Introduction: In India, OVCa is women’s third most common and lethal cancer type, accounting for 6.7% of observed cancer incidences. The contribution of somatic mutations, aberrant expression of gene and splice forms in determining the cell fate, gene networks, tumour-specific variants, and the role of immune fraction infiltration have been proven essential in understanding tumorigenesis. However, their interplay in OVCa in a histotype-specific manner remains unclear in the Indian context. In the present study, we aimed to unravel the Indian population histotype-specific exome variants, differentially expressed gene modules, splice events and immune profiles of OVCa samples.Methods: We analysed 10 tumour samples across 4 ovarian cancer histotypes along with 2 normal patient samples. This included BCFtool utilities and CNVkit for exome, WGCNA and DESeq2 for obtaining differential module hub genes and dysregulated miRNA targets, CIBERSORTx for individual immune profiles and rMATS for tumour specific splice variants.Result: We identified population-specific novel mutations in Cancer Gene Census Tier1 and Tier2 genes. MUC16, MUC4, CIITA, and NCOR2 were among the most mutated genes, along with TP53. Transcriptome analysis showed significant overexpression of mutated genes MUC16, MUC4, and CIITA, whereas NCOR2 was downregulated. WGCNA revealed histotype-specific gene hubs and networks. Among the significant pathways, alteration in the immune system was one of the pathways, and immune profiling using CIBERSORTx revealed histotype-specific immune cell fraction. miRNA analysis revealed miR-200 family, miR-200a and miR-429 were upregulated in HGSOCs.Splice factor abrasion caused splicing perturbations, with the most abundant alternative splice event being exon skipping and the most spliced gene, SNHG17. Pathway analysis of spliced genes revealed translational elongation and Base excision repair as the pathways altered in OVCa.Conclusion: Integrated exome, transcriptome, and splicing patterns revealed different population-specific molecular signatures of ovarian cancer histotypes in the Indian Cohort.
Breast cancer (BC) is one of the leading causes of cancer-associated death in women. Despite the progress in therapeutic regimen, resistance and recurrence of breast cancer have affected the overall survival of patients. The present signatures, such as PAM50 and Oncotype DX, do not segregate the Indian breast samples based on molecular subtypes. This study aims at finding signatures of long noncoding RNA (lncRNA) and mRNA in Indian breast cancer patients using RNA-seq. We have analyzed the survival based on the menopausal and hormone status of 380 Indian breast cancer patients, and of these, we have sequenced and analyzed matched tumor–normal transcriptome of 17 (pre- and postmenopausal) Indian breast cancer patients representing six different subtypes, namely, four patients in triple-positive, three patients in estrogen receptor–positive (ER+ve), three patients in estrogen and progesterone receptors–positive (ER+ve, PR+ve), two patients in human epidermal growth factor receptor (Her2+ve), three patients in triple-negative, and one patient in ER+ve and Her2+ve subtypes. We have identified a 25 mRNA–27 lncRNA gene set, which segregated the subtypes in our data. A pathway analysis of the differentially expressed genes revealed downregulated ECM interaction and upregulated immune regulation, cell cycle, DNA damage response and repair, and telomere elongation in premenopausal women. Postmenopausal women showed downregulated metabolism, innate immune system, upregulated translation, sumoylation, and AKT2 activation. A Kaplan–Meier survival analysis revealed that menopausal status, grade of the tumor, and hormonal status displayed statistically significant effects (p < 0.05) on the risk of mortality due to breast cancer. Her2+ve patients showed low overall survival. One of the unique lncRNA-mRNA pairs specific to the EP-subtype, SNHG12 and EPB41, showed interaction, which correlates with their expression level; SNHG12 is downregulated and EPB41 is upregulated in EP samples.
Despite several treatment options for blood cancer, mortality remains high due to relapse and the disease’s aggressive nature. Elevated levels of HSP90, a molecular chaperone essential for protein folding, are associated with poor prognosis in leukemia and lymphoma. HSP90 as a target for chemotherapy has been met with limited success due to toxicity and induction of heat shock. This study tested the activity of an HSP90 inhibitor, SP11, against leukemic cells, mouse lymphoma allograft, and xenograft models. SP11 induced cytotoxicity in vitro in leukemic cell lines and induced cell death via apoptosis, with minimal effect on normal cells. SP11 induced cell death by altering the status of HSP90 client proteins both in vitro and in vivo. SP11 reduced the tumor burden in allograft and xenograft mouse models without apparent toxicity. The half-life of SP11 in the plasma was approximately 2 h. SP11 binding was observed at both the N-terminal and C-terminal domains of HSP90. C-terminal binding was more potent than N-terminal binding of HSP90 in silico and in vitro using isothermal calorimetry. SP11 bioavailability and minimal toxicity in vivo make it a potential candidate to be developed as a novel anticancer agent.
BackgroundBreast cancer (BC) is one of the leading causes of cancer-associated death in women. Despite the progress in therapeutic regimen, resistance and recurrence of Breast cancer have impacted Overall Survival. Transcriptomic profiling of tumour samples has led to identifying subtype-specific differences, identifying biomarkers, and designing therapeutic strategies. Although there are multiple transcriptomic studies on breast cancer patients from different geographical regions, a comprehensive study on long noncoding RNA (lncRNA) and mRNA in Indian Breast cancer patients in multiple subtypes are very limited. This study aims to understand the subtype-specific alterations and mRNA-lncRNA gene sets.MethodWe have performed transcriptome analysis of 17 Indian breast cancer patients and matched normal belonging to 6 different subtypes, i.e., four patients in triple positive, three patients in estrogen receptor-positive (ER+ve), three patients in estrogen and progesterone receptor-positive (ER+ve, PR+ve), two patients in Human epidermal growth factor receptor (Her2+ve), three patients in triple-negative and one patient in ER+ve and Her2 +ve subtypes. Hierarchical clustering and principal component analysis were performed using R packages to derive gene sets. Univariate and multivariate Cox analyses were performed for survival analysis.ResultsmRNA and lncRNA expression profiles segregated Indian Breast cancer subtypes with minimum overlap. We have identified a 25mRNA-27 lncRNA gene set, which displayed proper segregation of the subtypes in our data. The same gene set also segregated premenopausal women samples in The Cancer Genome Atlas (TCGA) data. Pathway analysis of the differentially expressed genes revealed unique pathways for premenopausal and postmenopausal women. Kaplan-Meier survival analysis revealed menopausal status, grade of the tumour, and hormonal status displayed statistically significant effects (p < 0.05) on the risk of mortality due to breast cancer. Her2+ve patients showed low overall survivalConclusionThis is the first study describing subtype-specific mRNA and lncRNA gene expression in Indian Breast Cancer patients with unique pathway signatures for premenopausal and postmenopausal breast cancer patients. Additionally, our data identified an mRNA-lncRNA gene set that could segregate pre and postmenopausal women with Breast Cancer. Although the sample size is small, results from this study could be a foundation that could be validated further in a larger dataset to establish an mRNA-lncRNA signature specific to the Indian population which might, in turn, improve therapeutic decisions.
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