Whole genome and transcriptome analysis of pancreatic acinar cell carcinoma elucidates mechanisms of homologous recombination deficiency and unravels novel relevant fusion events.

Pancreatic acinar cell carcinoma (PACC) is a rare pancreatic tumor with a heterogeneous clinical course and, except for radical surgery, limited treatment options. We present a comprehensive study encompassing whole-genome and RNA sequencing of 7 tumor samples from 3 metastatic PACC patients to further delineate its genomic landscape and potential therapeutic implications. Our findings reveal distinct signatures of homologous recombination deficiency (HRD) in patients harboring pathogenic germline BRCA1/2 and FANCL mutations, demonstrating favorable responses to poly (ADP-ribose) polymerase 1 (PARP) inhibitors with prolonged disease-free intervals.

Emerging molecular phenotypes and potential therapeutic targets in esophageal and gastric adenocarcinoma unearthed by whole genome and transcriptome analyses.

Background: Adenocarcinoma of the esophagus and stomach demands a deeper molecular understanding to advance treatment strategies and improve patient outcomes. Here, we profiled the genome and transcriptome landscape of these cancers, explored molecular characteristics that are undetectable by other sequencing platforms, and analyzed their potential clinical ramifications.

Methods: Our study employed state-of-the-art integrative analyses of whole genome and transcriptome sequencing on 51 matched tumor and germline samples from 46 patients.

Novel structural variants that impact cell cycle genes are elucidated in metastatic gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasm of the digestive tract. Despite multiple therapeutic advances, patients with advanced disease frequently develop resistance to tyrosine kinase inhibitors (TKIs), and therefore represent a therapeutic challenge. We employed whole genome sequencing (WGS) on three metastatic GISTs refractory to various TKIs and explored a publicly available cohort of 499 GISTs.

Enhancing the detection of clinically relevant biomarkers in advanced uterine and tubo-ovarian carcinomas through genome-wide analysis.

Background: Advanced-stage tube-ovarian cancers (TOC) and uterine cancers (UC) significantly contribute to cancer mortality. While surgery achieves clinical remission in most cases, recurrence often necessitates systemic therapy. Recent molecular phenotype studies have advanced targeted therapies.

Whole genome sequencing elucidates etiological differences in MCPyV-negative Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine neoplasm of the skin. Immunosuppression, ultraviolet radiation and the integration of Merkel cell polyomavirus (MCPyV) have all been shown to be involved in the pathogenesis of this malignancy. We performed whole genome sequencing on two MCPyV-negative cases of MCC that demonstrated very different clinical presentations and outcomes, and mutational profiles.

Integrative Transcriptomic and Single-Cell Protein Characterization of Colorectal Carcinoma Delineates Distinct Tumor Immune Microenvironments Associated with Overall Survival.

Colorectal carcinoma (CRC) is a heterogeneous group of tumors with varying therapeutic response and prognosis, and evidence suggests the tumor immune microenvironment (TIME) plays a pivotal role. Using advanced molecular and spatial biology technologies, we aimed to evaluate the TIME in patients with CRC to determine whether specific alterations in the immune composition correlated with prognosis. We identified primary and metastatic tumor samples from 31 consented patients, which were profiled with whole-exome sequencing and bulk RNA-seq.

Whole-Genome Sequencing Analysis of Male Breast Cancer Unveils Novel Structural Events and Potential Therapeutic Targets.

The molecular characterization of male breast cancer (MaBC) has received limited attention in research, mostly because of its low incidence rate, accounting for only 0.5% to 1% of all reported cases of breast cancer each year. Managing MaBC presents significant challenges, with most treatment protocols being adapted from those developed for female breast cancer.

Noninvasive Detection of Neuroendocrine Prostate Cancer through Targeted Cell-free DNA Methylation.

Unlabelled: Castration-resistant prostate cancer (CRPC) is a heterogeneous disease associated with phenotypic subtypes that drive therapy response and outcome differences. Histologic transformation to castration-resistant neuroendocrine prostate cancer (CRPC-NE) is associated with distinct epigenetic alterations, including changes in DNA methylation. The current diagnosis of CRPC-NE is challenging and relies on metastatic biopsy.

Evolution of structural rearrangements in prostate cancer intracranial metastases.

Intracranial metastases in prostate cancer are uncommon but clinically aggressive. A detailed molecular characterization of prostate cancer intracranial metastases would improve our understanding of their pathogenesis and the search for new treatment strategies. We evaluated the clinical and molecular characteristics of 36 patients with metastatic prostate cancer to either the dura or brain parenchyma.

Long-molecule scars of backup DNA repair in BRCA1- and BRCA2-deficient cancers.

