David Sidransky

Late-stage cancers often lack effective management and treatment options, emphasizing the importance of early diagnosis for better prognosis and lower mortality rates. Molecular markers, such as DNA methylation tests, have shown promise in predicting and detecting cancer at its earliest stages. The COVID-19 post-pandemic scenario is providing a one in one-hundred-year opportunity of utilizing the excess installed PCR capacity world-wide to develop novel Quantitative Methylation Specific PCR (qMSP) screening strategies for cervical cancer screening in low-resource settings. This study aimed to compare the use of commercial bisulfite conversion kits in cervical epithelium liquid cytology samples (liquid cytology) from cancer screening clinics in the United States. Commercially available rapid bisulfite conversion protocols using silica spin column and magnetic beads were compared with conventional DNA …

Mitochondria are essential cellular organelles that play critical roles in cancer. Here, as part of the International Cancer Genome Consortium/The Cancer Genome Atlas Pan-Cancer Analysis of Whole Genomes Consortium, which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we performed a multidimensional, integrated characterization of mitochondrial genomes and related RNA sequencing data. Our analysis presents the most definitive mutational landscape of mitochondrial genomes and identifies several hypermutated cases. Truncating mutations are markedly enriched in kidney, colorectal and thyroid cancers, suggesting oncogenic effects with the activation of signaling pathways. We find frequent somatic nuclear transfers of mitochondrial DNA, some of which disrupt therapeutic target genes. Mitochondrial copy number varies greatly within and across cancers and …

Differentially methylated regions (DMRs) can be used as head and neck squamous cell carcinoma (HNSCC) diagnostic, prognostic and therapeutic targets in precision medicine workflows. DNA from 21 HNSCC and 10 healthy oral tissue samples was hybridized to a genome‑wide tiling array to identify DMRs in a discovery cohort. Downstream analyses identified differences in promoter DNA methylation patterns in oral, laryngeal and oropharyngeal anatomical regions associated with tumor differentiation, nodal involvement and survival. Genome‑wide DMR analysis showed 2,565 DMRs common to the three subsites. A total of 738 DMRs were unique to laryngeal cancer (n= 7), 889 DMRs were unique to oral cavity cancer (n= 10) and 363 DMRs were unique to pharyngeal cancer (n= 6). Based on the genome‑wide analysis and a Gene Ontology analysis, 10 candidate genes were selected to test for prognostic …

Ribosomes in cancer cells accumulate numerous patient-specific structural and functional modifications that facilitate tumor progression by modifying protein translation. We have taken a unique synthetic chemistry approach to generate novel macrolides, Ribosome modulating agents (RMA), that are proposed to act distal to catalytic sites and exploit cancer ribosome heterogeneity. The RMA ZKN-157 shows two levels of selectivity: (i) selective translation inhibition of a subset of proteins enriched for components of the ribosome and protein translation machinery that are upregulated by MYC; and (ii) selective inhibition of proliferation of a subset of colorectal cancer cell lines. Mechanistically, the selective ribosome targeting in sensitive cells triggered cell-cycle arrest and apoptosis. Consequently, in colorectal cancer, sensitivity to ZKN-157 in cell lines and patient-derived organoids was restricted to the consensus …

A study uses single-cell RNA sequencing to profile human papillomavirus (HPV)-positive and -negative oropharyngeal squamous cell carcinoma, revealing considerable diversity within and between tumors. Within HPV-positive tumors, subsets of malignant cells are found with undetectable HPV expression and decreased HPV-related phenotypes, which may influence prognosis and response to therapy.

Cervical cancer is one of the most common cancers in women. Despite progress in prevention through Human Papilloma Virus (HPV) vaccination and success in early detection of cervical cancer through cytologic screening and HPV detection, there remains an unequal cervical cancer burden in low-resource settings, both in developed and developing countries. We have previously shown that the CervicalMethDx test can provide a Cervical Intraepithelial Neoplasia (CIN) grade 2-3 risk score, by assessing DNA methylation in a panel of three human genes (ZNF516, FKBP6 and INTS1) in samples from the United States (US), Puerto Rico, and Chile. We now tested the performance of the CervicalMethDx test on HPV-positive CIN2 and CIN3 cases (n=113) from Honduras collected from participants in the ESTAMPA clinical trial (NCT01881659). ESTAMPA (EStudio multicéntrico de TAMizaje y triaje de cáncer de …

Head and neck squamous cell carcinoma (HNSCC) is a global health problem. Successful immunotherapy in HNSCC is currently based on the ability to block the interaction of PD1 and PDL1 and abolish the inhibition of CD8+ T cells, thus enhancing the antitumor activity. T cells recognize peptide antigens in the context of MHC molecules through the clonally distributed T Cell receptor (TCR), which offers the means to detect and track specific T cells. We characterized TCR signatures in unique HNSCC paired samples (including L = Lymphocyte, S = Saliva, T = Tumor) to profile TCR repertoire diversity and clonality in different compartments. A total of 48 HNSCC samples corresponding to 14 patients (2 assayed 2X) were obtained from Johns Hopkins University. DNA samples were submitted for TCR sequencing (TCR-seq) via enrichment of the human TCRB locus using Human-TCRB-PD4bx. CDR3 sequences …

Cervical cancer is one of the most common cancers in women. Despite progress in prevention through Human Papilloma Virus [HPV] vaccination and success in early detection of cervical cancer through cytologic screening and HPV detection, there remains an unequal burden in low-resource settings in developed and developing countries. Applying novel methylation-based detection methods, we validated a panel of three human methylated genes (ZNF516, FKBP6 and INTS1) on discarded cervical liquid cytology samples from clinical laboratories in the United States during the development of the CervicalMethDx test. We hypothesized that the CervicalMethDx test can identify HPV positive women most likely to be diagnosed with Cervical Intraepithelial Neoplasia (CIN) grades 2 and 3 by anatomic pathologists, before they are referred to colposcopy-driven biopsies. We assessed DNA methylation by Quantitative …