Gastric cancer with enhanced myogenesis is associated with less cell proliferation, enriched epithelial-to-mesenchymal transition and angiogenesis, and poor clinical outcomes.

Gastric cancer (GC) remains a lethal disease, with over 26,000 new cases and more than 11,000 deaths annually in the US. Thus, a deeper understanding of GC biology is critical to improve survival. Myogenesis is the formation of muscle fibers, which is a mesodermal tissue. In cancer, epithelial-to-mesenchymal transition (EMT) is a known phenomenon that promotes metastasis and poor survival. Given that myogenesis produces mesenchymal cells, we hypothesized that GC with increased myogenesis is linked to aggressive tumor behaviors and less favorable outcomes. In this study, three GC patient cohorts: TCGA (n=375), GSE26253 (n=432), and GSE84437 (n=482), were analyzed. The "MYOGENESIS" set in the Hallmark collection which comprises 200 myogenesis-related genes was analyzed to perform gene set variation analysis to create a score to quantify the myogenesis activity. Our results showed that T category of AJCC cancer staging that reflects the tumor invasion to stomach wall consistently correlated with myogenesis activity in two GC cohorts. High myogenesis GC was associated with lower cell proliferation, evidenced by reduced proliferation scores, decreased Ki67 gene expression, and less enrichment of E2F Targets, G2M checkpoint, MYC Targets V1, and V2 gene sets. High myogenesis tumors showed increased stromal cells (fibroblasts and adipocytes) infiltration within the tumor microenvironment, as well as less silent and non-silent mutation rates and copy number alterations. Higher lymphocyte infiltration, leukocyte fraction, T-cell receptor richness, and B-cell receptor richness were associated with high myogenesis GC. However, infiltration of CD4 cells, T helper type 1 and 2 cells, Natural Killer cells, regulatory T cells, and plasma cells was lower, with increased infiltration of dendritic cells in high myogenesis GC. High myogenesis GC enriched EMT, Hedgehog, TGF-ß, and KRAS gene sets. Furthermore, it was associated with enhanced angiogenesis, evidenced by enrichment of Angiogenesis, Coagulation, and Hypoxia gene sets, and increased infiltration of microvascular and lymphatic endothelial cells and pericytes. High myogenesis GC consistently correlated with worse overall survival in all three cohorts, and worse disease-specific and progression-free survival in the TCGA cohort. Hence, our findings suggest that GC with enhanced myogenesis is associated with decreased cell proliferation, increased EMT and angiogenesis, and worse prognosis.

A 44-Year-Old Woman With a 10-Year History of Dyspnea and Pulmonary Nodules.

CASE PRESENTATION: A 44-year-old woman was referred for evaluation of dyspnea on exertion and multiple nodular opacities on a chest CT scan. She had a medical history of autoimmune encephalitis, diabetes mellitus, hypertension, migraines, and allergic rhinitis. Ten years earlier, the patient was admitted to an outside institution with symptoms of shortness of breath. She was found to have multiple pulmonary nodules and was diagnosed empirically with and treated for sarcoidosis. She was told that her pulmonary nodules had improved on follow up. However, she continued to have symptoms of dyspnea. Due to progressive symptoms of shortness of breath, she was referred to pulmonology. She reported a weight gain of 80 pounds over the last year. She denied fever, chills, hemoptysis, night sweats, joint swelling, or skin rash. She is a former cigarette smoker with a 15 pack-year smoking history, quit smoking in 2005. She denied alcohol or drug use. She resided in Arkansas and Texas over the past decade. She previously worked as a teacher and is currently unemployed. She had no other relevant exposures. She denied a family history of autoimmune diseases or malignancies.