Pathogenic variants in human DNA damage repair genes mostly arose in recent human history.

BACKGROUND: Genome stability is maintained by the DNA damage repair (DDR) system composed of multiple DNA repair pathways of hundreds of genes. Germline pathogenic variation (PV) in DDR genes damages function of the affected DDR genes, leading to genome instability and high risk of diseases, in particular, cancer. Knowing evolutionary origin of the PVs in human DDR genes is essential to understand the etiology of human diseases. However, answer to the issue remains largely elusive. In this study, we analyzed evolutionary origin for the PVs in human DDR genes. METHODS: We identified 169 DDR genes by referring to various databases and identified PVs in the DDR genes of modern humans from ClinVar database. We performed a phylogenetic analysis to analyze the conservation of human DDR PVs in 100 vertebrates through cross-species genomic data comparison using the phyloFit program of the PHAST package and visualized the results using the GraphPad Prism software and the ggplot module. We identified DDR PVs from over 5000 ancient humans developed a database to host the DDR PVs ( https://genemutation.fhs.um.edu.mo/dbDDR-AncientHumans ). Using the PV data, we performed a molecular archeological analysis to compare the DDR PVs between modern humans and ancient humans. We analyzed evolution selection of DDR genes across 20 vertebrates using the CodeML in PAML for phylogenetic analysis. RESULTS: Our phylogenic analysis ruled out cross-species conservation as the origin of human DDR PVs. Our archeological approach identified rich DDR PVs shared between modern and ancient humans, which were mostly dated within the last 5000 years. We also observed similar pattern of quantitative PV distribution between modern and ancient humans. We further detected a set of ATM, BRCA2 and CHEK2 PVs shared between human and Neanderthals. CONCLUSIONS: Our study reveals that human DDR PVs mostly arose in recent human history. We propose that human high cancer risk caused by DDR PVs can be a by-product of human evolution.

HR-positive/HER2-negative breast cancer arising in patients with or without BRCA2 mutation: different biological phenotype and similar prognosis.

Background: BRCA2 plays a key role in homologous recombination. However, information regarding its mutations in Chinese patients with breast cancer remains limited. Objectives: This study aimed to assess the clinicopathological characteristics of BRCA2 mutation breast cancer and explore the mutation's effect on hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer survival in China. Design: This hospital-based cohort study prospectively included 629 women with breast cancer diagnosed from 2008 to 2023 at Zhejiang Cancer Hospital in China. Methods: We compared the clinicopathological characteristics and metastatic patterns and analysed the invasive disease-free survival (iDFS), distant relapse-free survival (DRFS) and first-line progression-free survival (PFS1) of patients with HR-positive/HER2-negative breast cancer according to BRCA2 mutations. Results: Among the 629 patients, 78 had BRCA2 mutations (12.4%) and 551 did not (87.6%). The mean age at diagnosis was lower in the BRCA2 mutation breast cancer group than in the non-mutation breast cancer group (38.91 versus 41.94 years, p = 0.016). BRCA2 mutation breast cancers were more likely to be lymph node-positive than non-mutation breast cancers (73.0% versus 56.6%, p = 0.037). The pathological grade was higher in 47.1% of BRCA2 mutation breast cancers than in 29.6% of non-mutation breast cancers (p = 0.014). The proportions of patients with BRCA2 mutations who developed contralateral breast cancer (19.2% versus 8.8%, p = 0.004), breast cancer in the family (53.8% versus 38.3%, p = 0.009) and ovarian cancer in the family (7.6% versus 2.4%, p = 0.022) were higher than those of patients without the mutation. The median follow-up time was 92.78 months. Multivariate analysis showed that BRCA2 mutation was not associated with poorer iDFS [hazard ratio = 0.9, 95% confidence interval (CI) = 0.64-1.27, p = 0.56] and poorer distant relapse-free survival (DRFS) (hazard ratio = 1.09, 95% CI = 0.61-1.93, p = 0.76). There was no significant difference between the two groups with regard to metastatic patterns in the advanced disease setting. In the first-line metastatic breast cancer setting, PFS1 expression was broadly similar between the two groups irrespective of chemotherapy or endocrine therapy. Conclusion: HR-positive/HER2-negative breast cancer with BRCA2 mutations differs from those without mutations in clinical behaviour and reflects more aggressive tumour behaviour. Our results indicate that BRCA2 mutations have no significant effect on the survival of Chinese women with HR-positive/HER2-negative breast cancer.

