A preoperative-progesterone intervention increases disease-free survival in patients with breast cancer, with an unknown underlying mechanism. We elucidated the role of non-coding RNAs in response to ...progesterone in human breast cancer.
Whole transcriptome sequencing dataset of 30 breast primary tumors (10 tumors exposed to hydroxyprogesterone and 20 tumors as control) were re-analyzed to identify differentially expressed non-coding RNAs followed by real-time PCR analyses to validate the expression of candidates. Functional analyses were performed by genetic knockdown, biochemical, and cell-based assays.
We identified a significant downregulation in the expression of a long non-coding RNA, Down syndrome cell adhesion molecule antisense DSCAM-AS1, in response to progesterone treatment in breast cancer. The progesterone-induced expression of DSCAM-AS1 could be effectively blocked by the knockdown of progesterone receptor (PR) or treatment of cells with mifepristone (PR-antagonist). We further show that knockdown of DSCAM-AS1 mimics the effect of progesterone in impeding cell migration and invasion in PR-positive breast cancer cells, while its overexpression shows an opposite effect. Additionally, DSCAM-AS1 sponges the activity of miR-130a that regulates the expression of ESR1 by binding to its 3'-UTR to mediate the effect of progesterone in breast cancer cells. Consistent with our findings, TCGA analysis suggests that high levels of miR-130a correlate with a tendency toward better overall survival in patients with breast cancer.
This study presents a mechanism involving the DSCAM-AS1/miR-130a/ESR1 genomic axis through which progesterone impedes breast cancer cell invasion and migration. The findings highlight the utility of progesterone treatment in impeding metastasis and improving survival outcomes in patients with breast cancer.
Response to immunotherapies can be variable and unpredictable. Pathology-based phenotyping of tumors into 'hot' and 'cold' is static, relying solely on T-cell infiltration in single-time single-site ...biopsies, resulting in suboptimal treatment response prediction. Dynamic vascular events (tumor angiogenesis, leukocyte trafficking) within tumor immune microenvironment (TiME) also influence anti-tumor immunity and treatment response. Here, we report dynamic cellular-level TiME phenotyping in vivo that combines inflammation profiles with vascular features through non-invasive reflectance confocal microscopic imaging. In skin cancer patients, we demonstrate three main TiME phenotypes that correlate with gene and protein expression, and response to toll-like receptor agonist immune-therapy. Notably, phenotypes with high inflammation associate with immunostimulatory signatures and those with high vasculature with angiogenic and endothelial anergy signatures. Moreover, phenotypes with high inflammation and low vasculature demonstrate the best treatment response. This non-invasive in vivo phenotyping approach integrating dynamic vasculature with inflammation serves as a reliable predictor of response to topical immune-therapy in patients.
During the past decade, the incidence of EGFR mutation has been shown to vary across different ethnicities. It occurs at the rate of 10-15% in North Americans and Europeans, 19% in African-Americans, ...20-30% in various East Asian series including Chinese, Koreans, and Japanese. Frequency of EGFR mutations in India however remains sparsely explored.
We report 23% incidence of Epidermal growth factor receptor (EGFR) mutations in 907 Non small cell lung cancer (NSCLC) patients of Indian ethnicity, in contrast to 10-15% known in Caucasians and 27-62% among East Asians. In this study, EGFR mutations were found to be more common in never-smokers 29.4% as compared to smokers 15.3%. Consistent with other populations, mutation rates among adenocarcinoma-males were predominantly lower than females with 32% incidence. However unlike Caucasians, EGFR mutation rate among adenocarcinoma-never-smoker females were comparable to males suggesting lack of gender bias among never smokers likely to benefit from EGFR targeted therapy.
This study has an overall implication for establishing relevance for routine EGFR mutation diagnostics for NSCLC patients in clinics and emphasizes effectiveness for adoption of EGFR inhibitors as the first line treatment among Indian population. The intermediate frequency of EGFR mutation among Indian population compared to Caucasians and East Asians is reminiscent of an ancestral admixture of genetic influence from Middle Easterners, Central Asians, and Europeans on modern- Indian population that may confer differential susceptibility to somatic mutations in EGFR.
