Identification of prognostic molecular subtypes and model based on CD8+ T cells for lung adenocarcinoma

Background:Cytotoxic T lymphocytes(CD8+T)cells function critically in mediating anti-tumor immune response in cancer patients.Characterizing the specific functions of CD8+T cells in lung adenocarcinoma(LUAD)could help better understand local anti-tumor immune responses and estimate the effect of immunotherapy.Methods:Gens related to CD8+T cells were identified by cluster analysis based on the single-cell sequencing data of three LUAD tissues and their paired normal tissues.Weighted gene co-expression network analysis(WGCNA),consensus clustering,differential expression analysis,least absolute shrinkage and selection operator(LASSO)and Cox regression analysis were conducted to classify molecular subtypes for LUAD and to develop a risk model using prognostic genes related to CD8+T cells.Expression of the genes in the prognostic model,their effects on tumor cell invasion,and interactions with CD8+T cells were verified by cell experiments.Results:This study defined two LUAD clusters(CD8+0 and CD8+1)based on CD8+T cells,with cluster CD8+0 being significantly associated with the prognosis of LUAD.Three heterogeneous subtypes(clusters 1,2,and 3)differing in prognosis,genome mutation events,and immune status were categorized using 42 prognostic genes.A prognostic model created based on 11 significant genes(including CD200R1,CLEC17A,ZC3H12D,GNG7,SNX30,CDCP1,NEIL3,IGF2BP1,RHOV,ABCC2,and KRT81)was able to independently estimate the death risk for patients in different LUAD cohorts.Moreover,the model also showed general applicability in external validation cohorts.Low-risk patients could benefit more from taking immunotherapy and were significantly related to the resistance to anticancer drugs.The results from cell experiments demonstrated that the expression of CD200R1,CLEC17A,ZC3H12D,GNG7,and SNX30 was significantly downregulated,while that of CDCP1,NEIL3,IGF2BP1,RHOV,ABCC2 and KRT81 was upregulated in LUAD cells.Inhibition of CD200R1 greatly increased the invasiveness of the LUAD cells,but inhibiting CDCP1 expression weakened the invasion ability of LUAD cells.Conclusion:This study defined two prognostic CD8+T cell clusters and classified three heterogeneous molecular subtypes for LUAD.A prognostic model predictive of the potential effects of immunotherapy on LUAD patients was developed.

Molecular subtyping of hepatocellular carcinoma:A step toward precision medicine

Hepatocellular carcinoma(HCC)is one of the most prevalent and fatal digestive tumors.Treatment for this disease has been constraint by heterogeneity of this group of tumors,which has greatly limited the progress in personalized therapy.Although existing studies have revealed the genetic and epigenetic blueprints that drive HCCs,many of the molecular mechanisms that lead to HCCs remain elusive.Recent advances in techniques for studying functional genomics,such as genome sequencing and transcriptomic analyses,have led to the discovery of molecular mechanisms that participate in the initiation and evolution of HCC.Integrative multi-omics analyses have identified several molecular subtypes of HCC associated with specific molecular characteristics and clinical outcomes.Deciphering similar molecular features among highly heterogeneous HCC patients is a prerequisite to implementation of personalized therapeutics.This review summarizes the current research progresses in precision therapy on the backbone of molecular subtypes of HCC.

Classification of patients with metastatic colorectal cancer into consensus molecular subtypes into real-world: A pilot study

