Double pathogenic mutations occurring in an individual are considered a rare event. The introduction of a multiple-gene panel at Hong Kong Hereditary Breast Cancer Family Registry has allowed the identification of pathogenic variants in multiple genes, providing more information on clinical management and surveillance to the proband and their family members. Breast cancer patients who are double heterozygous (DH) for different hereditary breast and ovarian cancer syndrome (HBCO)-related genes were identified from a cohort of 3649 Chinese patients. Nine patients (0.25%) were observed to have germline DH mutations in ATM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MSH6, PALB2, and TP53. Three probands were diagnosed with unilateral breast cancer, two patients were diagnosed with bilateral breast cancer, and four patients had multiple primary cancers. The median age for breast cancer diagnosis was an early age of 36 years. Chinese DH carriers did not show worse phenotypes or have a significantly downhill clinical presentation. However, seven out of nine (77.8%) of our DH carriers harbored a BRCA1 mutation, and four of them (44.4%) developed bilateral breast cancer, suggesting Chinese DH individuals may have a higher chance of having bilateral breast cancer than other populations (p = 0.0237).

BACKGROUND: The aim of this study was to assess homologous recombination deficiency (HRD) status and its correlation with carboplatin treatment response in early triple-negative breast cancer (TNBC) patients.
METHODS: Tumor tissues from 225 consecutive TNBC patients were evaluated with an HRD panel and homologous recombination-related (HRR) gene expression data. HRD positivity was defined as a high HRD score and/or BRCA1/2 pathogenic or likely pathogenic mutation. Clinicopathological factors, neoadjuvant treatment response, and prognosis were analyzed with respect to HRD status in these TNBC patients.
RESULTS: HRD positivity was found in 53.3% of patients and was significantly related to high Ki67 levels (P = 0.001). In patients who received neoadjuvant chemotherapy, HRD positivity (P = 0.005) or a high HRD score (P = 0.003) was significantly associated with a greater pathological complete response (pCR) rate, especially in those treated with carboplatin-containing neoadjuvant regimens (HRD positivity vs. negativity: 50.00% vs. 17.65%, P = 0.040). HRD positivity was associated with favorable distant metastasis-free survival (hazard ratio HR 0.49, 95% confidence interval CI 0.26-0.90, P = 0.022) and overall survival (HR 0.45, 95% CI 0.20-0.99, P = 0.049), irrespective of carboplatin treatment.
CONCLUSIONS: TNBC patients with high HRDs had high Ki67 levels and BRCA mutations. HRD-positive TNBC patients treated with carboplatin had a higher pCR rate. Patients with HRD positivity had a better prognosis, irrespective of carboplatin treatment, warranting further evaluation.

BACKGROUND: Recently, genes involved in homologous recombination repair (HRR) pathway have been extensively studied. However, the landscapes of HRR gene mutations remain poorly defined in Chinese high-risk breast cancer (BC) patients. Our study aims to identify the status of germline and somatic HRR gene mutations and their association with clinicopathological features in these patients.
METHODS: A total of 100 high-risk BC patients from our institution who underwent paired peripheral blood germline and BC tissues somatic 26 genes next-generation sequencing (NGS) from January 2018 to July 2023 were enrolled for retrospective analysis.
RESULTS: Out of 100 high-risk BC patients, 55 (55%) had at least one germline or somatic mutation in HRR genes. Among them, 22% carried germline pathogenic variants (19 BRCA1/2 and 3 non-BRCA genes), 9% harbored somatic pathogenic mutations (3 BRCA1/2 and 6 non-BRCA genes). Among high-risk factors, family history and early onset BC showed a correlation with HRR gene mutations (p < 0.05). BRCA1 germline and HRR gene somatic mutations showed a correlation with TNBC, but BRCA2 germline mutations were associated with Luminal B/HER2-negative BC (p < 0.05). Patients with HRR gene somatic pathogenic variant more likely had a lympho-vascular invasion and distant metastasis (p < 0.05).
CONCLUSIONS: The prevalence of HRR gene germline and somatic mutations were higher in Chinese BC patients with high risk factors. We strongly recommend that these high-risk BC patients receive comprehensive gene mutation testing, especially HRR genes, which are not only related to genetic consultation for BC patients and provide a theoretical basis for necessary prevention and individualized treatment.

