Biology subjects

De Sarkar, N.

Publications and source records attributed to De Sarkar, N..

3 recordsLinked to original sources

bioRxiv2023

Discovery of new deregulated miRNAs in gingivo buccal carcinoma using Group Benjamini Hochberg method: a commentary on "A quest for miRNA bio-marker: a track back approach from gingivo buccal cancer to two different types of precancers"

This formal comment is in response to "A quest for miRNA bio-marker: a track back approach from gingivo buccal cancer to two different types of precancers" written by De Sarkar and colleagues in 2014. The above-mentioned paper found seven miRNAs to be significantly deregulated in 18 gingivo-buccal cancer samples. However, they suspected more miRNAs to be deregulated based on their exploratory statistical analysis. To control the false discovery rate (FDR), the authors used the Benjamini Hochberg (BH) method, which does not leverage any available biological information on the miRNAs. In this work, we show that some specialized versions of the BH method, which can exploit positional information on the miRNAs, can lead to seven more discoveries with this data. Specifically, we group the closely located miRNAs, and use the group Benjamini Hochberg (GBH) methods (Hu et al., 2010), which reportedly have more statistical power than the BH method (Liu et al., 2019). The whole transcriptome analysis of Sing et al. (2017) and previous literature on the miRNAs suggest that most of the newly discovered miRNAs play a role in oncogenesis. In particular, the newly discovered miRNAs include hsa-miR-1 and hsa-miR-21-5p, whose cancer-related activities are well-established. Our findings indicate that incorporating the GBH method into suitable microarray studies may potentially enhance scientific discoveries via the exploitation of additional biological information.

cancer biology↗

bioRxiv2022

Nucleosome patterns in circulating tumor DNA reveal transcriptional regulation of advanced prostate cancer phenotypes

Advanced prostate cancers comprise distinct phenotypes, but tumor classification remains clinically challenging. Here, we harnessed circulating tumor DNA (ctDNA) to study tumor phenotypes by ascertaining nucleosome positioning patterns associated with transcription regulation. We sequenced plasma ctDNA whole genomes from patient-derived xenografts representing a spectrum of androgen receptor active (ARPC) and neuroendocrine (NEPC) prostate cancers. Nucleosome patterns associated with transcriptional activity were reflected in ctDNA at regions of genes, promoters, histone modifications, transcription factor binding, and accessible chromatin. We identified the activity of key phenotype-defining transcriptional regulators from ctDNA, including AR, ASCL1, HOXB13, HNF4G, and NR3C1. Using these features, we designed a prediction model which distinguished NEPC from ARPC in patient plasma samples across three clinical cohorts with 97-100% sensitivity and 85-100% specificity. While phenotype classification is typically assessed by immunohistochemistry or transcriptome profiling, we demonstrate that ctDNA provides comparable results with numerous diagnostic advantages for precision oncology. STATEMENT OF SIGNIFICANCEThis study provides key insights into the dynamics of nucleosome positioning and gene regulation associated with cancer phenotypes that can be ascertained from ctDNA. The new methods established for phenotype classification extend the utility of ctDNA beyond assessments of DNA alterations with important implications for molecular diagnostics and precision oncology.

cancer biology↗

bioRxiv2020

Reprogramming of the FOXA1 cistrome in treatment-emergent neuroendocrine prostate cancer

Lineage plasticity, the ability of a cell to alter its identity, is an increasingly common mechanism of adaptive resistance to targeted therapy in cancer1,2. An archetypal example is the development of neuroendocrine prostate cancer (NEPC) after treatment of prostate adenocarcinoma (PRAD) with inhibitors of androgen signaling. NEPC is an aggressive variant of prostate cancer that aberrantly expresses genes characteristic of neuroendocrine (NE) tissues and no longer depends on androgens. To investigate the epigenomic basis of this resistance mechanism, we profiled histone modifications in NEPC and PRAD patient-derived xenografts (PDXs) using chromatin immunoprecipitation and sequencing (ChIP-seq). We identified a vast network of cis-regulatory elements (N~15,000) that are recurrently activated in NEPC. The FOXA1 transcription factor (TF), which pioneers androgen receptor (AR) chromatin binding in the prostate epithelium3,4, is reprogrammed to NE-specific regulatory elements in NEPC. Despite loss of dependence upon AR, NEPC maintains FOXA1 expression and requires FOXA1 for proliferation and expression of NE lineage-defining genes. Ectopic expression of the NE lineage TFs ASCL1 and NKX2-1 in PRAD cells reprograms FOXA1 to bind to NE regulatory elements and induces enhancer activity as evidenced by histone modifications at these sites. Our data establish the importance of FOXA1 in NEPC and provide a principled approach to identifying novel cancer dependencies through epigenomic profiling.

cancer biology↗