Stability and variability of molecular subtypes:comparative analysis of primary and metastatic triple-negative breast cancer

Objective:Triple-negative breast cancer(TNBC)is a heterogeneous and aggressive cancer.Although our previous study classified primary TNBC into four subtypes,comprehensive longitudinal investigations are lacking.Methods:We assembled a large-scale,real-world cohort comprised of 880 TNBC patients[465 early-stage TNBC(eTNBC)and 415 metastatic TNBC(mTNBC)patients]who were treated at Fudan University Shanghai Cancer Center.The longitudinal dynamics of TNBC subtypes during disease progression were elucidated in this patient cohort.Comprehensive analysis was performed to compare primary and metastatic lesions within specific TNBC subtypes.Results:The recurrence and metastasis rates within 3 years after initial diagnosis in the eTNBC cohort were 10.1%(47/465).The median overall survival(OS)in the mTNBC cohort was 27.2 months[95%confidence interval(CI),24.4–30.2 months],which indicated a poor prognosis.The prognostic significance of the original molecular subtypes in both eTNBC and mTNBC patients was confirmed.Consistent molecular subtypes were maintained in 77.5%of the patients throughout disease progression with the mesenchymal-like(MES)subtype demonstrating a tendency for subtype transition and brain metastasis.Additionally,a precision treatment strategy based on the metastatic MES subtype of target lesions resulted in improved progression-free survival in the FUTURE trial.Conclusions:Our longitudinal study comprehensively revealed the clinical characteristics and survival of patients with the original TNBC subtypes and validated the consistency of most molecular subtypes throughout disease progression.However,we emphasize the major importance of repeat pathologic confirmation of the MES subtype.

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.

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.

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.

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.

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.

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.

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.

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.

Different response to neoadjuvant chemotherapy for different molecular subtypes in patients with locally advanced breast cancer

Objective： The aim of this study was to evaluate the impact of different molecular subtypes defined by immunohistochemistry （IHC） staining on the response rate for patients with locally advanced breast cancer received neoadjuvant chemotherapy. Methods： One hundred and seven breast cancer patients admitted from 2007 to 2011 who received 4 cycles of docetaxel/epirubicin-combined （TE） neoadjuvant chemotherapy were retrospectively reviewed, the patients were classified into 4 subtypes： luminal A, luminal B, HER-2 and triple negative breast cancer （TNBC） according to different combination patterns of estrogen receptor （ER）, progesterone receptor （PR） and human epidermal growth factor-2 （HER-2） expression defined by IHC method. The correlation between response rate and the molecular subtypes were analyzed. Results： The pathological complete response （PCR）, clinical complete response （CCR）, clinical partial response （CPR）, and clinical stable disease （CSD） rate of whole group was 15.89% （17/107）, 22.43% （24/107）, 63.55% （68/107）, 14.02% （15/107）, respectively, and the overall response rate （ORR） was 85.98% （92/107）. The PCR rate and ORR of luminal A, luminal B, HER-2 and TNBC subtypes was 4.76% and 73.81%; 16.67% and 83.33%;17.65% and 100.00%; 30.00% and 96.67%, respectively. The PCR and ORR rate of HER-2/TNBC subtypes was higher than that of luminal A/B subtypes （P = 0.019, P = 0.002, respectively）. Conclusion： Different molecular subtypes display different response rate for patients with locally advanced breast cancer received neoadjuvant TE chemotherapy, HER-2JTNBC subtypes have a higher PCR and ORR rate than that of luminal NB subtypes.

Molecular subtypes of colorectal cancer:Evaluation of outcomes and treatment

Colorectal cancer(CRC) is a biologically heterogeneous disease with diverse clinical outcomes and responses to treatment. In the past two to three decades, a major effort has focused on classifying colorectal cancer subtypes based on causation, etiology, gene expression profiles, different pathways, and translational data from clinical trials. The goal is to uncover prognostic and predictive factors for outcomes in patients with colorectal cancer and to guide therapeutic approaches and management for the improvement of overall survival. Significant advances have been achieved in this area. However, tremendous work is still needed to accomplish the goal of better understanding intratumoral heterogeneity and the influence of the colonic environment, among other facets of colorectal cancer.

