Background: Recently, a trial of adjuvant imatinib for primary R0-resected intermediate and high-risk gastrointestinal stromal tumors (GISTs) significantly improved recurrence-free survival. But identifying patients having higher chances of recurrence will reduce economic losses and prevent adverse side effects caused by adjuvant treatment. Methods: Tissue samples from 93 patients with high-risk GISTs were studied for p16, CD34, and CD44 protein expression and mutations of KIT and PDGFRA gene. Clinicopathologic, immunohistochemical, and mutation results were compared with clinical outcome by univariate and multivariate analyses. Results: KIT mutations were observed in 75 cases (81%) including 46 exon 11 deletion mutations and 31 deletions affecting codons 557–558. A novel 12 bp deletion mutation (KHNG484-488) on KIT exon 9 was detected in a small intestinal GIST. For recurrence-free survival, R0 resection, organ-confined disease stage, and female sex are better prognostic factors in univariate analysis and disease stage was the only factor predicting recurrence (P = 0.02) in multivariate analysis. In overall survival, mutation types, presence of mutation, location of GISTs, and mitosis were significant by univariate analysis. After multivariate analysis, mitotic counts and presence of KIT mutation corresponded to independent prognostic factors. Moreover, mitosis, KIT exon 11 deletion mutation, and deletions affecting exon 557–558 predict recurrence in R0-resected high-risk GISTs (P < 0.05). Conclusion: Prognostic stratification in high-risk GISTs will help identify patients with high-risk GIST who may benefit from adjuvant therapy.

Collagen is a major component in the tumor microenvironment. This study reveals a novel biomarker candidate, type VII collagen (COL7A1), in patients with gastric cancer. To identify genes differentially expressed in gastric cancer tissue, we analyzed cancerous (n = 20) and noncancerous tissues (n = 13) using a DNA microarray. To perform immunohistochemistry and validate the upregulation of COL7A1 expression, we collected 200 more gastric cancer tissues and 100 normal gastric tissues from 200 randomly selected patients who underwent gastrectomy for gastric cancer between January 2010 and December 2013. The correlations between COL7A1 expression and clinicopathological parameters and patients’ overall survival (OS) were analyzed. In the microarray, COL7A1 was upregulated in gastric cancer tissue compared with normal tissue. In the immunohistochemistry study, COL7A1 was more highly expressed in cancer tissue than in normal tissue (p = 0.001). Patients with intracellular COL7A1 expression had significantly poorer five-year OS than those with only extracellular expression (41.5 versus 69.7%, p = 0.001), and the site of expression was an independent prognostic factor of OS (hazard ratio 2.00, 95% CI 1.26–3.16, p = 0.003). Also, we found a significant association between the COL7A1 immunohistochemistry score and distant metastasis (high versus low, odds ratio 4.45, 95% CI 1.40–14.16, p = 0.011). The site and total immunohistochemistry score of COL7A1 expression in gastric cancer showed prognostic significance for OS and distant metastasis, respectively. COL7A1 could be a novel biomarker with diagnostic and therapeutic value.

Park ES, et al. Korean J Pathol. 2012 Jun;46(3):287-291. http://dx.doi.org/10.4132/KoreanJPathol.2012.46.3.287

Successful identification and targeting of oncogenic gene fusion is a major breakthrough in cancer treatment. Here, we investigate the therapeutic implications and feasibility of using a targeted RNA sequencing panel to identify fusion genes in gastrointestinal and rare cancers. From February through December 2017, patients with gastrointestinal, hepatobiliary, gynecologic, sarcoma, or rare cancers were recruited for a clinical sequencing project at Samsung Medical Center (NCT #02593578). The median age of the patients was 58 years (range, 31–81 years), and the male-to-female ratio was 1.3 : 1. A total of 118 patients passed the quality control process for a next-generation sequencing- (NGS-) based targeted sequencing assay. The NGS-based targeted sequencing assay was performed to detect gene fusions in 36–53 cancer-implicated genes. The following cancer types were included in this study: 28 colorectal cancers, 27 biliary tract cancers, 25 gastric cancers, 18 soft tissue sarcomas, 9 pancreatic cancers, 6 ovarian cancers, and 9 other rare cancers. Strong fusion was detected in 25 samples (21.2%). We found that 5.9% (7/118) of patients had known targetable fusion genes involving NTRK1 (n=3), FGFR (n=3), and RET (n=1), and 10.2% (12/118) of patients had potentially targetable fusion genes involving RAF1 (n=4), BRAF (n=2), ALK (n=2), ROS1 (n=1), EGFR (n=1), and CLDN18 (n=2). Thus, we successfully identified a substantial proportion of patients harboring fusion genes by RNA panel sequencing of gastrointestinal/rare cancers. Targetable and potentially targetable involved fusion genes were NTRK1, RET, FGFR3, FGFR2, BRAF, RAF1, ALK, ROS1, and CLDN18. Detection of fusion genes by RNA panel sequencing may be beneficial in refractory patients with gastrointestinal/rare cancers.

Background: The purpose of this study was to evaluate the clinical outcomes following postoperative chemotherapy (XP) versus chemoradiotherapy (XP-RT) according to mesenchymal subtype based on RNA sequencing in gastric cancer (GC) in a cohort of the Adjuvant chemoRadioTherapy In Stomach Tumor (ARTIST) trial. Methods: Of the 458 patients enrolled in the ARTIST trial, formalin-fixed, paraffin-embedded (FFPE) specimens were available from 106 (23.1%) patients for RNA analysis. The mesenchymal subtype was classified according to a previously reported 71-gene MSS/EMT signature using the NanoString assay. Results: Of the 106 patients analyzed (50 in XP arm, 56 in XP-RT arm), 36 (34.0%) patients were categorized as mesenchymal subtype by NanoString assay. Recurrence-free survival (RFS, p = 0.009, hazard ratio (HR) = 2.11, 95% confidence interval (CI): 1.21–3.70) and overall survival (OS, p = 0.003, HR = 2.28, 95% CI: 1.31–3.96) were significantly lower in the mesenchymal subtype than in the non-mesenchymal subtype. In terms of post-operative radiotherapy (RT), mesenchymal subtype was not an independent variable to predict RFS or OS regardless to the assigned arm (XP with or without RT) in this patient cohort. However, there was a trend in the adjuvant XP arm, which showed higher OS than the XP-RT arm for the mesenchymal subtype and lower OS than the XP-RT arm for the non-mesenchymal subtype. Conclusions: We could not determine any significant differences between the mesenchymal and non-mesenchymal subtypes with respect to the effects of adjuvant XP with or without RT in gastric cancer following curative surgery.