BACKGROUND Colorectal cancer is a complex disease with high mortality rates.Over time,the treatment of metastatic colorectal cancer(mCRC)has gradually improved due to the development of modern chemotherapy and targeted therapy regimens.However,due to the inherent heterogeneity of this condition,identifying reliable predictive biomarkers for targeted therapies remains challenging.A recent promising classification system—the consensus molecular subtype(CMS)system—offers the potential to categorize mCRC patients based on their unique biological and molecular characteristics.Four distinct CMS categories have been defined:immune(CMS1),canonical(CMS2),metabolic(CMS3),and mesenchymal(CMS4).Nevertheless,there is currently no standardized protocol for accurately classifying patients into CMS categories.To address this challenge,reverse transcription polymerase chain reaction(RT-qPCR)and next-generation genomic sequencing(NGS)techniques may hold promise for precisely classifying mCRC patients into their CMSs.AIM To investigate if mCRC patients can be classified into CMS categories using a standardized molecular biology workflow.METHODS This observational study was conducted at the University of Chile Clinical Hospital and included patients with unresectable mCRC who were undergoing systemic treatment with chemotherapy and/or targeted therapy.Molecular biology techniques were employed to analyse primary tumour samples from these patients.RT-qPCR was utilized to assess the expression of genes associated with fibrosis(TGF-βandβ-catenin)and cell growth pathways(c-MYC).NGS using a 25-gene panel(TumorSec)was performed to identify specific genomic mutations.The patients were then classified into one of the four CMS categories according to the clinical consensus of a Tumour Board.Informed consent was obtained from all the patients prior to their participation in this study.All techniques were conducted at University of Chile.RESULTS Twenty-six patients were studied with the techniques and then evaluated by the Tumour Board to determine the specific CMS.Among them,23%(n=6),19%(n=5),31%(n=8),and 19%(n=5)were classified as CMS1,CMS2,CMS3,and CMS4,respectively.Additionally,8%of patients(n=2)could not be classified into any of the four CMS categories.The median overall survival of the total sample was 28 mo,and for CMS1,CMS2,CMS3 and CMS4 it was 11,20,30 and 45 mo respectively,with no statistically significant differences between groups.CONCLUSION A molecular biology workflow and clinical consensus analysis can be used to accurately classify mCRC patients.This classification process,which divides patients into the four CMS categories,holds significant potential for improving research strategies and targeted therapies tailored to the specific characteristics of mCRC.

Genomic alterations and molecular subtypes of gastric cancers in Asians

Gastric cancer(GC) is a highly heterogenic disease,and it is the second leading cause of cancer death in the world.Common chemotherapies are not very effective for GC,which often presents as an advanced or metastatic disease at diagnosis.Treatment options are limited,and the prognosis for advanced GCs is poor.The landscape of genomic alterations in GCs has recently been characterized by several international cancer genome programs,including studies that focused exclusively on GCs in Asians.These studies identified major recurrent driver mutations and provided new insights into the mutational heterogeneity and genetic profiles of GCs.An analysis of gene expression data by the Asian Cancer Research Group(ACRG) further uncovered four distinct molecular subtypes with well-defined clinical features and their intersections with actionable genetic alterations to which targeted therapeutic agents are either already available or under clinical development.In this article,we review the ACRG GC project.We also discuss the implications of the genetic and molecular findings from various GC genomic studies with respect to developing more precise diagnoses and treatment approaches for GCs.

Optimization of Pulse-Field Gel Electrophoresis for Borrelia burgdorferi Subtyping

Objective To optimize the performance of Pulsed-Field Gel Electrophoresis （PFGE） for the comparison of inter-laboratory results and information exchange of Borrelia burgdorferi subtypingo Methods A panel of 34 strains of B. burgdorferi were used to optimize PFGE for subtyping. In order to optimize the electrophoretic parameters （EPs）, all 34 strains of B. burgdorferi were analyzed using four EPs, yielding different Simpson diversity index （D） values and the epidemiological concordance was also evaluated. Results The EP of a switch time of l s to 25 s for13 h and l s to10 s for 6 h produced the highest D value and was declared to be optimal for Mlul and 5mal PFGE of B. burgdorferi. Mlul and Smal were selected as the first and second restriction enzymes for PFGE subtyping of B. burgdorferi according to discrimination and consistency with epidemiological data. Conclusion PFGE can be used as a valuable test for routine genospecies identification of B burgdorferi.

Establishment and Comparison of Pulsed-field Gel Electrophoresis,Multiple-locus Variable Number Tandem Repeat Analysis and Automated Ribotyping Methods for Subtyping of Citrobacter Strains

