Publications by authors named "Trevor J Pugh"

The naked mole-rat (NMR; ) is a eusocial subterranean rodent with a highly unusual set of physiological traits that has attracted great interest amongst the scientific community. However, the genetic basis of most of these traits has not been elucidated. To facilitate our understanding of the molecular mechanisms underlying NMR physiology and behaviour, we generated a long-read chromosomal-level genome assembly of the NMR.

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Background And Objectives: Adoption of molecular classification in endometrial cancer (EC) into clinical practice remains challenging due to complexity in coordination of multiple assays. We aimed to develop a simple molecular technique to classify ECs into four subgroups using our custom-designed targeted sequencing panel.

Methods: Patients with newly diagnosed ECs were prospectively recruited from three cancer centres in Ontario, Canada.

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A diverse antibody repertoire is essential for humoral immunity. Antibody diversification requires the introduction of deoxyuridine (dU) mutations within immunoglobulin genes to initiate somatic hypermutation (SHM) and class switch recombination (CSR). dUs are normally recognized and excised by the base excision repair (BER) protein uracil-DNA glycosylase 2 (UNG2).

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Germline pathogenic TP53 variants predispose individuals to a high lifetime risk of developing multiple cancers and are the hallmark feature of Li-Fraumeni syndrome (LFS). Our group has previously shown that LFS patients harbor shorter plasma cell-free DNA fragmentation; independent of cancer status. To understand the functional underpinning of cfDNA fragmentation in LFS, we conducted a fragmentomic analysis of 199 cfDNA samples from 82 TP53 mutation carriers and 30 healthy TP53-wildtype controls.

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Purpose: Immune gene expression signatures are emerging as potential biomarkers for immunotherapy (IO). VIGex is a 12-gene expression classifier developed in both nCounter (Nanostring) and RNA sequencing (RNA-seq) assays and analytically validated across laboratories. VIGex classifies tumor samples into hot, intermediate-cold (I-Cold), and cold subgroups.

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Background: The use of immunotherapy in mismatch repair proficient colorectal cancer (pMMR-CRC) or pancreatic adenocarcinoma (PDAC) is associated with limited efficacy. DAPPER (NCT03851614) is a phase 2, basket study randomizing patients with pMMR CRC or PDAC to durvalumab with olaparib (durvalumab + olaparib) or durvalumab with cediranib (durvalumab + cediranib).

Methods: PDAC or pMMR-CRC patients were randomized to either durvalumab+olaparib (arm A), or durvalumab + cediranib (arm B).

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Article Synopsis
  • CREBBP and KMT2D are important genes that, when mutated together, can lead to more serious lymphomas in mice compared to when either gene is mutated alone.
  • These mutations create an environment where T-cells, which are important for fighting off infections and cancer, become tired and fail to function properly.
  • The study discovered that the mutations affect how the immune system interacts with lymphoma cells, showing that these gene changes work together to help cancer grow.
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Unlabelled: Early kinetics of circulating tumor DNA (ctDNA) in plasma predict response to pembrolizumab but typically requires sequencing of matched tumor tissue or fixed gene panels. We analyzed genome-wide methylation and fragment-length profiles using cell-free methylated DNA immunoprecipitation and sequencing (cfMeDIP-seq) in 204 plasma samples from 87 patients before and during treatment with pembrolizumab from a pan-cancer phase II investigator-initiated trial (INSPIRE). We trained a pan-cancer methylation signature using independent methylation array data from The Cancer Genome Atlas to quantify cancer-specific methylation (CSM) and fragment-length score (FLS) for each sample.

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  • Researchers looked at the costs and benefits of a special genetic test called NGS for patients with advanced cancer in a study done in Canada.
  • The study compared patients who had the NGS test to those who didn’t, to see if it helped them live longer or join clinical trials.
  • They found that while the NGS test cost more, it did lead to more patients joining clinical trials and had better quality of care at the end of life, but it didn't really help them live longer overall.
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Immunotherapies targeting PD-1/PD-L1 are now widely used in the clinic to treat a variety of malignancies. While most of the research on T cell exhaustion and PD-1 blockade has been focused on conventional αβ T cells, the contribution of innate-like T cells such as γδ T cells to anti-PD-1/PD-L1 mediated therapy is limited. Here we show that tumor reactive γδ T cells respond to PD-1 blockade in a Merkel cell carcinoma (MCC) patient experiencing a complete response to therapy.

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Article Synopsis
  • - A new immune-based gene expression risk score was created to predict distant metastases (DM) in cervical cancer patients, based on RNA sequencing of tumor biopsies from 81 individuals before treatment.
  • - The risk score, derived from 55 immune-related genes, was validated in additional patient cohorts and showed strong predictive ability for both DM and lower cause-specific survival, with higher scores linked to lower levels of immune cells in the tumor microenvironment.
  • - The study emphasizes the relationship between high tumor mutational burden, a lack of immune cells in tumors (classified as "cold"), and the increased risk of metastatic recurrence, urging further validation of the risk score for clinical use.
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Objectives: Abnormalities in mismatch repair have been described in ovarian cancer, but few studies have examined the causes of mismatch repair deficiency (MMRd). To address this, we completed targeted mutational and methylation sequencing on MMRd ovarian cancer cases. The objective of this study was to explore the molecular mechanism of MMRd using our targeted next generation sequencing panel.