Comprehensive multi-omics profiling identifies novel molecular subtypes of pancreatic ductal adenocarcinoma

Pancreatic cancer,a highly fatal malignancy,is predicted to rank as the second leading cause of cancer-related death in the next decade.This highlights the urgent need for new insights into personalized diagnosis and treatment.Although molecular subtypes of pancreatic cancer were well established in genomics and transcriptomics,few known molec-ular classifications are translated to guide clinical strategies and require a paradigm shift.Notably,chronically developing and continuously improving high-throughput technologies and systems serve as an important driving force to further portray the molecular landscape of pancreatic cancer in terms of epigenomics,proteomics,metabonomics,and metagenomics.Therefore,a more comprehensive understanding of molecular classifications at multiple levels using an integrated multi-omics approach holds great promise to exploit more potential ther-apeutic options.In this review,we recapitulated the molecular spectrum from different omics levels,discussed various subtypes on multi-omics means to move one step forward towards bench-to-beside translation of pancreatic cancer with clinical impact,and proposed some methodological andscientific challengesinstore.

Hierarchical learning of gastric cancer molecular subtypes by integrating multi-modal DNA-level omics data and clinical stratification

Molecular subtyping of gastric cancer(GC)aims to comprehend its genetic landscape.However,the efficacy of current subtyping methods is hampered by their mixed use of molecular features,a lack of strategy optimization,and the limited availability of public GC datasets.There is a pressing need for a precise and easily adoptable subtyping approach for early DNA-based screening and treatment.Based on TCGA subtypes,we developed a novel DNA-based hierarchical classifier for gastric cancer molecular subtyping(HCG),which employs gene mutations,copy number aberrations,and methylation patterns as predictors.By incorporating the closely related esophageal adenocarcinomas dataset,we expanded the TCGA GC dataset for the training and testing of HCG(n=453).The optimization of HCG was achieved through three hierarchical strategies using Lasso-Logistic regression,evaluated by their overall the area under receiver operating characteristic curve(auROC),accuracy,F1 score,the area under precision-recall curve(auPRC)and their capability for clinical stratification using multivariate survival analysis.Subtype-specific DNA alteration biomarkers were discerned through difference tests based on HCG defined subtypes.Our HCG classifier demonstrated superior performance in terms of overall auROC(0.95),accuracy(0.88),F1 score(0.87)and auPRC(0.86),significantly improving the clinical stratification of patients(overall p-value=0.032).Difference tests identified 25 subtype-specific DNA alterations,including a high mutation rate in the SYNE1,ITGB4,and COL22A1 genes for the MSI subtype,and hypermethylation of ALS2CL,KIAA0406,and RPRD1B genes for the EBV subtype.HCG is an accurate and robust classifier for DNA-based GC molecular subtyping with highly predictive clinical stratification performance.The training and test datasets,along with the analysis programs of HCG,are accessible on the GitHub website(github.com/LabxSCUT).

The prognostic role of circulating tumor DNA across breast cancer molecular subtypes:A systematic review and meta-analysis

Objective:Circulating tumor DNA(ctDNA)is increasingly being used as a potential prognostic biomarker in cancer patients.We aimed to assess the prognostic value of ctDNA in different subtypes of breast cancer patients throughout the whole treatment cycle.Materials and methods:PubMed,Web of Science,Embase,Cochrane Library,Scopus,and clinical trials.gov databases were searched from January 2016 to May 2022.The following search terms were used:ctDNA OR circulating tumor DNA AND breast cancer OR breast carcinoma.Only studies written in English were included.The following pre-specified criteria should be met for inclusion:(i)original articles,conference abstracts,etc.;(ii)patients with breast cancer;(iii)ctDNA measurement;and(iv)clinical outcome data such as recurrence-free survival(RFS)and overall survival(OS).The random-effects model was preferred considering the potential het-erogeneity across studies.The main outcomes are ctDNA detection rate and postoperative long-term outcomes(RFS and OS).Results:A total of 24 studies were screened.At every measurement time,the ctDNA detection rate of the HR+subgroup was similar to that of the HR-subgroup(P=0.075;P=0.458;P=0.744;and P=0.578),and the ctDNA detection rate of the HER2+subgroup was similar to that of the HER2-subgroup(P=0.805;P=0.271;P=0.807;and P=0.703).In the HR+subgroup,RFS and OS of ctDNA positive patients were similar to those of ctDNA negative patients(P=0.589 and P=0.110),while RFS and OS of the ctDNA positive group was significantly shorter than those of the ctDNA negative patients in the HR-subgroup(HR=4.03,P<0.001;HR=3.21,P<0.001).According to HER grouping,the results were the same as above.In the triple negative breast cancer(TNBC)subgroup,the RFS and OS of ctDNA-positive patients was significantly shorter than of the ctDNA negative patients before and after surgery.Conclusions:ctDNA was more predictive of recurrence-free survival and overall survival in the HR-subgroup than in the HR+subgroup,and the same result was showed in the HER2-subgroup vs.HER2+subgroup.The prognosis of the TNBC subtype is closely related to ctDNA before and after surgery.