Objective To establish and compare the pulsed-field gel electrophoresis （PFGE）, multiple-locus variable number tandem repeat analysis （MLVA） and automated ribotyping for subtyping of Citrobacter strains. Methods PFGE protocol was optimized in terms of plug preparation procedure, restriction enzymes and configuration of electrophoretic parameters. MLVA method was evaluated by finding variable number tandem repeats in two genomes of Citrobacter strains. The ribotyping was performed by using the automated RiboPrinter system. Results We optimized the plug preparation procedure, focused on the cell suspension concentration （turbidity of 2.5 to 3.5）, SDS addition （no SDS needed） and lysis time （1 h）, and selected the appropriate restriction enzyme （Xbal） and the electrophoretic parameters （1.0 s-20.0 s for 19 h） of PFGE. There was nearly no discriminatory power of MLVA between Citrobacter strains. For 51 Citrobacter strains, automated ribotyping gave a D-value of 0.9945, while PFGE gave a D-value of 0.9969. Both PFGE and automated ribotyping clustered strains from the same sources （with the same species from the same place at the same time identified as the same source） and divided strains from different sources （from different years, places and hosts） into different subtypes. Conclusion PFGE protocol established in this paper and automated ribotyping are suitable for application in Citrobacter subtyping.

Clinicopathological Features of Breast Cancer with Different Molecular Subtypes in Chinese Women

A retrospective study was performed to explore the relationship between molecular subtypes and clinicopathological features of breast cancer in Chinese women. Six hundred and twenty-eight Chi- nese women with breast cancer were classified into four molecular subtypes according to their estrogen receptor （ER）, progesterone receptor （PR） and Her-2 status. The prevalence rate of each molecular sub- type was analyzed. Relationship between the subtypes and clinicopathologic features was determined. The distribution of molecular subtypes was as follows： luminal A 46.5%, luminal B 17.0%, basal 21.5%, HER2/neu 15.0%. The subtypes had no significant difference under different menopausal status. How- ever, in the age-specific groups, the age group of〈35 years was more likely to get basal cell-like cancer （36.9%）. Statistically significant differences were found among molecular subtypes by age, nuclear grade, tumor size, lymph node （LN） metastasis, tumor stage by American Joint Committee on Cancer （AJCC）, radiotherapy but not by chemotherapy, types of surgery. After adjusting for several relative confounding factors, the basal subtype more likely had lower nodal involvement in both the incidence of LN metastasis （〉1 positive LN） and incidence of high-volume LN metastasis （〉4 positive LN）. The HER2/neu subtype had higher nodal involvement in the incidence of high-volume LN metastases. After adjusting for relative confounding factors, the HER2/neu subtype more likely had higher AJCC tumor stages. It was suggested that there existed close relationship between molecular subtypes and clinicopa- thological features of breast cancer. In addition, the breast cancer subtypes have been proven to be an independent predictor of LN involvement and AJCC tumor stage. These findings are very important for understanding the occurrence, development, prognosis and treatment of breast cancer in Chinese popu-lation.

Prognostic effect analysis of molecular subtype on young breast cancer patients

Objective： To make a prognostic effect analysis of molecular subtype on young breast cancer patients.Methods： Totally 187 cases of young breast cancer patients less than 40 years old treated in Obstetrics and Gynecology Hospital of Fudan University between June 2005 and June 2011 were included in our study. We described their clinical-pathological characteristics, disease-free survival（DFS） rate, and overall survival（OS） rate after a median follow-up period of 61 months. The factors associated with prognosis were also evaluated by univariate and multivariate analyses.Results： All patients were premenopausal, with an average age of 35.36±3.88 years old. The mean tumor size was 2.43±1.53 cm. Eighty-one cases had lymph node metastasis（43.3%）, 126 cases had lymphovascular invasion（67.4%）, and 125 cases had histological grade III（66.8%） disease. Twenty-seven cases（14.4%） were Luminal A subtype, 99 cases（52.9%） were Luminal B subtype, 29 cases（15.5%） were human epidermal growth factor receptor 2（HER-2） overexpression subtype, while 32 cases（17.1%） were triple negative breast cancer（TNBC） subtype according to 2013 St Gallen expert consensus. One hundred and thirty-five cases underwent mastectomy whereas 52 cases had breast-conserving surgery. One hundred and seventy-eight cases underwent adjuvant or neoadjuvant chemotherapy. Recurrence or metastasis occurred in 29 cases, 13 of which died. The 5-year DFS and OS rates were 84% and 92%. Multivariate analysis showed that nodal status（P=0.041） and molecular subtype（P=0.037） were both independent prognostic factors of DFS, while nodal status（P=0.037） and TNBC subtype（P=0.048） were both independent prognostic factors of OS. Conclusions： Molecular subtype is an independent prognostic factor of young breast cancer patients. TNBC has a high risk of relapse and death.

