Genomic Profiling of Submucosal-Invasive Gastric Cancer by Array-Based Comparative Genomic Hybridization

Akiko Kuroda,Chisato Nakada,Naoki Hijiya,Tomohisa Uchida,Tadayoshi Okimoto,Keiko Matsuura,Masao Seto,Masahiro Uchida,Masatsugu Moriyama,Kazunari Murakami,Tsuyoshi Noguchi,Masaaki Kodama,Lam Tung Nguyen,Toshio Fujioka,Hisao Ito,Yoshiyuki Tsukamoto,Ichiro Takeuchi,Giuseppe Novelli

doi:10.1371/journal.pone.0022313

Akiko Kuroda, Chisato Nakada + Show 16 more

Open Access

https://doi.org/10.1371/journal.pone.0022313

Copy DOI

Abstract

Genomic copy number aberrations (CNAs) in gastric cancer have already been extensively characterized by array comparative genomic hybridization (array CGH) analysis. However, involvement of genomic CNAs in the process of submucosal invasion and lymph node metastasis in early gastric cancer is still poorly understood. In this study, to address this issue, we collected a total of 59 tumor samples from 27 patients with submucosal-invasive gastric cancers (SMGC), analyzed their genomic profiles by array CGH, and compared them between paired samples of mucosal (MU) and submucosal (SM) invasion (23 pairs), and SM invasion and lymph node (LN) metastasis (9 pairs). Initially, we hypothesized that acquisition of specific CNA(s) is important for these processes. However, we observed no significant difference in the number of genomic CNAs between paired MU and SM, and between paired SM and LN. Furthermore, we were unable to find any CNAs specifically associated with SM invasion or LN metastasis. Among the 23 cases analyzed, 15 had some similar pattern of genomic profiling between SM and MU. Interestingly, 13 of the 15 cases also showed some differences in genomic profiles. These results suggest that the majority of SMGCs are composed of heterogeneous subpopulations derived from the same clonal origin. Comparison of genomic CNAs between SMGCs with and without LN metastasis revealed that gain of 11q13, 11q14, 11q22, 14q32 and amplification of 17q21 were more frequent in metastatic SMGCs, suggesting that these CNAs are related to LN metastasis of early gastric cancer. In conclusion, our data suggest that generation of genetically distinct subclones, rather than acquisition of specific CNA at MU, is integral to the process of submucosal invasion, and that subclones that acquire gain of 11q13, 11q14, 11q22, 14q32 or amplification of 17q21 are likely to become metastatic.

Highlights

Gastric cancer remains one of the most deadly diseases, despite its steadily declining trend worldwide
By comparing the copy number aberrations (CNAs) between metastatic and non-metastatic submucosal-invasive gastric cancers (SMGC), we identified the candidate CNAs related to lymph node (LN) metastasis of early gastric cancer
The predominant population may be replaced by distinct subpopulations within a single tumor mass through the effects of environmental selection pressure and/or the stage of tumor progression

Summary

Introduction

Gastric cancer remains one of the most deadly diseases, despite its steadily declining trend worldwide. Clinical outcome is better when the tumor cells are confined to the mucosa. Once the tumor cells pass through the muscularis mucosa, the clinical outcome becomes worse, since the risk of lymph node metastasis, which is one of the most important prognostic factors in gastric cancer, increases significantly to 18% or more, compared with less than 4% when the tumor cells remain limited to the mucosa [2,3]. It has been reported that the total number of genomic aberrations increases with tumor progression in various types of tumors [5]. It has recently been reported that, during the course of tumor progression, a single tumor cell of origin evolves into several genetically distinct subpopulations through the acquisition of a wide variety of genomic aberrations. The resulting tumor mass, which is composed of genetically heterogeneous subpopulations, is considered to become resistant to a variety of environmental selection pressures [7,8,9,10]

Methods

Results

Conclusion