Enhancer activation serves as the main mechanism regulating signal-dependent transcriptional programs, ensuring cellular plasticity, yet central questions persist regarding their mechanism of activation. Here, by successfully mapping topoisomerase I–DNA covalent complexes genome-wide, we find that most, if not all, acutely activated enhancers, including those induced by 17β-estradiol, dihydrotestosterone, tumor necrosis factor alpha and neuronal depolarization, are hotspots for topoisomerase I–DNA covalent complexes, functioning as epigenomic signatures read by the classic DNA damage sensor protein, Ku70. Ku70 in turn nucleates a heterochromatin protein 1 gamma (HP1γ)–mediator subunit Med26 complex to facilitate acute, but not chronic, transcriptional activation programs. Together, our data uncover a broad, unappreciated transcriptional code, required for most, if not all, acute signal-dependent enhancer activation events in both mitotic and postmitotic cells.

The prevalence and clinical relevance of pathogenic germline variants in MMR genes have not been investigated in large series of breast cancers. In this study, we screened the germline variants in MMR genes in 8085 consecutive Chinese breast cancer patients, and investigated the MMR/PD-L1 protein expression and tumor mutation burden (TMB) of breast tumors from MMR variant carriers. We found that 15 of 8085 patients (0.19%) carried a pathogenic germline variant in MMR genes. Compared with non-carriers, MMR variant carriers might have worse recurrence-free survival (unadjusted hazard ratios [HR] = 2.70, 95% CI: 1.12–6.49, P = 0.027) and distant recurrence-free survival (unadjusted HR = 3.24, 95% CI: 1.45–7.22, P = 0.004). More importantly, some of the breast cancers from MMR carriers displayed MMR protein loss (5/13), TMB-high (2/10), and PD-L1 positive expression (9/13). This study showed that MMR variant carriers were rare in breast cancer. They might have worse survival and part of them might benefit from immunotherapy.

PURPOSE: Data about the clinical impact of human epidermal growth factor receptor 2 (HER2)–low expression in BRCA1/2 -mutated breast cancer (BC) are limited. This study aimed to clarify the clinical relevance of HER2-low in operable BRCA1/2 -mutated BC. MATERIALS AND METHODS: A total of 495 HER2-negative operable BC with germline BRCA1/2 pathogenic variants treated at our institute between October 2003 and September 2020 were included. HER2-low was defined as immunohistochemistry (IHC) 1+ or 2+/fluorescence in situ hybridization–negative, while HER2-zero as IHC 0. Tumor DNA from 25 BRCA1/2 -mutated triple-negative BCs (TNBCs) was subjected to whole-exome sequencing. RESULTS: Among the 186 BRCA1 carriers, 38.8% of TNBC (n = 121) and 52.3% of hormone receptor–positive/HER2-negative BC (n = 65) exhibited HER2-low tumors in the BRCA1 subgroup; among 309 BRCA2 carriers, 44.9% of TNBC (n = 49) and 68.1% of hormone receptor–positive/HER2-negative BC (n = 260) exhibited HER2-low tumors in the BRCA2 subgroup. After a median follow-up of 10.9 years (range, 1.23-19.8 years), among BRCA1 -mutated TNBC, HER2-low tumors were significantly associated with better recurrence-free survival (RFS; 10-year RFS: 90.3% v 75.1%; P = .015), distant recurrence-free survival (DRFS; 10-year DRFS: 92.4% v 76.5%; P = .010), and overall survival (OS; 10-year OS: 94.6% v 77.4%; P = .007) than HER2-zero tumors. However, the impact of HER2-low in survival was not observed either in BRCA2 -mutated TNBC or in BRCA1- and BRCA2 -mutated hormone receptor–positive/HER2-negative BC. Notably, BRCA1- mutated TNBC with HER2-low tumors showed higher homologous recombination deficiency scores than those with HER2-zero tumors. CONCLUSION: BRCA1 -mutated TNBC patients with HER2-low tumors have a significantly favorable survival, highlighting the possibility of stratifying these patients into two subgroups on the basis of HER2-low status.

Background: The high risk of contralateral breast cancer (CBC) in carriers of germline BRCA1/2 pathogenic variants (PVs) is well established, whereas differences in tumor subtype and risk of CBC between BRCA1 and BRCA2 carriers remain largely unknown. Methods: This cohort study included 738 unselected Chinese patients with breast cancer who carried BRCA1/2 PVs (289 BRCA1 and 449 BRCA2 carriers) and were treated at Peking University Cancer Hospital between October 2003 and August 2021. Tumor subtypes and the cumulative incidence of CBC were analyzed in both BRCA1 and BRCA2 carriers. Results: After a median follow-up of 9.0 years, 52 (18.0%) of 289 BRCA1 carriers and 49 (10.9%) of 449 BRCA2 carriers had developed CBC. The 10-year cumulative incidence of CBC was significantly higher in BRCA1 than in BRCA2 carriers (18.9% vs. 11.7%; p = 0.01). Among patients aged 40 years or younger, the 10-year cumulative incidence of CBC was higher in BRCA1 carriers than in BRCA2 carriers (27.5% vs. 12.5%; p = 0.007; adjusted hazard ratio, 2.58 [95% CI, 1.06–6.29]; p = 0.04). In addition, among BRCA1 carriers who developed CBC, the majority of primary tumors (62.7%) were triple-negative breast cancers (TNBCs). Among these patients with primary TNBC, approximately 77.4% of contralateral breast tumors were also TNBC. In contrast, primary and contralateral tumors in BRCA2 carriers were predominantly hormone receptor-positive (72.9% and 66.7%, respectively). Conclusions:BRCA1 carriers have a higher CBC risk than BRCA2 carriers. TNBC is the predominant phenotype of both primary and subsequent contralateral tumors in BRCA1 carriers. These findings provide useful data to inform the optimal management of CBC risk in BRCA1/2 carriers.

Purpose: To evaluate the pathogenicity of BRCA2 variants of uncertain significance (VUS) located within the functionally critical exons 15–26 using published SGE data, and to reclassify these VUS by integrating clinical phenotypes. Methods: A total of 15,092 breast cancer patients were enrolled in this study, among which 457 distinct BRCA2 VUS were identified in 1051 carriers. Based on SGE scores, 88 BRCA2 VUSs within exons 15–26 were functionally assessed and carriers reclassified as functionally pathogenic, functionally benign, or remaining VUS. Clinicopathological characteristics were subsequently compared across variant groups. Results: Of these 88 evaluated BRCA2 VUSs (187 carriers), 15 were reclassified as functionally pathogenic (20 carriers), 66 as functionally benign (154 carriers), and 7 remained VUS (13 carriers). Compared with non-carriers, carriers with functionally pathogenic variants exhibited a significantly higher prevalence of a family history of any cancer (65.0% vs. 31.1%, p = 0.002), particularly breast and/or ovarian cancer (35.0% vs. 10.0%, p = 0.002), as well as a trend toward a higher incidence of bilateral breast cancer (10.0% vs. 2.4%, p = 0.085). In contrast, individuals harboring functionally benign variants demonstrated clinicopathological characteristics similar to non-carriers. Conclusion: SGE-based functional scoring system provides a reliable approach for reclassifying BRCA2 VUS. When integrated with clinical phenotypes, it enhanced the accuracy of pathogenicity assessment.