MAT1 correlates with molecular subtypes and predicts poor survival in breast cancer

Objective：Menage a trois 1（MAT1）is a targeting subunit of cyclin-dependent kinase-activating kinase and general transcription factor IIH kinase,which modulates cell cycle,transcription and DNA repair.Its dysregulation is responsible for diseases including cancers.To further explore the role of MAT1 in breast cancer,we investigated the pathways in which MAT1 might be involved,the association between MAT1 and molecular subtypes,and the role of MAT1 in clinical outcomes of breast cancer patients.Methods：We conducted immunohistochemistry staining on tissue microarray and immunofluorescence staining on sections of MAT1 stable breast cancer cells.Also,we performed Kyoto Encyclopedia of Genes and Genomes pathway analysis,correlation analysis and prognosis analysis on public databases.Results：MAT1 was involved in multiple pathways including normal physiology signaling and disease-related signaling.Furthermore,MAT1 positively correlated with the protein status of estrogen receptor and progesterone receptor,and was enriched in luminal-type and human epidermal growth factor receptor 2-enriched breast cancer in comparison with basal-like subtype at both m RNA and protein levels.Correlation analysis revealed significant association between MAT1 m RNA amount and epithelial markers,mesenchymal markers,cancer stem cell markers,apoptosis markers,transcription markers and oncogenes.Consistently,the results of immunofluorescence stain indicated that MAT1 overexpression enhanced the protein abundance of epidermal growth factor receptor,vimentin,sex determining region Y-box 2 and sine oculis homeobox homolog 1.Importantly,Kaplan-Meier Plotter analysis reflected that MAT1 could serve as a prognostic biomarker predicting worse relapse-free survival and metastasis-free survival.Conclusions：MAT1 is correlated with molecular subtypes and is associated with unfavorable prognosis for breast cancer patients.

Signature based on molecular subtypes of deoxyribonucleic acid methylation predicts overall survival in gastric cancer

BACKGROUND Gastric cancer(GC) ranks as the third leading cause of cancer-related death worldwide. Epigenetic alterations contribute to tumor heterogeneity in early stages.AIM To identify the specific deoxyribonucleic acid(DNA) methylation sites that influence the prognosis of GC patients and explore the prognostic value of a model based on subtypes of DNA methylation.METHODS Patients were randomly classified into training and test sets. Prognostic DNA methylation sites were identified by integrating DNA methylation profiles and clinical data from The Cancer Genome Atlas GC cohort. In the training set, unsupervised consensus clustering was performed to identify distinct subgroups based on methylation status. A risk score model was built based on Kaplan-Meier, least absolute shrinkage and selector operation, and multivariate Cox regression analyses. A test set was used to validate this model.RESULTS Three subgroups based on DNA methylation profiles in the training set were identified using 1061 methylation sites that were significantly associated with survival. These methylation subtypes reflected differences in T, N, and M category, age, stage, and prognosis. Forty-one methylation sites were screened as specific hyper-or hypomethylation sites for each specific subgroup. Enrichment analysis revealed that they were mainly involved in pathways related to carcinogenesis, tumor growth, and progression. Finally, two methylation sites were chosen to generate a prognostic model. The high-risk group showed a markedly poor prognosis compared to the low-risk group in both the training [hazard ratio(HR) = 2.24, 95% confidence interval(CI): 1.28-3.92, P < 0.001] and test(HR = 2.12, 95%CI: 1.19-3.78, P = 0.002) datasets.CONCLUSION DNA methylation-based classification reflects the epigenetic heterogeneity of GC and may contribute to predicting prognosis and offer novel insights for individualized treatment of patients with GC.