Lysine methyltransferase 5A (KMT5A) is the sole mammalian enzyme known to catalyse the mono‑methylation of histone H4 lysine 20 and non‑histone proteins such as p53, which are involved in the occurrence and progression of numerous cancers. The present study aimed to determine the function of KMT5A in inducing docetaxel (DTX) resistance in patients with breast carcinoma by evaluating glucose metabolism and the underlying mechanism involved. The upregulation or downregulation of KMT5A‑related proteins was examined after KMT5A knockdown in breast cancer (BRCA) cells by Tandem Mass Tag proteomics. Through differential protein expression and pathway enrichment analysis, the upregulated key gluconeogenic enzyme fructose‑1,6‑bisphosphatase 1 (FBP1) was discovered. Loss of FBP1 expression is closely related to the development and prognosis of cancers. A dual‑luciferase reporter gene assay confirmed that KMT5A inhibited the expression of FBP1 and that overexpression of FBP1 could enhance the chemotherapeutic sensitivity to DTX through the suppression of KMT5A expression. The KMT5A inhibitor UNC0379 was used to verify that DTX resistance induced by KMT5A through the inhibition of FBP1 depended on the methylase activity of KMT5A. According to previous literature and interaction network structure, it was revealed that KMT5A acts on the transcription factor twist family BHLH transcription factor 1 (TWIST1). Then, it was verified that TWSIT1 promoted the expression of FBP1 by using a dual‑luciferase reporter gene experiment. KMT5A induces chemotherapy resistance in BRCA cells by promoting cell proliferation and glycolysis. After the knockdown of the KMT5A gene, the FBP1 related to glucose metabolism in BRCA was upregulated. KMT5A knockdown expression and FBP1 overexpression synergistically inhibit cell proliferation and block cells in the G2/M phase. KMT5A inhibits the expression of FBP1 by methylating TWIST1 and weakening its promotion of FBP1 transcription. In conclusion, KMT5A was shown to affect chemotherapy resistance by regulating the cell cycle and positively regulate glycolysis‑mediated chemotherapy resistance by inhibiting the transcription of FBP1 in collaboration with TWIST1. KMT5A may be a potential therapeutic target for chemotherapy resistance in BRCA.

UNASSIGNED: The DNA damage repair (DDR) system in human genome is pivotal in maintaining genomic integrity. Pathogenic variation (PV) in DDR genes impairs their function, leading to genome instability and increased susceptibility to diseases, especially cancer. Understanding the evolution origin and arising time of DDR PV is crucial for comprehending disease susceptibility in modern humans.
UNASSIGNED: We used big data approach to identify the PVs in DDR genes in modern humans. We mined multiple genomic databases derived from 251,214 modern humans of African and non-Africans. We compared the DDR PVs between African and non-African. We also mined the DDR PVs in the genomic data derived from 5,031 ancient humans. We used the DDR PVs from ancient humans as the intermediate to further the DDR PVs between African and non-African.
UNASSIGNED: We identified 1,060 single-base DDR PVs across 77 DDR genes in modern humans of African and non-African. Direct comparison of the DDR PVs between African and non-African showed that 82.1% of the non-African PVs were not present in African. We further identified 397 single-base DDR PVs in 56 DDR genes in the 5,031 ancient humans dated between 45,045 and 100 years before present (BP) lived in Eurasian continent therefore the descendants of the latest out-of-Africa human migrants occurred 50,000-60,000 years ago. By referring to the ancient DDR PVs, we observed that 276 of the 397 (70.3%) ancient DDR PVs were exclusive in non-African, 106 (26.7%) were shared between non-African and African, and only 15 (3.8%) were exclusive in African. We further validated the distribution pattern by testing the PVs in BRCA and TP53, two of the important genes in genome stability maintenance, in African, non-African, and Ancient humans. Our study revealed that DDR PVs in modern humans mostly emerged after the latest out-of-Africa migration. The data provides a foundation to understand the evolutionary basis of disease susceptibility, in particular cancer, in modern humans.

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Ferroptosis is a new way of cell death, and stimulating the process of cell ferroptosis is a new strategy to treat breast cancer. NGR1 has good anti-cancer activity and is able to slow the progression of breast cancer. However, NGR1 has not been reported in the field related to ferroptosis. By searching the online database for potential targets of NGR1 and the breast cancer disease database, among 11 intersecting genes we focused on Runt-related transcription factor 2 (RUNX2), which is highly expressed in breast cancer, and KEGG pathway enrichment showed that the intersecting genes were mainly enriched in the AGE (advanced glycosylation end products)-RAGE (receptor of AGEs) signaling pathway. After that, we constructed overexpression and down-regulation breast cancer cell lines of RUNX2 in vitro, and tested whether NGR1 treatment induced ferroptosis in breast cancer cells by regulating RUNX2 to inhibit the AGE-RAGE signaling pathway through phenotyping experiments of ferroptosis, Western blot experiments, QPCR experiments, and electron microscopy observation. The results showed that NGR1 was able to inhibit the expression level of RUNX2 and suppress the AGE/PAGE signaling pathway in breast cancer cells. NGR1 was also able to promote the accumulation of Fe2+ and oxidative damage in breast cancer cells by regulating RUNX2 and then down-regulating the expression level of GPX4, FIH1 and up-regulating the expression level of ferroptosis-related proteins such as COX2, ACSL4, PTGS2 and NOX1, which eventually led to the ferroptosis of breast cancer cells.

