Abstract 2152: Genome-wide single nucleotide polymorphism arrays in endometrial carcinomas associate extensive chromosomal instability with poor prognosis and unveil prevalent alterations in Ras/PI3-kinase pathway
Authors: Katsutoshi Oda, Satsuki Murayama-Hosokawa, Shunsuke Nakagawa, Shumpei Ishikawa, Shogo Yamamoto, Keiko Shoji, Yuji Ikeda, Yuriko Uehara, Osamu Hiraike-Wada, Kei Kawana, Tetsu Yano, Frank McCormick, Shiro Kozuma, Yuji Taketani, Hiroyuki Aburatani
Journal: Cancer Research (2010)

Abstract [Objectives]: Endometrial cancer is one of the tumor types, in which either chromosomal instability (CIN) or microsatellite instability (MSI) may occur, and is known to possess mutations frequently in Ras-PI3K (phosphatidylinositol 3’-kinase) pathway. In this study, we attempted to clarify prognostic impact of genomic instability, determined by CIN and MSI status, and figure out the relationship between alterations in the Ras-PI3K pathway genes and the status of genomic instability. [Materials and Methods]: Under the approval of institutional ethical committees, we analyzed allele-specific chromosomal copy number alterations by SNP typing arrays in 31 endometrioid endometrial adenocarcinomas with paired DNA (25 by the 50K and six by the 250K probes). We also screened 25 of the 31 samples for MSI status with five microsatellite markers, and 22 samples for mutations in PIK3CA (exon 9 and 20), PTEN (exons 1-8) and K-Ras (exon1 and 2). Survival curves were constructed using the Kaplan-Meier method and compared with a log-rank test. [Results]: We detected five or more copy number changes (classified as CIN-extensive) in nine (29%), one to four changes (CIN-intermediate) in 17 (55%) and no changes (CIN-negative) in five (16%) tumors. Positive MSI was detected in ten (40%) of the 25 tumors and was less common in CIN-extensive tumors (14%), compared with CIN-intermediate/negative tumors (50%). CIN-extensive was significantly poor prognostic (p=0.0034), and the prognosis was shown to be independent from any other clinicpopathological characteristics by multivariate analysis. In contrast, positive MSI showed a trend to be a favorable prognostic factor (p=0.069), in spite of the association with vascular invasion (p=0.049). SNP array analysis unveiled copy number neutral LOH at 54 loci in 13 tumors (42%), including four at the locus of PTEN, and homozygous deletions at five regions in three tumors, including the locus of PTEN and NF1. Totally we detected eight (26%) tumors with PTEN deletions, and four (13%) with NF1 deletions. We identified mutations of PTEN, PIK3CA and K-Ras in 16 (73%), 6 (27%) and 2 (9%) out of 22 tumors, respectively. Seven (78%) of the nine CIN-extensive tumors harbor deletions at the loci of PTEN and/or NF1, with less frequent PTEN mutations (22%). On the other hand, PTEN mutations were detected in all the ten MSI-positive tumors, five of which coexist with PIK3CA and/or K-Ras mutations. We detected no deletions of NF1 and only one (10%) LOH of PTEN in the ten MSI-positive tumors. [Conclusion]: Our results demonstrated that the degree of CIN is a useful biomarker for prognosis in endometrial carcinomas. In addition, genomic alterations in the Ras-PI3K pathway are remarkably widespread in endometrial carcinomas, regardless of the type of genomic instability. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2152.