Drug resistance gene expression and chemotherapy sensitivity detection in Chinese women with different molecular subtypes of breast cancer

Objective:The aim of the study was to identify specific chemosensitivity drugs for various molecular subtypes of breast tumors in Chinese women,by detecting the expression of drug resistance genes and by using the drug sensitivity test on different molecular subtypes of breast cancers.Methods:The expression of drug resistance genes including Topo Ⅱ,GST-π,P-gp,LRP,and CD133 were detected with immunohistochemistry in a tissue microarray.Drug sensitivity tests included those for paclitaxel,epirubicin,carboplatin,vinorelbine,and fluorouracil and were conducted on primary cancer tissue cells and cell lines,including the T47 D,BT-474,and MDA-MB-231 cells and human breast cancer xenografts in nude mice.Results:The different drug resistant genes Topo Ⅱ,GST-π,P-gp,and LRP were differentially expressed among different molecular subtypes of breast cancers(P<0.05).Positive expression of CD133 was highest in basal-like breast cancer(P<0.05).Kaplan-Meier survival analysis showed that positive expressions of Topo Ⅱ and CD133 both correlated with shorter disease-free survival(DFS)(P<0.05)and overall survival(P<0.05),and positive expression of LRP correlated only with shorter DFS(P<0.05).BT-474 showed chemosensitivity to paclitaxel and epirubicin,while MDA-MB-231 showed chemosensitivities to paclitaxel,epirubicin,carboplatin,and fluorouracil(T/C≤50%).The basal-like and HER2+breast cancer primary cells showed chemosensitivities to paclitaxel and epirubicin with significant differences compared with luminal breast cancer primary cells(P<0.05).Conclusions:The differential expression of drug resistance genes and the differential chemosensitivities of drugs in different molecular subtype of breast cancers suggested that individual treatment should be given for each type of breast cancer.

Clinical significance of molecular subtypes of gastrointestinal tract adenocarcinoma

Adenocarcinomas of the gastrointestinal tract(esophagus,stomach,and colon)represent a heterogeneous group of diseases with distinct etiology,clinical features,treatment approaches,and prognosis.Studies are ongoing to isolate molecular genetic subtypes,perform complete biological characterization of the tumor,determine prognostic groups,and find predictive markers to the effectiveness of therapy.Separate molecular genetic classifications were created for esophageal adenocarcinoma[The Cancer Genome Atlas(TCGA)],stomach cancer(TCGA,Asian Cancer Research Group),and colon cancer(Colorectal Cancer Subtyping Consortium).In 2018,isolation of TCGA molecular genetic subtypes for adenocarcinomas of the gastrointestinal tract(esophagus,stomach,and colon)highlighted the need for further studies and clinical validation of subtyping of gastrointestinal adenocarcinomas.However,this approach has limitations.The aim of our work was to critically analyze integration of molecular genetic subtyping of gastrointestinal adenocarcinomas in clinical practice.

Comprehensive molecular characterization and identification of prognostic signature in stomach adenocarcinoma on the basis of energy-metabolism-related genes

BACKGROUND Stomach adenocarcinoma(STAD)is a leading cause of cancer deaths,but its molecular and prognostic characteristics has never been fully illustrated.AIM To describe a molecular evaluation of primary STAD and develop new therapies and identify promising prognostic signatures.METHODS We describe a comprehensive molecular evaluation of primary STAD based on comprehensive analysis of energy-metabolism-related gene(EMRG)expression profiles.RESULTS On the basis of 86 EMRGs that were significantly associated to patients’progression-free survival(PFS),we propose a molecular classification dividing gastric cancer into two subtypes:Cluster 1,most of which are young patients and display more immune and stromal cell components in tumor microenvironment and lower tumor priority;and Cluster 2,which show early stages and better PFS.Moreover,we construct a 6-gene signature that can classify the prognostic risk of patients after a three-phase training test and validation process.Compared with patients with low-risk score,patients with high-risk score had shorter overall survival.Furthermore,calibration and DCA analysis plots indicate the excellent predictive performance of the 6-gene signature,and which present higher robustness and clinical usability compared with three previous reported prognostic gene signatures.According to gene set enrichment analysis,gene sets related to the high-risk group were participated in the ECM receptor interaction and hedgehog signaling pathway.CONCLUSION Identification of the EMRG-based molecular subtypes and prognostic gene model provides a roadmap for patient stratification and trials of targeted therapies.

