Biology subjects

Choudhury, A. D.

Publications and source records attributed to Choudhury, A. D..

7 recordsLinked to original sources

bioRxiv2024

DirectHRD enables sensitive scar-based classification of homologous recombination deficiency (HRD)

Homologous recombination deficiency (HRD) is a predictive biomarker for efficacy of PARP inhibition and platinum chemotherapy but remains challenging to detect from low tumor fraction samples such as liquid biopsies. Here, we describe DirectHRD, a whole-genome sequencing (WGS) scar-based classifier that is 10x more sensitive than state-of-the-art methods. DirectHRD can detect HRD at >=1% tumor fraction using 50x WGS of cell-free DNA.

bioinformatics↗

bioRxiv2024

FinaleMe: Predicting DNA methylation by the fragmentation patterns of plasma cell-free DNA

Analysis of DNA methylation in cell-free DNA (cfDNA) reveals clinically relevant biomarkers but requires specialized protocols and sufficient input material that limits its applicability. Millions of cfDNA samples have been profiled by genomic sequencing. To maximize the gene regulation information from the existing dataset, we developed FinaleMe, a non-homogeneous Hidden Markov Model (HMM), to predict DNA methylation of cfDNA and, therefore, tissues-of-origin directly from plasma whole-genome sequencing (WGS). We validated the performance with 80 pairs of deep and shallow-coverage WGS and whole-genome bisulfite sequencing (WGBS) data.

bioinformatics↗

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↗

bioRxiv2022

CRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer

Prostate cancer (PCa) harboring BRCA1/2 mutations is often exquisitely sensitive to PARP inhibition. However, genomic alterations in other DNA damage response genes have not been consistently predictive of clinical response to PARP inhibitors (PARPis). Here, we perform genome-wide CRISPR-Cas9 knockout screens in BRCA1/2-proficient PCa cell lines and identify novel genes whose loss has a profound impact on PARPi sensitivity and resistance. Specifically, MMS22L deletion, frequently observed (up to 14%) in PCa, renders cells hypersensitive to PARPis by disrupting RAD51 loading required for homologous recombination repair, although this response is TP53-dependent. Unexpectedly, loss of CHEK2 confers resistance rather than sensitivity to PARPis in PCa cells through increased expression of BRCA2, a target of CHEK2-TP53-E2F7-mediated transcriptional repression. Combined PARP and ATR inhibition overcomes PARPi resistance caused by CHEK2 loss. Our findings may inform the use of PARPis beyond BRCA1/2-deficient tumors and support reevaluation of currently used biomarkers for PARPi treatment in PCa.

cancer biology↗

bioRxiv2022

Patterns of Structural Variation Define Prostate Cancer Across Disease States

The complex genomic landscape of prostate cancer evolves across disease states under therapeutic pressure directed toward inhibiting androgen receptor (AR) signaling. While significantly altered genes in prostate cancer have been extensively defined, there have been fewer systematic analyses of how structural variation shapes the genomic landscape of this disease across disease states. We uniformly characterized structural alterations across 278 localized and 143 metastatic prostate cancers profiled by whole genome and transcriptome sequencing. We observed distinct significantly recurrent breakpoints in localized and metastatic castration-resistant prostate cancers (mCRPC), with pervasive alterations in noncoding regions flanking the AR, MYC, FOXA1, and LSAMP genes enriched in mCRPC and TMPRSS2-ERG rearrangements enriched in localized prostate cancer. We defined nine subclasses of mCRPC based on signatures of structural variation, each associated with distinct genetic features and clinical outcomes. Our results comprehensively define patterns of structural variation in prostate cancer and identify clinically actionable subgroups based on whole genome profiling.

genomics↗

bioRxiv2021

MAESTRO affords 'breadth and depth' for mutation testing

The ability to assay large numbers of low-abundance mutations is crucial in biomedicine. Yet, the technical hurdles of sequencing multiple mutations at extremely high depth and accuracy remain daunting. For sequencing low-level mutations, its either depth or breadth but not both. Here, we report a simple and powerful approach to accurately track thousands of distinct mutations with minimal reads. Our technique called MAESTRO (minor allele enriched sequencing through recognition oligonucleotides) employs massively-parallel mutation enrichment to empower duplex sequencing--one of the most accurate methods--to track up to 10,000 low-frequency mutations with up to 100-fold less sequencing. In example use cases, we show that MAESTRO could enable mutation validation from cancer genome sequencing studies. We also show that it could track thousands of mutations from a patients tumor in cell-free DNA, which may improve detection of minimal residual disease from liquid biopsies. In all, MAESTRO improves the breadth, depth, accuracy, and efficiency of mutation testing.

molecular biology↗

bioRxiv2019

Targeting EZH2 Increases Therapeutic Efficacy of Check-Point Blockade in Models of Prostate Cancer

Prostate cancers are considered immunologically cold tumors given the very few patients who respond to checkpoint inhibitor therapy (CPI). Recently, enrichment of interferon (IFN) response genes predicts a favorable response to CPI across various disease sites. The enhancer of zeste homolog-2 (EZH2) is over-expressed in prostate cancer and is known to negatively regulate IFN response genes. Here, we demonstrate that inhibition of EZH2 catalytic activity in prostate cancer models derepresses expression of double-strand RNA (dsRNA), associated with upregulation of genes involved in antigen presentation, Th-1 chemokine signaling, and interferon (IFN) response, including PD-L1. Similarly, application of a novel EZH2 derived gene signature to human prostate sample analysis indicated an inverse correlation between tumor EZH2 activity/expression with T-cell inflamed and IFN gene signatures and PD-L1 expression. EZH2 inhibition combined with PD-1 CPI significantly enhances antitumor response that is dependent on up-regulation of tumor PD-L1 expression. Further, combination therapy significantly increases intratumoral trafficking of activated CD8+ T-cells and M1 tumor associated macrophages (TAMs) with concurrent loss of M2 TAMs. Our study identifies EZH2 as a potent inhibitor of antitumor immunity and responsiveness to CPI. This data suggests EZH2 inhibition as a novel therapeutic direction to enhance prostate cancer response to PD-1 CPI.

cancer biology↗