Evaluation of the Aggressive-Variant Prostate Cancer Molecular Signature in Clinical Laboratory Improvement Amendments (CLIA) Environments.

(AVPCs) are a subset of metastatic castrate-resistant prostate cancers (mCRPCs) characterized by defects in ≥ two of three of , , and (AVPCm), a profile linked to lineage plasticity, androgen indifference, and platinum sensitivity. Men with mCRPC undergoing biopsies for progression were assessed for AVPCm using immunohistochemistry (IHC), next-generation sequencing (NGS) of solid tumor DNA (stDNA), and NGS of circulating tumor DNA (ctDNA) assays in CLIA-certified labs. Biopsy characteristics, turnaround times, inter-reader concordance, and inter-assay concordance were assessed.

HIF2 Regulates Intestinal Wnt5a Expression.

Radiation therapy for abdominal tumors is challenging because the small intestine is exquisitely radiosensitive. Unfortunately, there are no FDA-approved therapies to prevent or mitigate GI radiotoxicity. The EGLN protein family are oxygen sensors that regulate cell survival and metabolism through the degradation of hypoxia-inducible factors (HIFs).

Pan cancer patterns of allelic imbalance from chromosomal alterations in 33 tumor types.

Somatic copy number alterations (SCNAs) serve as hallmarks of tumorigenesis and often result in deviations from one-to-one allelic ratios at heterozygous loci, leading to allelic imbalance (AI). The Cancer Genome Atlas (TCGA) reports SCNAs identified using a circular binary segmentation algorithm, providing segment mean copy number estimates from single-nucleotide polymorphism DNA microarray total intensities (log R ratio), but not allele-specific intensities ("B allele" frequencies) that inform of AI. Our approach provides more sensitive identification of SCNAs by modeling the "B allele" frequencies jointly, thereby bolstering the catalog of chromosomal alterations in this widely utilized resource.

Multiomics profiling of primary lung cancers and distant metastases reveals immunosuppression as a common characteristic of tumor cells with metastatic plasticity.

Background: Metastasis is the primary cause of cancer mortality accounting for 90% of cancer deaths. Our understanding of the molecular mechanisms driving metastasis is rudimentary.

Results: We perform whole exome sequencing (WES), RNA sequencing, methylation microarray, and immunohistochemistry (IHC) on 8 pairs of non-small cell lung cancer (NSCLC) primary tumors and matched distant metastases.

Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes.

Most patients diagnosed with resected pancreatic adenocarcinoma (PDAC) survive less than 5 years, but a minor subset survives longer. Here, we dissect the role of the tumor microbiota and the immune system in influencing long-term survival. Using 16S rRNA gene sequencing, we analyzed the tumor microbiome composition in PDAC patients with short-term survival (STS) and long-term survival (LTS).

Mitochondrial fusion exploits a therapeutic vulnerability of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) requires mitochondrial oxidative phosphorylation (OXPHOS) to fuel its growth, however, broadly inhibiting this pathway might also disrupt essential mitochondrial functions in normal tissues. PDAC cells exhibit abnormally fragmented mitochondria that are essential to its oncogenicity, but it was unclear if this mitochondrial feature was a valid therapeutic target. Here, we present evidence that normalizing the fragmented mitochondria of pancreatic cancer via the process of mitochondrial fusion reduces OXPHOS, which correlates with suppressed tumor growth and improved survival in preclinical models.

Genomic landscape of allelic imbalance in premalignant atypical adenomatous hyperplasias of the lung.

Background: Genomic investigation of atypical adenomatous hyperplasia (AAH), the only known precursor lesion to lung adenocarcinomas (LUAD), presents challenges due to the low mutant cell fractions. This necessitates sensitive methods for detection of chromosomal aberrations to better study the role of critical alterations in early lung cancer pathogenesis and the progression from AAH to LUAD.

Methods: We applied a sensitive haplotype-based statistical technique to detect chromosomal alterations leading to allelic imbalance (AI) from genotype array profiling of 48 matched normal lung parenchyma, AAH and tumor tissues from 16 stage-I LUAD patients.

Driver Mutations in Normal Airway Epithelium Elucidate Spatiotemporal Resolution of Lung Cancer.

Uninvolved normal-appearing airway epithelium has been shown to exhibit specific mutations characteristic of nearby non-small cell lung cancers (NSCLCs). Yet, its somatic mutational landscape in patients with early-stage NSCLC is unknown. To comprehensively survey the somatic mutational architecture of the normal airway epithelium in patients with early-stage NSCLC.

Classifying mild traumatic brain injuries with functional network analysis.

Background: Traumatic brain injury (TBI) represents a critical health problem of which timely diagnosis and treatment remain challenging. TBI is a result of an external force damaging brain tissue, accompanied by delayed pathogenic events which aggravate the injury. Molecular responses to different mild TBI subtypes have not been well characterized.

Directional allelic imbalance profiling and visualization from multi-sample data with RECUR.

Motivation: Genetic analysis of cancer regularly includes two or more samples from the same patient. Somatic copy number alterations leading to allelic imbalance (AI) play a critical role in cancer initiation and progression. Directional analysis and visualization of the alleles in imbalance in multi-sample settings allow for inference of recurrent mutations, providing insights into mutation rates, clonality and the genomic architecture and etiology of cancer.

Single-Cell Transcriptomics of Pancreatic Cancer Precursors Demonstrates Epithelial and Microenvironmental Heterogeneity as an Early Event in Neoplastic Progression.