Magnetic Resonance Spectroscopy and Prognostic Analysis of Molecular Subtypes of Medulloblastoma

Aim: The aim of this study was to investigate whether magnetic resonance spectrum (MRS) and MR imaging features can be used for non-invasive medulloblastoma subgrouping, and analyse patient characteristics and prognosis of molecular subtypes of medulloblastoma. Material and Methods: 32 patients with medulloblastoma underwent MRI prior to surgical resection, 16 of them underwent MRS. MR imaging features and metabolites measured by MRS were analysed to distinguish molecular subtypes of medulloblastoma. Patient demographics, histopathological types, and prognosis of different molecular subtypes were analysed and compared respectively. Results: MRS and MR imaging features differed from different individuals, but without statistical significance that involves acquiring non-quantitative MR imaging features and NAA/Cr, Cho/Cr, Lip/Cr, Glu and Gln/Cr ratio, to be used to determine molecular subtypes. There was no significant difference of the three molecular subtypes in age, gender and pathological type. The 5-year event-free survival (EFS) of SHH, WNT and non SHH/WNT subtype respectively were 75%, 57.1%, 38.1%, with no significant difference (p = 0.382). 5-year EFS of non SHH/WNT subtype was significantly higher in ≤3 years old group than >3 years old group (p = 0.047). Conclusion: MRS and MR imaging features can’t be used to determine molecular subtypes based on our small sample study. There was no significant difference of the prognosis in the three molecular subtypes. The prognosis of ≤3 years old group of non SHH/WNT subtype is better than >3 years old group.

Immunoexpression of Cathepsin D and S100A4 Protein and Their Molecular Subtyptes in Canine Mammary Carcinomas

Cathepsin D (CD), a lysosomal protease, and S100A4 protein, a calcium binding motif, are considered to be involved in metastasis in various human cancers. No data regarding such proteins are available for canine mammary carcinomas (CMCs). Accordingly, their expression in association with known factors of prognosis was investigated in this study. For that, 66 surgically resected CMCs were submitted to an immunohistochemical evaluation using anti CD, S100A4 protein, HER2, estrogen receptor α, cytokeratin 5, and p63 antibodies, further characterizing the tumors' molecular subtype. An increase in S100A4 immunoexpression by neoplastic luminal mammary cells was associated with an infiltrative tumor mode of growth, consequently leading us to conclude that S100A4 protein could be related to progression in CMCs. Additionally, the occurrence of the luminal A molecular subtype was associated with the complex histotype in CMCs. Although we have demonstrated that changes in S100A4 protein immunoexpression occurs in CMCs, further studies are needed to determine whether this represents important independent biomarkers for CMCs.

Prognostic-related genes for pancreatic cancer typing and immunotherapy response prediction based on single-cell sequencing data and bulk sequencing data

Pancreatic cancer is associated with high mortality and is one of the most aggressive of malignancies,but studies have not fully evaluated its molecular subtypes,prognosis and response to immunotherapy of different subtypes.The purpose of this study was to explore the molecular subtypes and the key genes associated with the prognosis of pancreas cancer patients and study the clinical phenotype,prognosis and response to immunotherapy using single-cell seq data and bulk RNA seq data,and data retrieved from GEO and TCGA databases.Methods:Single-cell seq data and bioinformatics methods were used in this study.Pancreatic cancer data were retrieved from GEO and TCGA databases,the molecular subtypes of pancreatic cancer were determined using the six cGAS-STING related pathways,and the clinical phenotype,mutation,immunological characteristics and pathways related to pancreatic cancer were evaluated.Results:Pancreatic cancer was classified into 3 molecular subtypes,and survival analysis revealed that patients in Cluster3(C3)had the worst prognosis,whereas Cluster1(C1)had the best prognosis.The clinical phenotype and gene mutation were statistically different among the three molecular subtypes.Analysis of immunotherapy response revealed that most immune checkpoint genes were differentially expressed in the three subtypes.A lower risk of immune escape was observed in Cluster1(C1),indicating higher sensitivity to immunotherapeutic drugs and subjects in this Cluster are more likely to benefit from immunotherapy.The pathways related to pancreatic cancer were differentially enriched among the three subtypes.Five genes,namely SFRP1,GIPR,EMP1,COL17A and CXCL11 were selected to construct a prognostic signature.Conclusions:Single-cell seq data were to classify pancreatic cancer into three molecular subtypes based on differences in clinical phenotype,mutation,immune characteristics and differentially enriched pathways.Five prognosis-related genes were identified for prediction of survival of pancreatic cancer patients and to evaluate the efficacy of immunotherapy in various subtypes.

