Molecular Analysis of Persistent and Recurrent Barrett's Esophagus in the Setting of Endoscopic Therapy.

Introduction: Early neoplastic progression of Barrett's esophagus (BE) is often treated with endoscopic therapy. Although effective, some patients are refractory to therapy or recur after apparent eradication of the BE. The goal of this study was to determine whether genomic alterations within the treated BE may be associated with persistent or recurrent disease.

HER2 overexpression in urothelial carcinoma with GATA3 and PPARG copy number gains.

HER2, encoded by the ERBB2 gene, is an important druggable driver of human cancer gaining increasing importance as a therapeutic target in urothelial carcinoma (UC). The genomic underpinnings of HER2 overexpression in ERBB2 nonamplified UC are poorly defined. To address this knowledge gap, we investigated 172 UC tumors from patients treated at the University of California San Francisco, using immunohistochemistry and next-generation sequencing.

Expansion of a bacterial operon during cancer treatment ameliorates drug toxicity.

Dose-limiting toxicities remain a major barrier to drug development and therapy, revealing the limited predictive power of human genetics. Herein, we demonstrate the utility of a more comprehensive approach to studying drug toxicity through longitudinal study of the human gut microbiome during colorectal cancer (CRC) treatment (NCT04054908) coupled to cell culture and mouse experiments. 16S rRNA gene sequencing revealed significant shifts in gut microbial community structure during oral fluoropyrimidine treatment across multiple patient cohorts, in mouse small and large intestinal contents, and in patient-derived communities.

Molecular Pathology of Gastroesophageal Cancer.

Upper gastroesophageal carcinomas consist of cancers arising from the esophagus and stomach. Squamous cell carcinomas and adenocarcinomas are seen in the esophagus and despite arising from the same organ have different biology. Gastric adenocarcinomas are categorized into 4 molecular subtypes: high Epstein-Barr virus load, microsatellite unstable cancers, chromosomal unstable (CIN) cancers, and genomically stable cancers.

Feasibility Study Utilizing NanoString's Digital Spatial Profiling (DSP) Technology for Characterizing the Immune Microenvironment in Barrett's Esophagus Formalin-Fixed Paraffin-Embedded Tissues.

Characterization of the Barrett's esophagus (BE) microenvironment in patients with a known progression status, to determine how it may influence BE progression to esophageal adenocarcinoma (EAC), has been understudied, hindering both the biological understanding of the progression and the development of novel diagnostics and therapies. This study's aim was to determine if a highly multiplex interrogation of the microenvironment can be performed on endoscopic formalin-fixed, paraffin-embedded (FFPE) samples, utilizing the NanoString GeoMx digital spatial profiling (GeoMx DSP) platform and if it can begin to identify the types of immune cells and pathways that may mediate the progression of BE. We performed a spatial proteomic analysis of 49 proteins expressed in the microenvironment and epithelial cells of FFPE endoscopic biopsies from patients with non-dysplastic BE (NDBE) who later progressed to high-grade dysplasia or EAC 7) or from patients who, after at least 5 years follow-up, did not = 8).

Genomic signatures of past and present chromosomal instability in Barrett's esophagus and early esophageal adenocarcinoma.

The progression of precancerous lesions to malignancy is often accompanied by increasing complexity of chromosomal alterations but how these alterations arise is poorly understood. Here we perform haplotype-specific analysis of chromosomal copy-number evolution in the progression of Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) on multiregional whole-genome sequencing data of BE with dysplasia and microscopic EAC foci. We identify distinct patterns of copy-number evolution indicating multigenerational chromosomal instability that is initiated by cell division errors but propagated only after p53 loss.

Interleukin-33 as a Potential Therapeutic Target in Gastric Cancer Patients: Current Insights.

Gastric cancer is a significant global health problem as it is the fifth most prevalent cancer worldwide and the fourth leading cause of cancer-related mortality. While cytotoxic chemotherapy remains the primary treatment for advanced GC, response rates are limited. Recent progresses, focused on molecular signalling within gastric cancer, have ignited new hope for potential therapeutic targets that may improve survival and/or reduce the toxic effects of traditional therapies.

Bridging the Gap between Diseases of the Stomach and Lower Esophagus.

In this issue of Cancer Discovery, Nowicki-Osuch and colleagues perform an extensive characterization and analysis of single-cell RNA-sequencing data of the tubal gastrointestinal system, including a spectrum of inflammatory conditions and intestinal metaplasia of the stomach and esophagus. They show that both gastric and esophageal intestinal metaplasia share similarities at the transcript and protein levels. Interestingly, they show that individual cells within areas of metaplasia can coexpress transcriptional programs of both gastric and intestinal epithelia.

Degree of crypt atypia correlates with progression to high-grade dysplasia/adenocarcinoma in non-dysplastic Barrett's oesophagus.

Aims: Patients with non-dysplastic Barrett's oesophagus (BE) often show a wide range of 'atypical' histological features in the bases of the crypts. However, the significance of crypt atypia has never been evaluated, despite prior studies showing the presence of DNA content and other molecular abnormalities in this epithelium. The aim of this study was to evaluate whether the degree of crypt atypia in BE patients without dysplasia correlates with progression to high-grade dysplasia/adenocarcinoma (HGD/EAC).