Purpose: Early detection of pancreatic ductal adenocarcinoma (PDAC) remains elusive. Precursor lesions of PDAC, specifically intraductal papillary mucinous neoplasms (IPMNs), represent a pathway to invasive neoplasia, although the molecular correlates of progression remain to be fully elucidated. Single-cell transcriptomics provides a unique avenue for dissecting both the epithelial and microenvironmental heterogeneities that accompany multistep progression from noninvasive IPMNs to PDAC.

DNA Sequencing of Small Bowel Adenocarcinomas Identifies Targetable Recurrent Mutations in the ERBB2 Signaling Pathway.

Purpose: Little is known about the genetic alterations characteristic of small bowel adenocarcinoma (SBA). Our purpose was to identify targetable alterations and develop experimental models of this disease. Whole-exome sequencing (WES) was completed on 17 SBA patient samples and targeted-exome sequencing (TES) on 27 samples to confirm relevant driver mutations.

Circulating Nucleic Acids Are Associated With Outcomes of Patients With Pancreatic Cancer.

Background & Aims: We aimed to investigate the clinical utility of circulating tumor cell DNA (ctDNA) and exosome DNA (exoDNA) in pancreatic cancer.

Methods: We collected liquid biopsy samples from 194 patients undergoing treatment for localized or metastatic pancreatic adenocarcinoma from April 7, 2015, through October 13, 2017 (425 blood samples collected before [baseline] and during therapy). Additional liquid biopsy samples were collected from 37 disease control individuals.

Assessing inter-component heterogeneity of biphasic uterine carcinosarcomas.

Objective: Uterine carcinosarcoma (UCS) is a rare and aggressive form of uterine cancer. It is bi-phasic, exhibiting histological features of both malignant epithelial (carcinoma) and mesenchymal (sarcoma) elements, reflected in ambiguity in accepted treatment guidelines. We sought to study the genomic and transcriptomic profiles of these elements individually to gain further insights into the development of these tumors.

Immune Profiling of Premalignant Lesions in Patients With Lynch Syndrome.

Importance: Colorectal carcinomas in patients with Lynch syndrome (LS) arise in a background of mismatch repair (MMR) deficiency, display a unique immune profile with upregulation of immune checkpoints, and response to immunotherapy. However, there is still a gap in understanding the pathogenesis of MMR-deficient colorectal premalignant lesions, which is essential for the development of novel preventive strategies for LS.

Objective: To characterize the immune profile of premalignant lesions from a cohort of patients with LS.

Dynamic changes during the treatment of pancreatic cancer.

This manuscript follows a single patient with pancreatic adenocarcinoma for a five year period, detailing the clinical record, pathology, the dynamic evolution of molecular and cellular alterations as well as the responses to treatments with chemotherapies, targeted therapies and immunotherapies. DNA and RNA samples from biopsies and blood identified a dynamic set of changes in allelic imbalances and copy number variations in response to therapies. Organoid cultures established from biopsies over time were employed for extensive drug testing to determine if this approach was feasible for treatments.

Strategies for identification of somatic variants using the Ion Torrent deep targeted sequencing platform.

Background: 'Next-generation' (NGS) sequencing has wide application in medical genetics, including the detection of somatic variation in cancer. The Ion Torrent-based (IONT) platform is among NGS technologies employed in clinical, research and diagnostic settings. However, identifying mutations from IONT deep sequencing with high confidence has remained a challenge.

Mutational Heterogeneity in and Arises at the Crypt Level and Leads to Polyclonality in Early Colorectal Tumorigenesis.

The majority of genomic alterations causing intratumoral heterogeneity (ITH) in colorectal cancer are thought to arise during early stages of carcinogenesis as a burst but only after truncal mutations in have expanded a single founder clone. We have investigated if the initial source of ITH is consequent to multiple independent lineages derived from different crypts harboring distinct truncal and driver mutations, thus challenging the prevailing monoclonal monocryptal model. High-depth next-generation sequencing and SNP arrays were performed in whole-lesion extracts of 37 familial adenomatous polyposis colorectal adenomas.

Rapid and powerful detection of subtle allelic imbalance from exome sequencing data with hapLOHseq.

Motivation: The detection of subtle genomic allelic imbalance events has many potential applications. For example, identifying cancer-associated allelic imbalanced regions in low tumor-cellularity samples or in low-proportion tumor subclones can be used for early cancer detection, prognostic assessment and therapeutic selection in cancer patients. We developed hapLOHseq for the detection of subtle allelic imbalance events from next-generation sequencing data.

Genomic Landscape of Colorectal Mucosa and Adenomas.

The molecular basis of the adenoma-to-carcinoma transition has been deduced using comparative analysis of genetic alterations observed through the sequential steps of intestinal carcinogenesis. However, comprehensive genomic analyses of adenomas and at-risk mucosa are still lacking. Therefore, our aim was to characterize the genomic landscape of colonic at-risk mucosa and adenomas.

Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism.

Cancer-associated fibroblasts (CAFs) are a major cellular component of tumor microenvironment in most solid cancers. Altered cellular metabolism is a hallmark of cancer, and much of the published literature has focused on neoplastic cell-autonomous processes for these adaptations. We demonstrate that exosomes secreted by patient-derived CAFs can strikingly reprogram the metabolic machinery following their uptake by cancer cells.

Genetic risk factors for the development of osteonecrosis in children under age 10 treated for acute lymphoblastic leukemia.

Osteonecrosis is a dose-limiting toxicity in the treatment of pediatric acute lymphoblastic leukemia (ALL). Prior studies on the genetics of osteonecrosis have focused on patients ≥10 years of age, leaving the genetic risk factors for the larger group of children <10 years incompletely understood. Here, we perform the first evaluation of genetic risk factors for osteonecrosis in children <10 years.