Characterizing the Efficacy and Safety of Chemotherapy Plus Everolimus in HER2-Negative Metastatic Breast Cancer Harboring Altered PI3K/AKT/mTOR.

BACKGROUND: The clinical outcomes of chemotherapy (CT) for the treatment of metastatic triple-negative (TN) and hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) have proven to be disappointing. The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway, a tumor-promoting signaling cascade frequently mutated in breast cancer (BC), has been implicated in chemoresistance. In this study, our objective is to investigate the efficacy and safety of combining everolimus with chemotherapy in mBC patients exhibiting mutations in the PI3K/AKT/mTOR pathway. METHODS: We conducted a retrospective analysis to characterize the efficacy, safety, and their association with clinical and molecular characteristics of metastatic lesions in 14 patients with HER2- mBC. These patients harbored at least one altered member of the PI3K/AKT/mTOR signaling pathway and were treated with a combination of a chemotherapy agent and the mTOR inhibitor everolimus (CT+EVE). RESULTS: The majority of patients belonged to the triple-negative (TN) subtype (9/14, 64.3%), having already undergone 2 lines of chemotherapy (CT) in the metastatic setting (11, 78.6%). These patients carried altered phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and were administered a vinorelbine-containing regimen (10, 71.4%). The objective response rate (ORR) was 42.9%, with a disease control rate of 92.9%. The median progression-free survival (PFS) and overall survival (OS) were 5.9 (95% confidence interval (CI): 4.9-13.6) months and 14.3 (95% CI: 8.5-not reached (NR)) months, respectively. Patients with fewer prior treatment lines tended to exhibit longer PFS. OS, PFS, and ORR were comparable between hormone receptor-positive (HR+) and triple-negative breast cancer (TNBC) patients, but numerical improvements were noted in patients with a single PI3K pathway alteration compared to those with more than one alteration. Genomic alterations that surfaced upon progression on CT+EVE included cyclin dependent kinase 4 (CDK4) and epidermal growth factor receptor (EGFR) amplification, as well as neurofibromin 1 (NF1) mutation, suggesting potential mechanisms of acquired resistance. An analysis of adverse events indicated manageable toxicities. CONCLUSIONS: The findings of this study suggest both activity and safety for the combination of chemotherapy and the mTOR inhibitor everolimus (CT+EVE) in patients with HER2- mBC who have alterations in the PI3K pathway, particularly those who have received fewer prior chemotherapy. However, it is crucial to note that large-scale, randomized control studies are warranted to more comprehensively characterize the efficacy and safety of this combination therapy.

HGCMorph: joint discontinuity-preserving and pose-learning via GNN and capsule networks for deformable medical images registration.

Objective.This study aims to enhance medical image registration by addressing the limitations of existing approaches that rely on spatial transformations through U-Net, ConvNets, or Transformers. The objective is to develop a novel architecture that combines ConvNets, graph neural networks (GNNs), and capsule networks to improve the accuracy and efficiency of medical image registration, which can also deal with the problem of rotating registration.Approach.We propose an deep learning-based approach which can be utilized in both unsupervised and semi-supervised manners, named as HGCMorph. It leverages a hybrid framework that integrates ConvNets and GNNs to capture lower-level features, specifically short-range attention, while also utilizing capsule networks (CapsNets) to model abstract higher-level features, including entity properties such as position, size, orientation, deformation, and texture. This hybrid framework aims to provide a comprehensive representation of anatomical structures and their spatial relationships in medical images.Main results.The results demonstrate the superiority of HGCMorph over existing state-of-the-art deep learning-based methods in both qualitative and quantitative evaluations. In unsupervised training process, our model outperforms the recent SOTA method TransMorph by achieving 7%/38% increase on Dice score coefficient (DSC), and 2%/7% improvement on negative jacobian determinant for OASIS and LPBA40 datasets, respectively. Furthermore, HGCMorph achieves improved registration accuracy in semi-supervised training process. In addition, when dealing with complex 3D rotations and secondary randomly deformations, our method still achieves the best performance. We also tested our methods on lung datasets, such as Japanese Society of Radiology, Montgoermy and Shenzhen.Significance.The significance lies in its innovative design to medical image registration. HGCMorph offers a novel framework that overcomes the limitations of existing methods by efficiently capturing both local and abstract features, leading to enhanced registration accuracy, discontinuity-preserving, and pose-learning abilities. The incorporation of capsule networks introduces valuable improvements, making the proposed method a valuable contribution to the field of medical image analysis. HGCMorph not only advances the SOTA methods but also has the potential to improve various medical applications that rely on accurate image registration.

