Molecular profiling and comprehensive genome-wide analysis of somatic copy number alterations in gastric intramucosal neoplasias based on microsatellite status

Wataru Habano,Hiroo Yamano,Mitsumasa Osakabe,Tamotsu Sugai,Eiichiro Yamamoto,Makoto Eizuka,Masaki Endoh,Noriyuki Arakawa,Takayuki Matsumoto,Yasuko Fujita,Hiromu Suzuki

doi:10.1007/s10120-018-0810-5

Wataru Habano, Hiroo Yamano + Show 9 more

Open Access

https://doi.org/10.1007/s10120-018-0810-5

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Abstract

BackgroundWe attempted to identify the molecular profiles of gastric intramucosal neoplasia (IMN; low-grade dysplasia, LGD; high-grade dysplasia, HGD; intramucosal cancer, IMC) by assessing somatic copy number alterations (SCNAs) stratified by microsatellite status (microsatellite stable, MSS; microsatellite instable, MSI). Thus, microsatellite status was determined in 84 tumors with MSS status and 16 tumors with MSI status.MethodsOne hundred differentiated type IMNs were examined using SCNAs. In addition, genetic mutations (KRAS, BRAF, PIK3CA, and TP53) and DNA methylation status (low, intermediate and high) were also analyzed. Finally, we attempted to identify molecular profiles using a hierarchical clustering analysis.ResultsThree patterns could be categorized according to SCNAs in IMNs with the MSS phenotype: subgroups 1 and 2 showing a high frequency of SCNAs, and subgroup 3 displaying a low frequency of SCNAs (subgroup 1 > 2 > 3 for SCNA). Subgroup 1 could be distinguished from subgroup 2 by the numbers of total SCNAs (gains and losses) and SCN gains (subgroup 1 > 2). The SCNA pattern of LGD was different from that of HGD and IMC. Moreover, IMNs with the MSI phenotype could be categorized into two subtypes: high frequency of SCNAs and low frequency of SCNAs. Genetic mutations and DNA methylation status did not differ among subgroups in IMNs.ConclusionMolecular profiles stratified by SCNAs based on microsatellite status may be useful for elucidation of the mechanisms of early gastric carcinogenesis.

Highlights

Gastric cancer (GC) remains one of the leading causes of cancer-related death worldwide, despite recent decreases in the incidence and mortality rates associated with this disease [1]
We carried out hierarchical clustering analysis based on the Somatic copy number alteration (SCNA) pattern, including gains, loss of heterozygisity (LOH), and copy-neutral LOHs, to examine differences in genetic alterations in samples from patients with intramucosal neoplasia (IMN) with the microsatellite stable (MSS) and microsatellite instability (MSI) phenotypes
Examination of SCNAs in tumor cells may provide information for predicting tumor aggressiveness [3] because SCNAs are closely associated with driver events that are acquired during cancer evolution [3, 21]

Summary

Introduction

Gastric cancer (GC) remains one of the leading causes of cancer-related death worldwide, despite recent decreases in the incidence and mortality rates associated with this disease [1]. Histogenesis of GC has been classified into intestinal and diffuse types, which are thought to involve different molecular pathways [1,2,3,4,5,6] This classification is closely associated with clinicopathological findings and molecular alterations in GC. We attempted to identify the molecular profiles of gastric intramucosal neoplasia (IMN; low-grade dysplasia, LGD; high-grade dysplasia, HGD; intramucosal cancer, IMC) by assessing somatic copy number alterations (SCNAs) stratified by microsatellite status (microsatellite stable, MSS; microsatellite instable, MSI). IMNs with the MSI phenotype could be categorized into two subtypes: high frequency of SCNAs and low frequency of SCNAs. Genetic mutations and DNA methylation status did not differ among subgroups in IMNs. Conclusion Molecular profiles stratified by SCNAs based on microsatellite status may be useful for elucidation of the mechanisms of early gastric carcinogenesis

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