BACKGROUND: Adhesion G protein-coupled receptors (aGPCRs), a distinctive subset of the G protein-coupled receptor (GPCR) superfamily, play crucial roles in various physiological and pathological processes, with implications in tumor development. Despite the global prevalence of breast cancer (BRCA), specific aGPCRs as potential drug targets or biomarkers remain underexplored.
METHODS: UALCAN, GEPIA, Kaplan-Meier Plotter, MethSurv, cBiopportal, String, GeneMANIA, DAVID, Timer, Metascape, and qPCR were applied in this work.
RESULTS: Our analysis revealed significantly increased transcriptional levels of ADGRB2, ADGRC1, ADGRC2, ADGRC3, ADGRE1, ADGRF2, ADGRF4, and ADGRL1 in BRCA primary tumors. Further analysis indicated a significant correlation between the expressions of certain aGPCRs and the pathological stage of BRCA. High expression of ADGRA1, ADGRF2, ADGRF4, ADGRG1, ADGRG2, ADGRG4, ADGRG6, and ADGRG7 was significantly correlated with poor overall survival (OS) in BRCA patients. Additionally, high expression of ADGRF2 and ADGRF4 indicated inferior recurrence-free survival (RFS) in BRCA patients. The RT-qPCR experiments also confirmed that the mRNA levels of ADGRF2 and ADGRF4 were higher in BRCA cells and tissues. Functional analysis highlighted the diverse roles of aGPCRs, encompassing GPCR signaling and metabolic energy reserves. Moreover, aGPCRs may exert influence or actively participate in the development of BRCA through their impact on immune status.
CONCLUSIONS: aGPCRs, particularly ADGRF2 and ADGRF4, hold promise as immunotherapeutic targets and prognostic biomarkers in BRCA.

UNASSIGNED: The prevalence of breast cancer (BRCA), which is common among women, is on the rise. This study applied network pharmacology to explore the potential mechanism of action of herba sarcandrae in BRCA and construct a prognostic signature composed of inflammation-related genes.
UNASSIGNED: The active ingredients of herba sarcandrae were screened using the SymMap, TCMID, and TCMSP platforms, and the molecular targets were determined in the UniProt database. The \"drug-active compound-potential target\" network was established with Cytoscape 3.7.2. The molecular targets were subjected to disease ontology, gene ontology (GO), and Kyoto Encyclopedia of Genes (KEGG) analyses. AutoDock software was used for molecular docking. Differentially expressed genes (DEGs) related to inflammation were obtained from the BRCA Cancer Genome Atlas (TCGA) database. In the training cohort, the univariate Cox regression model was applied to preliminarily screen prognostic genes. A multigene signature was built by the least absolute shrinkage and selection operator (LASSO) regression model, followed by validation through Kaplan‒Meier, Cox, and receiver operating characteristic (ROC) analyses.
UNASSIGNED: Forty-one active compounds were identified, and 265 therapeutic targets for herba sarcandrae were predicted. GO enrichment results revealed significant enrichment of biological processes, such as response to xenobiotic stimuli, response to nutrient levels, and response to lipopolysaccharide. KEGG analysis revealed significant enrichment of pathways such as AGE-RAGE and chemical carcinogenesis receptor activation signaling pathways. In addition, the herbs Marc-Andre and rutin were shown to mediate BRCA cell proliferation and apoptosis via the interferon regulatory factor 1 (IRF1)/signal transducer and activator of transcription 3 (STAT3)/programmed death-ligand 1 (PD-L1) pathway. Sixteen inflammatory signatures, including BST2, GPR132, IL12B, IL18, IL1R1, IL2RB, IRF1, and others, were constructed, and the risk score was found to be a strong independent prognostic factor for overall survival in BRCA patients. The 16-inflammation signature was associated with several clinical features (age, clinical stage, T, and N classifications) and could reflect immune cell infiltration in tumor microenvironments with different immune cells.
UNASSIGNED: Herba sarcandrae and rutin were shown to mediate BRCA cell proliferation and apoptosis via the IRF1/STAT3/PD-L1 pathway, and the 16-member inflammatory signature might be a novel biomarker for predicting BRCA patient prognosis, providing more accurate guidance for clinical treatment prognosis evaluation and having important reference value for individualized treatment selection.

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