Vougiouklakis Theodore, Vanderbilt Chad, Rana Satshil, Mohanty Abhinita, Pareja Fresia, Brogi Edi, Schwartz Christopher, Arcila Maria E, Ladanyi Marc, Wen Hanna Y, Ross Dara S
Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
NPJ Precis Oncol. 2025 Aug 8;9(1):277. doi: 10.1038/s41698-025-01045-x.
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.
肿瘤突变负荷（TMB）已成为新抗原负荷的潜在替代指标和免疫检查点（IC）阻断反应的指标；然而，其在乳腺癌（BC）中的精确意义尚未完全明确。在此，我们全面表征了TMB≥10个突变/Mb的乳腺癌（TMB高 [n = 527]）的基因组图谱，以确定重要的推定预测因子。64.7%的肿瘤中主要的突变特征是载脂蛋白B mRNA编辑酶催化多肽（APOBEC）。TMB高的乳腺癌在KMT2C、ARID1A、PTEN、NF1和RB1改变中富集，这些改变与APOBEC诱变有关。进一步鉴定出功能缺失的ARID1A和PTEN改变，它们与免疫细胞排除有关。ESR1 p.E380Q在所有ESR1热点突变中占主导地位，支持APOBEC介导的效应。最后，DNA损伤反应和修复基因中的突变出现频率高于非TMB高的乳腺癌。这些发现为探索联合药物抑制以提高基于IC的疗效提供了依据。