Today's Mistakes and Tomorrow's Wisdom in Development and Use of Biomarkers for Barrett's Esophagus.

Background: A histological diagnosis of dysplasia is our current best predictor of progression in Barrett's esophagus (BE), the precursor of esophageal adenocarcinoma (EAC). Despite periodic endoscopic surveillance and assessment of dysplastic changes, we fail to identify the majority of those who progress before the development of EAC, whereas the majority of patients undergo endoscopy without showing progression.

Summary: Low-grade dysplasia (LGD), confirmed by expert pathologists, identifies BE patients at higher risk for progression, but the diagnosis of LGD is challenging.

Abnormal TP53 Predicts Risk of Progression in Patients With Barrett's Esophagus Regardless of a Diagnosis of Dysplasia.

Background And Aims: Barrett's esophagus (BE) is the precursor to esophageal adenocarcinoma. A major challenge is identifying the small group with BE who will progress to advanced disease from the many who will not. Assessment of p53 status has promise as a predictive biomarker, but analytic limitations and lack of validation have precluded its use.

Molecular Pathology of Gastroesophageal Cancer.

Upper gastroesophageal carcinomas consist of cancers arising from the esophagus and stomach. Squamous cell carcinomas and adenocarcinomas are seen in the esophagus and despite arising from the same organ have different biology. Gastric adenocarcinomas are categorized into 4 molecular subtypes: high Epstein-Barr virus load, microsatellite unstable cancers, chromosomal unstable (CIN) cancers, and genomically stable cancers.

Can Genomic Sequencing Identify High-Risk Barrett's Esophagus Earlier Than Pathologists?

Barrett's esophagus (BE) is a precursor to esophageal adenocarinoma, and screening for cancer risk focuses upon histologic assessment of dysplasia within endoscopic biopsies. A recent study in Nature Medicine contributes to growing evidence that genomic assessment of non-dysplastic BE samples can identify patients at greatest risk of progressing to cancer.

Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus-Unrelated Head and Neck Cancer: A Multicenter, Phase II Trial.

Purpose: Pembrolizumab improved survival in patients with recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). The aims of this study were to determine if pembrolizumab would be safe, result in pathologic tumor response (pTR), and lower the relapse rate in patients with resectable human papillomavirus (HPV)-unrelated HNSCC.

Patients And Methods: Neoadjuvant pembrolizumab (200 mg) was administered and followed 2 to 3 weeks later by surgical tumor ablation.

Early TP53 alterations engage environmental exposures to promote gastric premalignancy in an integrative mouse model.

Somatic alterations in cancer genes are being detected in normal and premalignant tissue, thus placing greater emphasis on gene-environment interactions that enable disease phenotypes. By combining early genetic alterations with disease-relevant exposures, we developed an integrative mouse model to study gastric premalignancy. Deletion of Trp53 in gastric cells confers a selective advantage and promotes the development of dysplasia in the setting of dietary carcinogens.

Gain-of-Function Mutations Promote Focal Adhesion Kinase Activation and Dependency in Diffuse Gastric Cancer.

Diffuse gastric cancer (DGC) is a lethal malignancy lacking effective systemic therapy. Among the most provocative recent results in DGC has been that of highly recurrent missense mutations in the GTPase RHOA. The function of these mutations has remained unresolved.

Clinicopathologic and genetic characteristics of interval colorectal carcinomas favor origin from missed or incompletely excised precursors.

Interval colorectal cancers may arise from missed or incompletely excised precursors or from a unique rapid progression pathway. We compared the clinicopathologic and molecular profiles of interval and matched non-interval colorectal cancer to determine whether interval colorectal cancers harbor any unique genetic characteristics. Fifty one of 982 colorectal cancer (5.

Biomarkers for Barrett's esophagus - a contemporary review.

Esophageal adenocarcinoma (EAC) has a poor 5-year survival rate (10%-18%), and incidence has increased dramatically in the past three decades. Barrett's esophagus (BE) is the precursor lesion to EAC and is the replacement of the normally squamous lined esophagus with columnar cells that develop an intestinal phenotype characterized by the presence of goblet cells. Given the known precursor state, EAC is amenable to screening and surveillance strategies (analogous to colon cancer).

Detection of Mutations in Barrett's Esophagus Before Progression to High-Grade Dysplasia or Adenocarcinoma.

Background & Aims: Barrett's esophagus (BE) is the greatest risk factor for esophageal adenocarcinoma (EAC), but only a small proportion of patients with BE develop cancer. Biomarkers might be able to identify patients at highest risk of progression. We investigated genomic differences in surveillance biopsies collected from patients whose BE subsequently progressed compared to patients whose disease did not progress.

Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma.

Gastroesophageal adenocarcinoma (GEA) is a lethal disease where targeted therapies, even when guided by genomic biomarkers, have had limited efficacy. A potential reason for the failure of such therapies is that genomic profiling results could commonly differ between the primary and metastatic tumors. To evaluate genomic heterogeneity, we sequenced paired primary GEA and synchronous metastatic lesions across multiple cohorts, finding extensive differences in genomic alterations, including discrepancies in potentially clinically relevant alterations.