ER-positive and BRCA2-mutated breast cancer: a literature review.

BRCA2-mutated carriers have a high lifetime risk of breast cancer (BC), an early age of onset, and an increased risk of other cancers (including ovarian, pancreatic, and prostate cancer). Almost 70-80% of BRCA2-mutated BC are estrogen receptor (ER)-positive, which is a particular type of ER-positive BC that differs from sporadic ER-positive BC. This article reviews the clinicopathological features, treatment, and prognosis of ER-positive and BRCA2-mutated BC to provide a reference for clinical decision-making.

Effect of rehabilitation therapy combined with neuromuscular electrical stimulation on cognitive dysfunction and activities of daily life in stroke patients.

OBJECTIVE: To determine the effects of rehabilitation therapy combined with neuromuscular electrical stimulation (NES) on cognitive dysfunction and ability to perform activities of daily living (ADLs) of stroke patients. METHODS: The clinical data of 100 stroke patients treated in the Second Affiliated Hospital of Soochow University from February 2019 to August 2021 were retrospectively analyzed. According to the therapeutic regimen, the patients given rehabilitation therapy combined with NES were assigned to a study group (n=52) and those given rehabilitation therapy alone were assigned to a control group (n=48). The treatment efficacy in the two groups was evaluated, and the levels of plasma cortisol (Cor) and neuropeptide Y (NPY), neurological function, motor function, balance ability, swallowing function, cognitive function, negative emotions, and quality of life (QoL) after therapy were evaluated. The maximum amplitude of surface electromyography (sEMG) and swallowing time were compared between the two groups. RESULTS: The study group yielded significantly better efficacy than the control group (P<0.05). Before therapy, there were no significant differences between the two groups in Cor and NPY levels, neurological function, motor function, balance ability, swallowing function, cognitive function, sEMG, swallowing time or negative emotions (P>0.05). After therapy, the above all indices all greatly improved, with more notso in the study group. In addition, after therapy, the study group had significantly better QoL indexes than the control group. CONCLUSION: Rehabilitation therapy combined with NES is effective in treating stroke. It can substantially ameliorate the cognitive dysfunction, prognosis and QoL in patients.

Radiomic Models Predict Tumor Microenvironment Using Artificial Intelligence-the Novel Biomarkers in Breast Cancer Immune Microenvironment.

Breast cancer is the most common malignancy in women, and some subtypes are associated with a poor prognosis with a lack of efficacious therapy. Moreover, immunotherapy and the use of other novel antibody‒drug conjugates have been rapidly incorporated into the standard management of advanced breast cancer. To extract more benefit from these therapies, clarifying and monitoring the tumor microenvironment (TME) status is critical, but this is difficult to accomplish based on conventional approaches. Radiomics is a method wherein radiological image features are comprehensively collected and assessed to build connections with disease diagnosis, prognosis, therapy efficacy, the TME, etc In recent years, studies focused on predicting the TME using radiomics have increasingly emerged, most of which demonstrate meaningful results and show better capability than conventional methods in some aspects. Beyond predicting tumor-infiltrating lymphocytes, immunophenotypes, cytokines, infiltrating inflammatory factors, and other stromal components, radiomic models have the potential to provide a completely new approach to deciphering the TME and facilitating tumor management by physicians.

Pyrotinib plus docetaxel as first-line treatment for HER2-positive metastatic breast cancer: the PANDORA phase II trial.

