Objective: There are many hereditary breast cancer patients in China, and multigene panel testing has been a new paradigm ofgenetic testing for these patients and their relatives. However, the magnitude of breast cancer risks related to multiple breast cancersusceptibility genes are largely unknown in Chinese women. Methods: We screened pathogenic variants in 15 established or potential breast cancer susceptibility genes from 8,067 consecutiveChinese female breast cancer patients and 13,129 Chinese cancer-free female controls. These breast cancer patients were unselectedfor age at diagnosis or family history. Results: We found that pathogenic variants in TP53 [odds ratio (OR): 16.9, 95% confidence interval (CI): 5.2–55.2]; BRCA2 (OR:10.4, 95% CI: 7.6–14.2); BRCA1 (OR: 9.7, 95% CI: 6.3–14.8); and PALB2 (OR: 5.2, 95% CI: 3.0–8.8) were associated with a highrisk of breast cancer. ATM, BARD1, CHEK2, and RAD51D were associated with a moderate risk of breast cancer with ORs rangingfrom 2-fold to 4-fold. In contrast, pathogenic variants of NBN, RAD50, BRIP1, and RAD51C were not associated with increasedrisk of breast cancer in Chinese women. The pathogenic variants of PTEN, CDH1, and STK11 were very rare, so they had a limitedcontribution to Chinese breast cancer. Patients with pathogenic variants of TP53, BRCA1, BRCA2, and PALB2 more often had earlyonsetbreast cancer, bilateral breast cancer, and a family history of breast cancer and/or any cancer. Conclusions: This study provided breast cancer risk assessment data for multiple genes in Chinese women, which is useful for genetictesting and clinical management of Chinese hereditary breast cancer.

Parthanatos, a novel form of programmed cell death mediated by PARP1 and driven by DNA damage, has not been comprehensively characterized in breast cancer (BC). Given the widespread clinical use of PARP1 inhibitors for treating BRCA-mutant breast cancers, understanding the role of parthanatos is crucial. In this study, we systematically analyzed the role and clinical significance of parthanatos in BC by integrating genomic, transcriptomic, and clinical data. Our analysis revealed significant differential expression of parthanatos-related genes between BC and normal breast tissues, with frequent copy number variations (CNVs) affecting gene expression. At the single-cell level, parthanatos-related genes were primarily expressed in breast cancer cells and macrophages, and genomic instability scores were positively correlated with parthanatos pathway scores. Unsupervised clustering identified two BC subtypes based on parthanatos-related gene expression: C1 (parthanatos-high) and C2 (parthanatos-low). C1 exhibited a poorer prognosis, reduced immune infiltration, and potential resistance to PARP inhibitors compared to C2. This study represents the first comprehensive investigation of parthanatos in BC, offering insights into its role in tumor progression and highlighting its potential link to PARP inhibitor resistance and poor clinical outcomes.

Background: S-Phase kinase associated protein 2 (SKP2) is a key regulator of the cell cycle and proliferation linked to cancer development. Our recent study has revealed that knocking out Skp2 in a mouse model significantly activates anti-tumor immunity. Although several studies have examined SKP2 in relation to the tumor immune microenvironment using public datasets, a comprehensive pan-cancer evaluation that integrates multi-omics layers and in vivo validation has remained limited. Methods: In this study, we integrated multi-omics data from diverse public datasets to comprehensively analyze SKP2 expression characteristics and its relationship to tumor immunity across pan-cancer. A multiplex immunofluorescence assay was performed on tumors from Skp2 knockout and Skp2-intact mouse models for validation. Results: Our findings indicate that SKP2 is overexpressed in various cancer types, leading to poor prognosis. Single-cell transcriptomic analyses further revealed that SKP2 is predominantly expressed in malignant and immune cells. Notably, a multiplex immunofluorescence assay on tumors from Skp2 knockout and Skp2-intact mouse models and pan-cancer data unveiled a correlation between SKP2 and the “immune-cold” microenvironment, which, possibly linked to the weakened antigen presentation, reduced secretion of chemokines in SKP2-overexpressing cancers. Additionally, we observed that SKP2 overexpression predicts worse immunotherapy efficacy. Conclusion: Our findings provide novel insights into the role of SKP2 in regulating the tumor immune microenvironment, suggesting targeting SKP2 as a promising strategy to enhance immunotherapy efficacy in pan-cancer settings.