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.

Ki-67 as a prognostic marker according to breast cancer molecular subtype

Objective: Ki-67 plays an important function in cell division, but its exact role is still unknown. Moreover, few works regarding its overall function were published. The present study evaluated the clinical significance of Ki-67 index as a prognostic marker and predictor of recurrence in different molecular subtypes of breast cancer. The relationship of Ki-67 index with different clinicopathological factors was also analyzed.Methods: Ki-67 index was measured in 107 cases of primary breast cancer from 2010-2012. These patients were evaluated for estrogen receptor, progesterone receptor, and HER2. Ki-67 was divided according to percentage levels: < 15% and > 15%. Followup ranged from 32 months up to 6 years.Results: Approximately 44, 23, 15, and 25 cases were grouped as luminal A, luminal B, HER2 subtype, and triple-negative(TN),respectively. No luminal A patients showed Ki-67 level higher than 15%, and their recurrence was 20%. In luminal B group, Ki-67 level higher than 15% was observed in 69% of patients, and recurrence was 39%. In HER2 subtype, Ki-67 was higher than 15% in34% of cases, and recurrence was 40%. In triple-negative cases, Ki-67 was higher than 15% in 60% of cases, and recurrence was detected in 32% of patients. Patients with Ki-67 less than 15% displayed better overall survival than those with Ki-67 higher than15%(P = 0.01). Patients with Ki-67 higher than 15% exhibited higher incidence of metastasis and recurrence than those with Ki-67 less than 15%(P = 0.000).Conclusions: Ki-67 may be considered as a valuable biomarker in breast cancer patients.

B-cell-specific signatures reveal novel immunophenotyping and therapeutic targets for hepatocellular carcinoma

BACKGROUND Immunotherapy presents both promises and challenges in treating hepatocellular carcinoma(HCC)due to its complex immunological microenvironment.The role of B cells,a key part of the immune system,remains uncertain in HCC.AIM To identify B-cell-specific signatures and reveal novel immunophenotyping and therapeutic targets for HCC.METHODS Using the Tumor Immune Single-cell Hub 2 database,we identified B-cell-related genes(BRGs)in HCC.Gene enrichment analysis was performed to explore the possible collaboration between B cells and T cells in HCC.We conducted univariate Cox regression analysis using The Cancer Genome Atlas liver HCC collection dataset to find BRGs linked to HCC prognosis.Subsequently,least absolute shrinkage and selection operator regression was utilized to develop a prognostic model with 11 BRGs.The model was validated using the International Cancer Genome Consortium dataset and GSE76427.RESULTS The risk score derived from the prognostic model emerged as an independent prognostic factor for HCC.Analysis of the immune microenvironment and cell infiltration revealed the immune status of various risk groups,supporting the cooperation of B and T cells in suppressing HCC.The BRGs model identified new molecular subtypes of HCC,each with distinct immune characteristics.Drug sensitivity analysis identified targeted drugs effective for each HCC subtype,enabling precision therapy and guiding clinical decisions.CONCLUSION We clarified the role of B cells in HCC and propose that the BRGs model offers promising targets for personalized immunotherapy.

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.

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.