The role of pyrotinib in the treatment of HER2-positive metastatic breast cancer (MBC) has been well-established. This multicenter, single-arm phase II trial (NCT03876587) aimed to assess the benefit of pyrotinib plus docetaxel as a first-line treatment for HER2-positive MBC. Women with HER2-positive MBC who had not undergone HER2 blockade or chemotherapy for metastatic disease were enrolled in the study and received daily oral pyrotinib 400 mg plus intravenous docetaxel 75 mg/m2 every 3 weeks. The primary endpoint was the objective response rate (ORR), secondary endpoints included progression-free survival (PFS), duration of response (DoR), clinical benefit rate (CBR), overall survival (OS) and safety. From June 2019 to June 2021, 79 patients were enrolled. The confirmed ORR was 79.7% (95% confidence interval [CI], 70.8-88.6), and the CBR was 87.3% (95%CI, 80.0-94.6) in the intention-to-treat population. The pre-specified primary endpoint was met. The median DoR was 15.9 months (interquartile range, 8.3-19.5); the median PFS was 16.0 months (95% CI, 11.2-20.8), and the median OS was not reached. The most common grade ≥3 treatment-related adverse events observed were leukopenia (29.1%), neutropenia (27.8%), and diarrhea (21.5%). This study demonstrates that pyrotinib plus docetaxel show an acceptable safety profile and promising antitumor activity as a first-line treatment option for patients with HER2-positive MBC.

An adaptively multi-correlations aggregation network for skeleton-based motion recognition.

Previous work based on Graph Convolutional Networks (GCNs) has shown promising performance in 3D skeleton-based motion recognition. We believe that the 3D skeleton-based motion recognition problem can be explained as a modeling task of dynamic skeleton-based graph construction. However, existing methods fail to model human poses with dynamic correlations between human joints, ignoring the information contained in the skeleton structure of the non-connected relationship during human motion modeling. In this paper, we propose an Adaptively Multi-correlations Aggregation Network(AMANet) to capture dynamic joint dependencies embedded in skeleton graphs, which includes three key modules: the Spatial Feature Extraction Module (SFEM), Temporal Feature Extraction Module (TFEM), and Spatio-Temporal Feature Extraction Module (STFEM). In addition, we deploy the relative coordinates of the joints of various parts of the human body via moving frames of Differential Geometry. On this basis, we design a Data Preprocessing Module (DP), enriching the characteristics of the original skeleton data. Extensive experiments are conducted on three public datasets(NTU-RGB+D 60, NTU-RGB+D 120, and Kinetics-Skeleton 400), demonstrating our proposed method's effectiveness.

Exploring the role of macrophages in the progression from atypical hyperplasia to endometrial carcinoma through single-cell transcriptomics and bulk transcriptomics analysis.

Introduction: In this study, we aimed to identify key genes in endometrial cancer by conducting single-cell analysis of macrophages. Methods: We sourced clinical data from the TCGA database as well as supplementary datasets GSE201926 and GSE173682. Using bulk-seq data of atypical endometrial hyperplasia and endometrial cancer, we pinpointed key differentially expressed genes. Single-cell RNA sequencing was utilized for further gene expression analysis. Cluster analysis was conducted on TCGA tumor data, identifying two distinct subtypes. Statistical methods employed included LASSO regression for diagnostic modeling and various clustering algorithms for subtype identification. Results: We found that subtype B was closely related to cellular metabolism. A diagnostic model was established using LASSO regression and was based on the genes CDH18, H19, PAGE2B, PXDN, and THRB. This model effectively differentiated the prognosis of cervical cancer. We also constructed a prognosis model and a column chart based on these key genes. Discussion: Through CIBERSORT analysis, CDH18 and PAGE2B were found to be strongly associated with macrophage M0. We propose that these genes influence the transformation from atypical endometrial hyperplasia to endometrial cancer by affecting macrophage M0. In conclusion, these key genes may serve as therapeutic targets for endometrial cancer. A new endometrial cancer risk prognosis model and column chart have been constructed based on these genes, offering a reliable direction for future cervical cancer treatment.

Improved liquid-liquid extraction followed by HPLC-UV for accurate and eco-friendly determination of tetramethylpyrazine in vinegar products.