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Article Synopsis
  • People with Li-Fraumeni syndrome (LFS) have a near 100% chance of developing cancer due to a mutation in the TP53 gene and undergo regular cancer screening.
  • A new liquid biopsy test combining various sequencing techniques was tested on 89 LFS patients, showing improved cancer detection rates compared to traditional methods.
  • This integrated testing approach demonstrated earlier detection of cancer signals, highlighting its potential as a valuable tool in patient care, although further validation is needed before widespread use.
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Unlabelled: Immune checkpoint inhibition (ICI) is effective for replication-repair-deficient, high-grade gliomas (RRD-HGG). The clinical/biological impact of immune-directed approaches after failing ICI monotherapy is unknown. We performed an international study on 75 patients treated with anti-PD-1; 20 are progression free (median follow-up, 3.

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Hereditary cancer syndromes (HCS) predispose individuals to a higher risk of developing multiple cancers. However, current screening strategies have limited ability to screen for all cancer risks. Circulating tumour DNA (ctDNA) detects DNA fragments shed by tumour cells in the bloodstream and can potentially detect cancers early.

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Article Synopsis
  • At least 5% of cancer diagnoses are linked to hereditary cancer syndromes (HCS), leading to lifelong monitoring and anxiety for those affected.
  • The CHARM Consortium was established in 2017 by genetics centers in Canada to explore the clinical validity of cell-free DNA (cfDNA) sequencing as a non-invasive cancer monitoring method for individuals with HCS.
  • The consortium aims to shift cancer surveillance strategies towards more accessible and frequent monitoring, leveraging early detection opportunities identified through their research on commonly characterized HCSs like hereditary breast and ovarian cancer and Lynch syndrome.
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Background: Neuroblastoma is an embryonal cancer of the developing sympathetic nervous system. The genetic contribution of rare pathogenic or likely pathogenic germline variants in patients without a family history remains unclear.

Methods: Germline DNA sequencing was performed on 786 neuroblastoma patients.

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Background: Cancer immunotherapies including immune checkpoint inhibitors and Chimeric Antigen Receptor (CAR) T-cell therapy have shown variable response rates in paediatric patients highlighting the need to establish robust biomarkers for patient selection. While the tumour microenvironment in adults has been widely studied to delineate determinants of immune response, the immune composition of paediatric solid tumours remains relatively uncharacterized calling for investigations to identify potential immune biomarkers.

Methods: To inform immunotherapy approaches in paediatric cancers with embryonal origin, we performed an immunogenomic analysis of RNA-seq data from 925 treatment-naïve paediatric nervous system tumours (pedNST) spanning 12 cancer types from three publicly available data sets.

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Article Synopsis
  • International cancer registries, like AACR Project GENIE, provide access to genomic and clinical data from over 130,000 cancer patients, but analyzing this combined data can be tricky.
  • The cBioPortal for Cancer Genomics has improved its features to help visualize and analyze longitudinal clinical and genomic data, allowing users to see how treatment impacts patient outcomes over time.
  • These enhancements enable researchers and clinicians to explore complex datasets, fostering discoveries on how specific genomic changes affect cancer prognosis and treatment effectiveness.
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The role of the immune microenvironment in maintaining disease remission in patients with multiple myeloma (MM) is not well understood. In this study, we comprehensively profile the immune system in patients with newly diagnosed MM receiving continuous lenalidomide maintenance therapy with the aim of discovering correlates of long-term treatment response. Leveraging single-cell RNA sequencing and T cell receptor β sequencing of the peripheral blood and CyTOF mass cytometry of the bone marrow, we longitudinally characterize the immune landscape in 23 patients before and one year after lenalidomide exposure.

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The GENCOV study aims to identify patient factors which affect COVID-19 severity and outcomes. Here, we aimed to evaluate patient characteristics, acute symptoms and their persistence, and associations with hospitalization. Participants were recruited at hospital sites across the Greater Toronto Area in Ontario, Canada.

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Background: Immunotherapy is effective, but current biomarkers for patient selection have proven modest sensitivity. Here, we developed VIGex, an optimized gene signature based on the expression level of 12 genes involved in immune response with RNA sequencing.

Methods: We implemented VIGex using the nCounter platform (Nanostring) on a large clinical cohort encompassing 909 tumor samples across 45 tumor types.

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Multiple primary tumors (MPTs) are a harbinger of hereditary cancer syndromes. Affected individuals often fit genetic testing criteria for a number of hereditary cancer genes and undergo multigene panel testing. Other genomic testing options, such as whole exome (WES) and whole genome sequencing (WGS) are available, but the utility of these genomic approaches as a second-tier test for those with uninformative multigene panel testing has not been explored.

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Summary: Cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) has emerged as a promising liquid biopsy technology to detect cancers and monitor treatments. While several bioinformatics tools for DNA methylation analysis have been adapted for cfMeDIP-seq data, an end-to-end pipeline and quality control framework specifically for this data type is still lacking. Here, we present the MEDIPIPE, which provides a one-stop solution for cfMeDIP-seq data quality control, methylation quantification, and sample aggregation.

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Article Synopsis
  • Li-Fraumeni syndrome (LFS) is a hereditary condition linked to a higher risk of various cancers, with about 70% of affected individuals carrying a detectable genetic variant, but some still remain cancer-free.
  • Researchers analyzed the genomes of 396 LFS patients to uncover additional cancer-related genetic factors and identified alternative cancer-associated mutations in those without a known variant.
  • The study highlights the need for more comprehensive genetic testing in LFS patients and suggests that cancer risk cannot be solely attributed to single gene mutations, but rather involves a complex interplay of genetic and epigenetic factors.
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