Profiling cancer-associated genetic alterations and molecular classification of cancer in Korean gastric cancer patients

// Yoonjung Kim 1 , Mee-Yon Cho 2 , Juwon Kim 3 , Sung Nam Kim 4 , Seoung Chul Oh 5 and Kyung-A Lee 1 1 Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Korea 2 Department of Pathology, Yonsei University Wonju College of Medicine, Wonju, Korea 3 Department of Laboratory Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea 4 Department of Pathology, Samkwang Medical Labotories, Seoul, Korea 5 Department of Laboratory Medicine, Gangnam Severance Hospital, Seoul, Korea Correspondence to: Kyung-A Lee, email: kal1119@yuhs.ac Juwon Kim, email: Juwon76@yonsei.ac.kr Keywords: gastric cancer, molecular subtyping, germline mutation, somatic mutaiton, targeted sequencing Received: October 26, 2016 Accepted: June 20, 2017 Published: July 22, 2017 ABSTRACT Recently, the Cancer Genome Atlas (TCGA) Research Network and Asian Cancer Research Group provided a new classification of gastric cancer (GC) to aid the development of biomarkers for targeted therapy and predict prognosis. We studied associations between genetically aberrant profiles of cancer-related genes, environmental factors, and histopathological features in 107 paired gastric tumor-non-tumor tissue GC samples. 6.5% of our GC cases were classified as the EBV subtype, 17.8% as the MSI subtype, 43.0% as the CIN subtype, and 32.7% as the GS subtype. The distribution of four GC subgroups based on the TCGA and our dataset were similar. The MSI subtype showed a hyper-mutated status and the best prognosis among molecular subtype. However, molecular classification based on the four GC subtypes showed no significant survival differences in terms of overall survival ( p = 0.548) or relapse-free survival (RFS, p =0.518). The P619fs * 43 in ZBTB20 was limited to MSI group (n= 5/19, 26.3%), showing similar trends observed in TCGA dataset. Genetic alterations of the RTK/RAS/MAPK and PI3K/AKT/mTOR pathways were detected in 34.6% of GC cases (37 individual cases). We also found two cases with likely pathogenic variants (NM_004360.4: c. 2494 G>A, p.V832M ) in the CDH1 gene. Here, we classified molecular subtypes of GC according to the TCGA system and provide a critical starting point for the design of more appropriate clinical trials based on a comprehensive analysis of genetic alterations in Korean GC patients.