The uncommonness of gallbladder cancer in the developed world has contributed to the generally poor understanding of the disease. Our integrated analysis of whole exome sequencing, copy number ...alterations, immunohistochemical, and phospho‐proteome array profiling indicates ERBB2 alterations in 40% early‐stage rare gallbladder tumors, among an ethnically distinct population not studied before, that occurs through overexpression in 24% (n = 25) and recurrent mutations in 14% tumors (n = 44); along with co‐occurring KRAS mutation in 7% tumors (n = 44). We demonstrate that ERBB2 heterodimerizes with EGFR to constitutively activate the ErbB signaling pathway in gallbladder cells. Consistent with this, treatment with ERBB2‐specific, EGFR‐specific shRNA or with a covalent EGFR family inhibitor Afatinib inhibits tumor‐associated characteristics of the gallbladder cancer cells. Furthermore, we observe an in vivo reduction in tumor size of gallbladder xenografts in response to Afatinib is paralleled by a reduction in the amounts of phospho‐ERK, in tumors harboring KRAS (G13D) mutation but not in KRAS (G12V) mutation, supporting an essential role of the ErbB pathway. In overall, besides implicating ERBB2 as an important therapeutic target under neo‐adjuvant or adjuvant settings, we present the first evidence that the presence of KRAS mutations may preclude gallbladder cancer patients to respond to anti‐EGFR treatment, similar to a clinical algorithm commonly practiced to opt for anti‐EGFR treatment in colorectal cancer.
What's new?
This study presents the first genomic landscape of early‐stage gallbladder cancer among an understudied ethnic population. Besides suggesting anti‐EGFR therapy as a therapeutic option based on ERBB2 alteration, the evidence suggests that presence of KRAS (G12V) but not KRAS (G13D) mutation may impede treatment response. The findings could potentially lead to early adoption of a clinical algorithm to treat gallbladder cancer patients under neo‐adjuvant or adjuvant settings similar to the one commonly used for anti‐EGFR treatment in colorectal cancer. Furthermore, the findings rationalize inclusion of gallbladder patients under genomically matched basket clinical trials such as the NCI‐Molecular Analysis for Therapy Choice.
Merkel cell carcinoma is a rare, lethal cancer histopathologically composed of cells showing similarity with mechanoreceptor Merkel cells. Merkel cell tumors manifest in two distinct forms. While a ...virus called Merkel cell polyomavirus is involved in the pathogenesis of one form of Merkel tumors, the other is driven by ultraviolet (UV)-linked mutations. In this study we investigated 18 cases, from the Indian population, of Merkel cell carcinoma for immunohistochemical (IHC) expression of Merkel cell polyomavirus (MCV) T antigen, including 12 cases tested by PCR, to identify viral etiopathology. We tested the tumors with two sensitive antibodies (CM2B4 and Ab3), targeting the viral large T antigen protein and with PCR primers targeting the N terminus of T antigen. Overall, we observed 38.8% (7/18) tumors displaying positive IHC expression of Merkel cell polyomavirus T antigen and 25% (3/12) tumors showing positive results, by both, immunohistochemistry and PCR. This constitutes the first report from India showing implication of MCV in Merkel cell carcinomas. Moreover, this is one of the larger series of Merkel cell carcinomas, tested for MCV, by both immunohistochemistry and PCR, in this part of the world. These results further indicate that a slightly more number of such cases in India are likely to be caused by UV-linked damage, as opposed to Merkel cell polyomavirus mediated tumorigenesis, which is definitely implicated in a subset of cases.
•We investigated 18 Merkel cell carcinoma cases, from the Indian population to identify viral etiopathology.•Overall, 38.8% (7/18) tumors displayed positive IHC expression for MCV T antigen using antibodies CM2B4 and Ab3.•Three of the twelve tumors, (25%) showed positive MCV presence, by both, immunohistochemistry and PCR.•Our study is the first report from India showing implication of Merkel cell polyomavirus (MCV) in Merkel cell carcinomas.