Role of mammogram and ultrasound imaging in predicting breast cancer subtypes in screening and symptomatic patients

BACKGROUND Breast cancer(BC)radiogenomics,or correlation analysis of imaging features and BC molecular subtypes,can complement genetic analysis with less resourceintensive diagnostic methods to provide an early and accurate triage of BC.This is pertinent because BC is the most prevalent cancer amongst adult women,resulting in rising demands on public health resources.AIM To find combinations of mammogram and ultrasound imaging features that predict BC molecular subtypes in a sample of screening and symptomatic patients.METHODS This retrospective study evaluated 328 consecutive patients in 2017-2018 with histologically confirmed BC,of which 237(72%)presented with symptoms and 91(28%)were detected via a screening program.All the patients underwent mammography and ultrasound imaging prior to biopsy.The images were retrospectively read by two breast-imaging radiologists with 5-10 years of experience with no knowledge of the histology results to ensure statistical independence.To test the hypothesis that imaging features are correlated with tumor subtypes,univariate binomial and multinomial logistic regression models were performed.Our study also used the multivariate logistic regression(with and without interaction terms)to identify combinations of mammogram and ultrasound(US)imaging characteristics predictive of molecular subtypes.RESULTS The presence of circumscribed margins,posterior enhancement,and large size is correlated with triple-negative BC(TNBC),while high-risk microcalcifications and microlobulated margins is predictive of HER2-enriched cancers.Ductal carcinoma in situ is characterized by small size on ultrasound,absence of posterior acoustic features,and architectural distortion on mammogram,while luminal subtypes tend to be small,with spiculated margins and posterior acoustic shadowing(Luminal A type).These results are broadly consistent with findings from prior studies.In addition,we also find that US size signals a higher odds ratio for TNBC if presented during screening.As TNBC tends to display sonographic features such as circumscribed margins and posterior enhancement,resulting in visual similarity with benign common lesions,at the screening stage,size may be a useful factor in deciding whether to recommend a biopsy.CONCLUSION Several imaging features were shown to be independent variables predicting molecular subtypes of BC.Knowledge of such correlations could help clinicians stratify BC patients,possibly enabling earlier treatment or aiding in therapeutic decisions in countries where receptor testing is not readily available.

KIF15 expression characteristics: Relevance toneo-adjuvant chemotherapy efficacy in breast cancer

Objective The relationship between the expression of kinesin family member 15 (KIF15) andclinicopathological features in breast cancer (BC) remains controversial. In this study, we aimed to explorethe influence of KIF15 expression on the efficacy of neoadjuvant chemotherapy (NAC) and evaluate itsclinical value in predicting prognosis for BC patients.Methods Immunohistochemistry was used to detect KIF15 expression in 93 BC patients undergoingNAC to analyze the relationship between KIF15 expression and clinical efficacy and analytical parameters.Results Of the 93 BC patients enrolled, 24.73% who underwent NAC had higher KIF15 expression levels,showing positive correlations with ER, HER-2, Ki67, and lymph node metastasis (P < 0.05). The clinicalbenefit of NAC was 70.97%, and the major histological response (MHR) rate was 61.29%. The effectivetherapeutic rate in patients with high KIF15 expression was 95.65%, while the MHR rate was 65.22%.Various molecular BC subtypes with varied clinical and pathological responses exhibited correlation toa large extent. Of all the BC patients studied, 84% of the triple-negative breast cancer (TNBC) patientswere evaluated as clinically effective, and 52% of the TNBC patients were evaluated as pathologicallyeffective, and these values were significantly higher than those of the other molecular types (P < 0.05).The expression of KIF15 in 25 TNBC patients showed positive correlations with lymph node metastasis.Conclusion Overexpression of KIF15 was shown to increase BC sensitivity to chemotherapy anddemonstrated better outcomes.