Homologous recombination (HR) deficiency is associated with DNA rearrangements and cytogenetic aberrations. Paradoxically, the types of DNA rearrangements that are specifically associated with HR-deficient cancers only minimally affect chromosomal structure. Here, to address this apparent contradiction, we combined genome-graph analysis of short-read whole-genome sequencing (WGS) profiles across thousands of tumours with deep linked-read WGS of 46 BRCA1- or BRCA2-mutant breast cancers.

Immunogenomic Landscape of Neuroendocrine Prostate Cancer.

Purpose: Patients with neuroendocrine prostate cancer (NEPC) are often managed with immunotherapy regimens extrapolated from small-cell lung cancer (SCLC). We sought to evaluate the tumor immune landscape of NEPC compared with other prostate cancer types and SCLC.

Experimental Design: In this retrospective study, a cohort of 170 patients with 230 RNA-sequencing and 104 matched whole-exome sequencing data were analyzed.

Multicenter phase 2 study of oral azacitidine (CC-486) plus CHOP as initial treatment for PTCL.

Peripheral T-cell lymphomas (PTCL) with T-follicular helper phenotype (PTCL-TFH) has recurrent mutations affecting epigenetic regulators, which may contribute to aberrant DNA methylation and chemoresistance. This phase 2 study evaluated oral azacitidine (CC-486) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) as initial treatment for PTCL. CC-486 at 300 mg daily was administered for 7 days before C1 of CHOP, and for 14 days before CHOP C2-6.

Case report: Metastatic urothelial cancer with an exceptional response to immunotherapy and comprehensive understanding of the tumor and the tumor microenvironment.

Although immune checkpoint inhibitors (ICIs) are increasingly used as second-line treatments for urothelial cancer (UC), only a small proportion of patients respond. Therefore, understanding the mechanisms of response to ICIs is critical to improve clinical outcomes for UC patients. The tumor microenvironment (TME) is recognized as a key player in tumor progression and the response to certain anti-cancer treatments.

Allele-informed copy number evaluation of plasma DNA samples from metastatic prostate cancer patients: the PCF_SELECT consortium assay.

Sequencing of cell-free DNA (cfDNA) in cancer patients' plasma offers a minimally-invasive solution to detect tumor cell genomic alterations to aid real-time clinical decision-making. The reliability of copy number detection decreases at lower cfDNA tumor fractions, limiting utility at earlier stages of the disease. To test a novel strategy for detection of allelic imbalance, we developed a prostate cancer bespoke assay, PCF_SELECT, that includes an innovative sequencing panel covering ∼25 000 high minor allele frequency SNPs and tailored analytical solutions to enable allele-informed evaluation.

Weakly-supervised tumor purity prediction from frozen H&E stained slides.

Background: Estimating tumor purity is especially important in the age of precision medicine. Purity estimates have been shown to be critical for correction of tumor sequencing results, and higher purity samples allow for more accurate interpretations from next-generation sequencing results. Molecular-based purity estimates using computational approaches require sequencing of tumors, which is both time-consuming and expensive.

Tumor-immune microenvironment revealed by Imaging Mass Cytometry in a metastatic sarcomatoid urothelial carcinoma with a prolonged response to pembrolizumab.

Sarcomatoid urothelial carcinoma (SUC) is a rare subtype of urothelial carcinoma (UC) that typically presents at an advanced stage compared to more common variants of UC. Locally advanced and metastatic UC have a poor long-term survival following progression on first-line platinum-based chemotherapy. Antibodies directed against the programmed cell death 1 protein (PD-1) or its ligand (PD-L1) are now approved to be used in these scenarios.

Detecting Neuroendocrine Prostate Cancer Through Tissue-Informed Cell-Free DNA Methylation Analysis.

Purpose: Neuroendocrine prostate cancer (NEPC) is a resistance phenotype that emerges in men with metastatic castration-resistant prostate adenocarcinoma (CR-PRAD) and has important clinical implications, but is challenging to detect in practice. Herein, we report a novel tissue-informed epigenetic approach to noninvasively detect NEPC.

Experimental Design: We first performed methylated immunoprecipitation and high-throughput sequencing (MeDIP-seq) on a training set of tumors, identified differentially methylated regions between NEPC and CR-PRAD, and built a model to predict the presence of NEPC (termed NEPC Risk Score).

Extracellular Matrix in Synthetic Hydrogel-Based Prostate Cancer Organoids Regulate Therapeutic Response to EZH2 and DRD2 Inhibitors.

Following treatment with androgen receptor (AR) pathway inhibitors, ≈20% of prostate cancer patients progress by shedding their AR-dependence. These tumors undergo epigenetic reprogramming turning castration-resistant prostate cancer adenocarcinoma (CRPC-Adeno) into neuroendocrine prostate cancer (CRPC-NEPC). No targeted therapies are available for CRPC-NEPCs, and there are minimal organoid models to discover new therapeutic targets against these aggressive tumors.