Tetramethylpyrazine (TMP) is an important bioactive compound in vinegars, contributing to their health-enhancing attributes. It serves as a crucial benchmark for the assessment of vinegar quality. Unfortunately, inaccuracies have arisen due to incomplete extraction techniques and the use of an inappropriate standard substance. These challenges have significantly curtailed comprehensive exploration into the underlying TMP formation mechanisms, impeding advancements within prevailing benchmarks and methodologies governing vinegar products. To address these challenges, several critical parameters, encompassing pH, solvent type, centrifugal force, extraction times and reference materials were investigated and optimized. The TMP content was determined by adjusting the pH to 9 using a sodium hydroxide solution, followed by extraction with ethyl acetate and subsequent re-extraction of the ethyl acetate layer with 0.2 mol/L HCl. A high-performance liquid chromatography method with an ultraviolet detector (UV) was developed and validated. This method demonstrated superior sensitivity compared to existing methods, with a limit of detection (LOD) of 0.0237 µg/g, limit of quantification (LOQ) of 0.0829 µg/g, method limit of detection (MLOD) of 0.10 µg/g and method limit of quantitation (MLOQ) of 0.25 µg/g. The modified method exhibited excellent linearity for TMP in the range of 0.1-118.4 µg/mL, with a good correlation coefficient (R2 > 0.999). The recovery rate of TMP in vinegar products ranged from 82.4 to 96.2%. Consequently, the proposed method exhibits substantial promise for systematic inquiry into TMP formation mechanisms and for ensuring consistent quality control during the production of premium-grade vinegars.

Wavelet transform-based frequency self-adaptive model for functional brain network.

The accurate estimation of functional brain networks is essential for comprehending the intricate relationships between different brain regions. Conventional methods such as Pearson Correlation and Sparse Representation often fail to uncover concealed information within diverse frequency bands. To address this limitation, we introduce a novel frequency-adaptive model based on wavelet transform, enabling selective capture of highly correlated frequency band sequences. Our approach involves decomposing the original time-domain signal from resting-state functional magnetic resonance imaging into distinct frequency domains, thus constructing an adjacency matrix that offers enhanced separation of features across brain regions. Comparative analysis demonstrates the superior performance of our proposed model over conventional techniques, showcasing improved clarity and distinctiveness. Notably, we achieved the highest accuracy rate of 89.01% using Sparse Representation based on Wavelet Transform, outperforming Pearson Correlation based on Wavelet Transform with an accuracy of 81.32%. Importantly, our method optimizes raw data without significantly altering feature topology, rendering it adaptable to various functional brain network estimation approaches. Overall, this innovation holds the potential to advance the understanding of brain function and furnish more accurate samples for future research and clinical applications.

A comprehensive analysis of Fanconi anemia genes in Chinese patients with high-risk hereditary breast cancer.

BACKGROUND: Four Fanconi anemia (FA) genes (BRCA1, BRCA2, PALB2 and RAD51C) are defined as breast cancer (BC) susceptibility genes. Other FA genes have been inconsistently associated with BC. Thus, the role of other FA genes in BC should be explored in specific populations. METHODS: Mutations in 16 FA genes were screened with a 98-gene panel sequencing assay in a cohort of 1481 Chinese patients with high-risk hereditary BC. The association between mutations and clinicopathological characteristics as well as prognosis was analyzed. The risk of BC in carriers of FA gene mutations was assessed in the Genome Aggregation Database and the Westlake Biobank for Chinese cohort. RESULTS: A total of 2.57% (38/1481) BC patients were identified who had 12 other FA gene germline mutations. Among them, the most frequently mutated gene was FANCA (8/1481, 0.54%). These 38 patients carried 35 distinct pathogenic/likely pathogenic variants, of which 21 were novel. We found one rare FANCB deleterious variant (c.1327-3dupT) in our cohort. There was a statistically significant difference in lymph node status between FA gene mutation carriers and non-carriers (p = 0.041). We observed a trend that mutation carriers had larger tumor sizes, lower estrogen receptor (ER) and progesterone receptor (PR) positivity rates, and lower 3.5-year invasive disease-free survival (iDFS) and distant recurrence-free survival (DRFS) rates than non-carriers (tumor size > 2 cm: 51.43% vs. 45.63%; ER positivity rates: 51.43% vs. 60.81%; PR positivity rates: 48.57% vs. 55.16%; 3.5-year iDFS rates: 58.8% vs. 66.7%; 3.5-year DRFS rates: 58.8% vs. 68.8%). The frequency of the mutations in FANCD2, FANCM and BRIP1 trended to be higher among BC cases than that in controls (p = 0.055, 0.08 and 0.08, respectively). CONCLUSION: This study comprehensively estimated the prevalence, clinicopathological characteristics, prognosis and risk of BC associated with deleterious variants in FA genes in Chinese high-risk hereditary BC patients. It enriches our understanding of the role of FA genes with BC.