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.

The long-held paradigm of solid tumors as sterile entities has been revised by the advent of advanced molecular profiling technologies, including high-throughput sequencing, spatial transcriptomics, and integrated multi-omics. These innovations have revealed tumors as dynamic, polymicrobial ecosystems, colonized by diverse communities of bacteria, fungi, viruses, and archaea. Intratumoral microbial communities display cancer-type specificity, reside in specialized microniches, and are frequently detected inside malignant and immune cells. Such close interactions enable microbes to regulate tumor development via multiple mechanisms. Microbial metabolites, such as butyrate and indole-3-aldehyde, modify epigenetic patterns, DNA damage control and cellular metabolism, affecting tumor proliferation, immune escape and metastatic capacity. Polymicrobial crosstalk among bacteria, fungi, and viruses further remodels immune cell infiltration and polarization, which modulates tumor responsiveness to chemotherapy, radiotherapy and immune checkpoint blockade. Tissue-resident and circulating microbial nucleic acid signatures act as minimally invasive biomarkers for tumor early diagnosis, prognostic assessment and patient stratification. Translational studies cover antimicrobials, engineered probiotics, bacteriophage treatments, metabolite analogs and intratumoral microbiota transplantation to improve therapeutic outcomes. Nevertheless, the field faces pressing challenges—including standardizing low-biomass sampling and sequencing workflows, robustly decontaminating data, establishing causal microbe–tumor relationships, integrating host and microbial multi-omics, and navigating regulatory and ethical frameworks. Addressing these hurdles through longitudinal cohort studies, rigorous mechanistic modeling, and cross-disciplinary collaboration will be essential to harness the tumor microbiome’s full potential and usher in a new epoch of microbiome-informed precision oncology.

Background: This study aimed to quantify the frequency and imaging features of new CT-detected pulmonary abnormalities during breast cancer chemotherapy and examine their associations with cumulative cyclophosphamide and paclitaxel exposure. Methods: This single-center retrospective study included 223 patients who underwent an on-treatment chest CT under an early-pandemic infection-control policy. New CT-detected pulmonary abnormalities were defined as new findings on this on-treatment CT that were absent on the pretreatment staging CT. Cumulative cyclophosphamide (C) and paclitaxel (T) doses (mg/m²) were calculated from treatment cycles before the on-treatment CT and dichotomized at 1800 and 960 mg/m², respectively. Associations were assessed using Firth-penalized logistic regression. Results: New CT-detected pulmonary abnormalities were identified in 34/223 patients (15.2%). Among 25 CT-positive cases with sufficiently detailed CT reports, patchy opacities (14/25, 56.0%) and ground-glass opacities (11/25, 44.0%) were the most frequent findings. Compared with patients with low cyclophosphamide and paclitaxel-equivalent exposure, combined exposure categories showed higher odds of the CT-detected outcome. In the Firth model, cyclophosphamide > 1800 mg/m² was associated with the CT-detected outcome (adjusted odds ratio (OR) 2.38, 95% CI 1.06–5.71; p = 0.036), whereas paclitaxel-equivalent exposure > 960 mg/m² (OR 2.46, 95% CI 0.86–6.80; p = 0.092) and age ≥ 60 years (OR 2.08, 95% CI 0.91–4.62; p = 0.083) were not statistically significant. Conclusions: New CT-detected pulmonary abnormalities were common during breast cancer chemotherapy (15.2%). Higher cumulative cyclophosphamide exposure was associated with the CT-detected outcome in multivariable analysis. Prospective longitudinal studies are needed to clarify the clinical significance of these abnormalities and their causality.