Clinicopathological Data of Breast Cancer in Diabetic Patients

Background: Diabetes mellitus and breast cancer are both chronic diseases. Breast cancer in patients with diabetes is often diagnosed at an advanced stage and has worse prognosis. Aim of work: To investigate the clinicopathological factors, hormonal receptor status and molecular subtypes of breast cancer in diabetic breast cancer patients. Patients and methods: Records of patients presenting to the radiotherapy committee of the breast cancer clinic of Ain Shams University Hospital in the period between January 2017 and January 2018 were revised regarding age, presence of diabetes, presence of comorbidities, and type of the surgery performed. Pathological data such as: Tumor size (T), LN staging (LN), ER, PR, Her2/neu and Ki67 status were also recorded. Patients were divided into 2 groups: Group (I): those with diabetes and Group (II): those without diabetes. Inclusion criteria were Breast cancer cases with proven pathological diagnosis, available IHC studies, clear record of comorbidity status, age > 18 years, cases who underwent upfront surgery. Exclusion criteria were metastatic cases, bilateral cases, cases with double primary, male breast cancer cases, and those with missing data for ER, PR and Her2/neu. Results: Retrieving data from the files of the patients that met the inclusion criteria in the allocated period revealed that 117 patients had diabetes (Group I) and 199 didn’t have the disease (Group II), There was a highly significant difference between both groups regarding the age as most of the patients with diabetes were above fifty years of age (84.6%) compared to only 44.7% of the patients without diabetes also the mean age of patients with diabetes was significantly higher (59 years) compared to 48 years of age for those without diabetes. Diabetes was associated with hypertension in most of the cases (69%). Comorbidities other than hypertension were recorded in 39 diabetic patients (33.3%) and 21 (10.6%) nondiabetic patients and the difference was statistically highly significant. In the diabetic group, the most encountered comorbidity was cardiac disease in 14.5% of patients. In the diabetic group, most of the patients underwent modified radical mastectomy (MRM) with a percentage of about 54.7% compared to 48.2% of patients for both groups respectively. Regarding pathological data apart from the finding that presence of diabetes was associated with more multiple tumors (p value: 0.013), no other statistically significant differences between both groups were found. Hormonal receptor status and molecular subtypes were also not affected by presence of diabetes in the studied breast cancer patients.

Identification of senescence-related molecular subtypes and key genes for prostate cancer

We identified distinct senescence-related molecular subtypes and critical genes among prostate cancer(PCa)patients undergoing radical prostatectomy(RP)or radical radiotherapy(RT).We conducted all analyses using R software and its suitable packages.Twelve genes,namely,secreted frizzled-related protein 4(SFRP4),DNA topoisomerase II alpha(TOP2A),pleiotrophin(PTN),family with sequence similarity 107 member A(FAM107A),C-X-C motif chemokine ligand 14(CXCL14),prostate androgen-regulated mucin-like protein 1(PARM1),leucine zipper protein 2(LUZP2),cluster of differentiation 38(CD38),cartilage oligomeric matrix protein(COMP),vestigial-like family member 3(VGLL3),apolipoprotein E(APOE),and aldehyde dehydrogenase 2 family member(ALDH2),were eventually used to subtype PCa patients from The Cancer Genome Atlas(TCGA)database and GSE116918,and the molecular subtypes showed good correlations with clinical features.In terms of the tumor immune environment(TME)analysis,compared with cluster 1,cancer-associated fibroblasts(CAFs)scored significantly higher,while endothelial cells scored lower in cluster 2 in TCGA database.There was a statistically significant correlation between both CAFs and endothelial cells with biochemical recurrence(BCR)-free survival for PCa patients undergoing RP.For the GSE116918 database,cluster 2 had significantly lower levels of CAFs and tumor purity and higher levels of stromal,immune,and Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data(ESTIMATE)scores than cluster 1;in addition,patients with high levels of CAFs,stromal scores,immune scores,and ESTIMATE scores and low levels of tumor purity tended to suffer from BCR.Based on the median of differentially expressed checkpoints,high expression of CD96,hepatitis A virus cellular receptor 2(HAVCR2),and neuropilin 1(NRP1)in GSE116918 and high expression of CD160 and tumor necrosis factor(ligand)superfamily member 18(TNFSF18)in TCGA database were associated with a significantly higher risk of BCR than their counterparts.In conclusion,we first constructed distinct molecular subtypes and critical genes for PCa patients undergoing RP or RT from the fresh perspective of senescence.