Case report: The intrauterine suture surgery-an original method in the treatment of old uterine false passage.

Objective: To introduce an effective approach using the hysteroscopy system for patients with old uterine false passage after a failed conservative treatment. Materials and methods: This study presents the case of a 34-year-old woman who was treated in the Department of Gynecology of Shenzhen Integrated Traditional Chinese and Western Medicine Hospital in 2018 with the complaint of "menstrual volumereduction for 2 years after abortion." A hysteroscopy was performed to make a clear diagnosis: (1) uterine cavity adhesion and (2) old uterine false passage. After the separation of adhesions, the patient was treated with estradiol and progesterone in sequence (estradiol valerate 3 mg, b.i.d., oral for 21 days; and dydrogesterone tablets 10 mg, b.i.d., oral for the second half of the cycle) for 3 months. After the review of the hysteroscopy results, it was found that there was no improvement in the old false passage; therefore, a suture and knotting surgery under hysteroscopy was performed to treat the old false passage in the uterus within 10 min, and the intraoperative blood loss was 2 ml. The patient was discharged 24 h postoperatively without any adverse perioperative complications. Results: Two months after the operation, the review of the hysteroscopy results showed that the old false passage in the uterus disappeared. After the 6-month follow-up, the menstrual volume increased compared with the previous one, close to the normal menstrual volume, and the patient experienced no pain and menstrual discomfort. The patient was lost to follow-up and was contacted again in 2022. It was found out that in 2019, she was pregnant with a baby boy who is now 3 years old and healthy. Conclusion: The intrauterine suture surgery presents a clear visual field to old uterine false passage after a failed conservative treatment. In patients with old uterine false passage suffering from reduced fertility, the intrauterine suture surgery can be a minimally invasive and effective alternative if the conservative treatment for old uterine false passage failed.

FOXK2 amplification and overexpression promotes breast cancer development and chemoresistance.

Activation of oncogenes through DNA amplification/overexpression plays an important role in cancer initiation and progression. Chromosome 17 has many cancer-associated genetic anomalies. This cytogenetic anomaly is strongly associated with poor prognosis of breast cancer. FOXK2 gene is located on 17q25 and encodes a transcriptional factor with a forkhead DNA binding domain. By integrative analysis of public genomic datasets of breast cancers, we found that FOXK2 is frequently amplified and overexpressed in breast cancers. FOXK2 overexpression in breast cancer patients is associated with poor overall survival. FOXK2 knockdown significantly inhibits cell proliferation, invasion and metastasis, and anchorage-independent growth, as well as causes G0/G1 cell cycle arrest in breast cancer cells. Moreover, inhibition of FOXK2 expression sensitizes breast cancer cells to frontline anti-tumor chemotherapies. More importantly, co-overexpression of FOXK2 and PI3KCA with oncogenic mutations (E545K or H1047R) induces cellular transformation in non-tumorigenic MCF10A cells, suggesting that FOXK2 is an oncogene in breast cancer and is involved in PI3KCA-driven tumorigenesis. Our study identified CCNE2, PDK1, and Estrogen receptor alpha (ESR1) as direct transcriptional targets of FOXK2 in MCF-7 cells. Blocking CCNE2- and PDK1-mediated signaling by using small molecule inhibitors has synergistic anti-tumor effects in breast cancer cells. Furthermore, FOXK2 inhibition by gene knockdown or inhibitors for its transcriptional targets (CCNE2 and PDK1) in combination with PI3KCA inhibitor, Alpelisib, showed synergistic anti-tumor effects on breast cancer cells with PI3KCA oncogenic mutations. In summary, we provide compelling evidence that FOXK2 plays an oncogenic role in breast tumorigenesis and targeting FOXK2-mediated pathways may be a potential therapeutic strategy in breast cancer.

Resistance to anti-HER2 therapy associated with the TSC2 nonsynonymous variant c.4349 C > G (p.Pro1450Arg) is reversed by CDK4/6 inhibitor in HER2-positive breast cancer.

