>, and <i>RB1</i> alterations, which are associated with APOBEC mutagenesis. Further identified were loss-of-function <i>ARID1A</i> and <i>PTEN</i> alterations, which are linked to immune cell exclusion. <i>ESR1</i> p.E380Q prevailed among all <i>ESR1</i> 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.</p>

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Genomic characterization of tumor mutational burden-high breast carcinomas

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月8日

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  • Theodore Vougiouklakis,
  • Chad Vanderbilt,
  • Satshil Rana,
  • Abhinita Mohanty,
  • Fresia Pareja,
  • Edi Brogi,
  • Christopher Schwartz,
  • Maria E. Arcila,
  • Marc Ladanyi,
  • Hanna Y. Wen,
  • Dara S. Ross

摘要

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.