Merkel cell carcinoma (MCC) is an uncommon, lethal cancer of the skin caused by either Merkel cell polyomavirus (MCPyV) or UV-linked mutations. MCPyV is found integrated into MCC tumor genomes, ...accompanied by truncation mutations that render the MCPyV large T antigen replication incompetent. We used the open access HPV Detector/Cancer-virus Detector tool to determine MCPyV integration sites in whole-exome sequencing data from five MCC cases, thereby adding to the limited published MCPyV integration site junction data. We also systematically reviewed published data on integration for MCPyV in the human genome, presenting a collation of 123 MCC cases and their linked chromosomal sites. We confirmed that there were no highly recurrent specific sites of integration. We found that chromosome 5 was most frequently involved in MCPyV integration and that integration sites were significantly enriched for genes with binding sites for oncogenic transcription factors such as LEF1 and ZEB1, suggesting the possibility of increased open chromatin in these gene sets. Additionally, in one case we found, for the first time, integration involving the tumor suppressor gene
, adding to previous reports of rare MCPyV integration into host tumor suppressor genes in MCC.
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Portrait of somatic alterations in HPV-negative early stage tongue tumors with tobacco signature.
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Upregulation of genes related to EMT pathway identified by transcriptome analysis.
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MMP10
could ...be a candidate prognostic biomarker to stratify patients who develop metastases.
Kirsten rat sarcoma viral oncogene homologue (
) mutations in lung cancers, long considered untargetable, have had a recent rise in interest due to promising data of agents targeting
p.G12C. As ...Indian data are scarce, we sought to identify baseline clinical characteristics, prognostic factors and outcomes of lung cancer patients with
mutations at our hospital.
Patients with KRAS mutant lung cancers treated at our institute from 2016 to 2022 were analysed.
133 patients with KRAS mutant lung cancers were identified. Median age was 57 (interquartile range 28-78) years, and 58 (43.6%) were smokers. 17 (12.7%) had brain metastases. The commonest variant was p.G12C, seen in 53 (39.8%) patients. Six (4.5%) had programmed death ligand 1 (PDL-1) expression >50% by Ventana SP263 PDL-1 assay, and 13 (9.7%) had epidermal growth factor mutation. Of 92 patients with available treatment details, the majority received intravenous chemotherapy, nine (9.8%) received tyrosine kinase inhibitors and four (4.4%) received immunotherapy (pembrolizumab). Median progression-free survival (PFS) with first-line therapy was 6 (95% confidence interval (CI) 2.8-9.2) months and median overall survival (OS) was 12 (CI 9.2-14.8) months. The incidence of brain metastases was higher in patients with G12C mutations (
= 0.025). Brain metastases (HR: 3.57,
< 0.001), Eastern Cooperative Oncology Group performance status (PS) ≥ 2 (HR: 2.13,
= 0.002) and G12C mutation (HR: 1.84,
= 0.011) were associated with inferior PFS, while brain metastases (HR: 4.6,
< 0.001), PS ≥ 2 (HR: 2.33,
= 0.001) and G12C mutation (HR: 1.93,
= 0.01) were associated with inferior OS.
This is the largest dataset of KRAS mutant lung cancers from India. Brain metastases were higher in patients with G12C mutations and associated with poorer PFS and OS. G12C mutation and PS ≥ 2 were also associated with inferior PFS and OS. Experience with targeted therapy for KRAS mutations remains an area of future exploration due to the unavailability of these agents in India.
The diverse subtypes of thyroid carcinoma have distinct clinical outcomes despite a comparable spectrum of underlying genetic alterations. Beyond genetic alterations, sparse efforts have been made to ...characterize the microbes associated with thyroid cancer. In this study, we examine the microbial profile of thyroid cancer.
We sequenced the whole transcriptome of 70 thyroid cancers (40 papillary and 30 anaplastic). Using Infectious Pathogen Detector IPD 2.0, we analysed the relative abundance of 1060 microbes across 70 tumours from patients with thyroid cancer against 118 tumour samples from patients with breast, cervical, colorectal, and tongue cancer.
Our analysis reveals a significant prevalence of
in 58.6% thyroid cancer samples compared to other cancer types (
). Immune cell fraction analysis between thyroid cancer samples with high and low
loads identify enrichment of immunosuppressive cells, including Tregs (
), and other anti-inflammatory cytokines in the tumour microenvironment, suggesting an immune evasion/immunosuppression
is associated with the infection. A higher burden of
was also found to be associated with poor survival defining a distinct sub-group of thyroid cancer.
is associated with immune suppression and poor prognosis in a subpopulation of thyroid cancer. This study may help design novel therapeutic measures involving appropriate antibiotics to manage the disease better.
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