HER2-positive breast cancer patients carrying the germline TSC2 nonsynonymous variant c.4349 C > G (p.Pro1450Arg) are resistant to anti-HER2 therapy. Multi-predictor in silico analysis reveals that this variant is deleterious. We explore the potential mechanism of this TSC2 variant and investigate methods for overcoming anti-HER2 resistance. TSC2 c.4349 C > G reverses the inhibitory effect on mTOR and downstream signaling by increasing TSC2 phosphorylation at Thr1462 and confers significant lapatinib resistance in vitro and in vivo. The combination of lapatinib and the CDK4/6 inhibitor palbociclib inhibits cyclin D1/CDK4/Rb alternative pathway and TSC2 phosphorylation, thereby partially attenuating mTOR activity and inducing TSC2-mutant cell blockage at G1/G0. In in vitro and xenograft models, palbociclib+lapatinib shows higher anti-tumor activity than monotherapy and overcomes the resistance of the TSC2 c.4349 C > G-related variant to anti-HER2 therapy. We reveal a new mechanism of resistance to anti-HER2 therapy and provide a strategy to increase the efficiency of anti-HER2 therapy in HER2-positive breast cancer.

The role of TSC2 in breast cancer: a literature review.

TSC2 is a tumor suppressor gene as well as a disease-causing gene for autosomal dominant disorder tuberous sclerosis complex (TSC). Research has found that some tumor tissues have lower TSC2 expression levels than normal tissues. Furthermore, low expression of TSC2 is associated with poor prognosis in breast cancer. TSC2 acts as a convergence point of a complex network of signaling pathways and receives signals from the PI3K, AMPK, MAPK, and WNT pathways. It also regulates cellular metabolism and autophagy through inhibition of a mechanistic target of rapamycin complex, which are processes relevant to the progression, treatment, and prognosis of breast cancer. In-depth study of TSC2 functions provides significant guidance for clinical applications in breast cancer, including improving the treatment efficacy, overcoming drug resistance, and predicting prognosis. In this review, protein structure and biological functions of TSC2 were described and recent advances in TSC2 research in different molecular subtypes of breast cancer were summarized.

The progress in our understanding of CIN in breast cancer research.

Chromosomal instability (CIN) is an important marker of cancer, which is closely related to tumorigenesis, disease progression, treatment efficacy, and patient prognosis. However, due to the limitations of the currently available detection methods, its exact clinical significance remains unknown. Previous studies have demonstrated that 89% of invasive breast cancer cases possess CIN, suggesting that it has potential application in breast cancer diagnosis and treatment. In this review, we describe the two main types of CIN and discuss the associated detection methods. Subsequently, we highlight the impact of CIN in breast cancer development and progression and describe how it can influence treatment and prognosis. The goal of this review is to provide a reference on its mechanism for researchers and clinicians.

BRCA-CRisk: A Contralateral Breast Cancer Risk Prediction Model for BRCA Carriers.

PURPOSE: The absolute cumulative risk of contralateral breast cancer (CBC) for patients with BRCA1/2 variants is unknown. The purpose of this study was to develop a CBC risk prediction model for assessing CBC risk for BRCA1/2 carriers. METHODS: The primary cohort of 491 patients with BRCA1/2 variants was derived from a large series of unselected patients with breast cancer. A nomogram was established on the basis of the results of a multivariate Cox regression analysis from this cohort. This model, named BRCA-CRisk, was further validated by an independent cohort of 205 patients with BRCA1/2 variants. Discrimination and calibration of the model were assessed. RESULTS: In the primary cohort of 491 patients, 66 developed contralateral breast cancer after a median follow-up of 7.0 years. Four variables were significantly associated with risk of CBC and were incorporated in the establishment of the BRCA-CRisk prediction model: younger age at first breast cancer (with continuous variable, P = .002), positive first-degree family history of breast and/or ovarian cancer (hazard ratio [HR], 1.89; 95% CI, 1.16 to 3.08; P = .011), variant located near the 3' region of BRCA (HR, 2.01; 95% CI, 1.23 to 3.30; P = .006), and endocrine therapy (HR, 0.54; 95% CI, 0.33 to 0.88; P = .013). The area under the time-dependent curves for the 5- and 10-year cumulative risks of CBC were 0.775 and 0.702, respectively. The model was well validated in the independent cohort of 205 BRCA1/2 carriers, with area under the curves of 0.750 and 0.691 for 5 and 10 years, respectively. CONCLUSION: BRCA-CRisk model provides a useful tool for assessing the absolute cumulative risk of CBC for BRCA1/2 carriers and may help carriers and clinicians optimally select risk-reducing strategies on the basis of individual CBC risk.