Development of a clinical polygenic risk score assay and reporting workflow.

Implementation of polygenic risk scores (PRS) may improve disease prevention and management but poses several challenges: the construction of clinically valid assays, interpretation for individual patients, and the development of clinical workflows and resources to support their use in patient care. For the ongoing Veterans Affairs Genomic Medicine at Veterans Affairs (GenoVA) Study we developed a clinical genotype array-based assay for six published PRS. We used data from 36,423 Mass General Brigham Biobank participants and adjustment for population structure to replicate known PRS-disease associations and published PRS thresholds for a disease odds ratio (OR) of 2 (ranging from 1.

Case Report: A Rare Case of Esophagogastric Junctional Squamous Cell Carcinoma After the Successful Treatment of Neuroendocrine Carcinoma: Clonal Tumor Evolution Revealed by Genetic Analysis.

Neuroendocrine carcinoma (NEC) of the esophagogastric junction (EGJ) is a rare disease with no established treatments. Herein, we describe a case of recurrent squamous cell carcinoma (SCC) after achieving complete response to chemotherapy against NEC of the EGJ. A 67-year-old man was referred to our hospital because of epigastric discomfort.

Effect of Low-dose and Standard-dose Aspirin on PGE Biosynthesis Among Individuals with Colorectal Adenomas: A Randomized Clinical Trial.

Low-dose aspirin is recommended by the U.S. Preventive Services Task Force for primary prevention of colorectal cancer in certain individuals.

Hepatic gap junctions amplify alcohol liver injury by propagating cGAS-mediated IRF3 activation.

Alcohol-related liver disease (ALD) accounts for the majority of cirrhosis and liver-related deaths worldwide. Activation of IFN-regulatory factor (IRF3) initiates alcohol-induced hepatocyte apoptosis, which fuels a robust secondary inflammatory response that drives ALD. The dominant molecular mechanism by which alcohol activates IRF3 and the pathways that amplify inflammatory signals in ALD remains unknown.

Homologous Recombination Repair Truncations Predict Hypermutation in Microsatellite Stable Colorectal and Endometrial Tumors.

Introduction: Somatic mutations in BRCA1/2 and other homologous recombination repair (HRR) genes have been associated with sensitivity to PARP inhibitors and/or platinum agents in several cancers, whereas hypermutant tumors caused by alterations in POLE or mismatch repair genes have demonstrated robust responses to immunotherapy. We investigated the relationship between somatic truncations in HRR genes and hypermutation in colorectal cancer (CRC) and endometrial cancer (EC).

Methods: We analyzed the mutational spectra associated with somatic BRCA1/2 truncations in multiple genomic cohorts (N = 2,335).

Colorectal cancer susceptibility variants and risk of conventional adenomas and serrated polyps: results from three cohort studies.

Background: Increasing evidence suggests that conventional adenomas (CAs) and serrated polyps (SPs) represent two distinct groups of precursor lesions for colorectal cancer (CRC). The influence of common genetic variants on risk of CAs and SPs remain largely unknown.

Methods: Among 27 426 participants within three prospective cohort studies, we created a weighted genetic risk score (GRS) based on 40 CRC-related single nucleotide polymorphisms (SNPs) identified in previous genome-wide association studies; and we examined the association of GRS (per one standard deviation increment) with risk of CAs, SPs and synchronous CAs and SPs, by multivariable logistic regression.

Continuity of transcriptomes among colorectal cancer subtypes based on meta-analysis.

Background: Previous approaches to defining subtypes of colorectal carcinoma (CRC) and other cancers based on transcriptomes have assumed the existence of discrete subtypes. We analyze gene expression patterns of colorectal tumors from a large number of patients to test this assumption and propose an approach to identify potentially a continuum of subtypes that are present across independent studies and cohorts.

Results: We examine the assumption of discrete CRC subtypes by integrating 18 published gene expression datasets and > 3700 patients, and contrary to previous reports, find no evidence to support the existence of discrete transcriptional subtypes.

Hepatic connexin 32 associates with nonalcoholic fatty liver disease severity.

Emerging data highlight the critical role for the innate immune system in the progression of nonalcoholic fatty liver disease (NAFLD). Connexin 32 (Cx32), the primary liver gap junction protein, is capable of modulating hepatic innate immune responses and has been studied in dietary animal models of steatohepatitis. In this work, we sought to determine the association of hepatic Cx32 with the stages of human NAFLD in a histologically characterized cohort of 362 patients with NAFLD.

Health Care Infrastructure for Financially Sustainable Clinical Genomics.

Next-generation sequencing has evolved technically and economically into the method of choice for interrogating the genome in cancer and inherited disorders. The introduction of procedural code sets for whole-exome and genome sequencing is a milestone toward financially sustainable clinical implementation; however, achieving reimbursement is currently a major challenge. As part of a prospective quality-improvement initiative to implement the new code sets, we adopted Agile, a development methodology originally devised in software development.

TFF2-CXCR4 Axis Is Associated with BRAF V600E Colon Cancer.

Oncogene-induced senescence (OIS), a tumor-suppressive mechanism that is induced by the replicative and metabolic stress of oncogene activation, is a key barrier in the development of BRAF V600E colon cancer. Inhibition of this mechanism has been observed through epigenetic changes observed in sporadic serrated polyps, as well as through the germline mutations associated with those who develop serrated polyposis. We hypothesize that upregulated autocrine factors exist that are specific to the serrated pathway and also promote bypass of oncogene-induced senescence.

Molecular pathways: aspirin and Wnt signaling-a molecularly targeted approach to cancer prevention and treatment.

The anti-inflammatory properties of aspirin have resulted in its widespread use as an analgesic, antipyretic, and cardioprotective agent. Beyond these applications, multiple observational studies and randomized controlled trials have demonstrated a chemopreventative role for aspirin, particularly in the development of colorectal neoplasia. Given the critical importance of Wnt dysregulation in colorectal carcinogenesis, the interplay between aspirin and canonical Wnt signaling has become a focus of investigation.

Recurrences are common after endoscopic ampullectomy for adenoma in the familial adenomatous polyposis (FAP) syndrome.

Background: Endoscopic ampullectomy is increasingly performed in patients with familial adenomatous polyposis (FAP)-associated ampullary adenomas. We sought to define the procedure-associated morbidities and long-term outcomes.

Methods: We performed a retrospective chart review of patients with FAP who underwent endoscopic ampullectomy at two tertiary institutions between 1999 and 2010.

Germline mutations in oncogene-induced senescence pathways are associated with multiple sessile serrated adenomas.

Background & Aims: Little is known about the genetic factors that contribute to the development of sessile serrated adenomas (SSAs). SSAs contain somatic mutations in BRAF or KRAS early in development. However, evidence from humans and mouse models indicates that these mutations result in oncogene-induced senescence (OIS) of intestinal crypt cells.