Abstract 3139: Chromosomal copy number alterations involved in Ras/PI3-kinase pathway in endometrial carcinomas

Abstract

[Objectives]: Activation of Ras/PI3-kinase (PI3K) pathway plays a direct causal role in human cancer. Oncogenic mutant Ras remains in active state, and activates various Ras effectors, including PI3K pathway. Ras/PI3K pathway activating mutations are very frequent in endometrial cancer, as reported at 35-55% for PTEN, 25-36% for PIK3CA and 10-20% for K-Ras. NF1 is a negative regulator of Ras and its alterations have been reported in several types of tumors. Although LOH at PTEN locus (10q23.3) is reported at 15-30%, other chromosomal imbalances involved in the Ras/PI3K pathway are not well characterized in endometrial cancer. In this study, we focused on chromosomal copy number alterations (CNAs), including copy number neutral (CNN) LOH, involved in the Ras/PI3K pathway in endometrial carcinomas. [Materials and Methods]: Under the approval of institutional ethical committees, we performed 250K or 50K Single Nucleotide Polymorphism (SNP) arrays in 31 endometrial carcinomas with paired DNA and examined allele-specific CNAs at K-Ras, NF1, PIK3CA and PTEN. [Results]: We detected deletions of PTEN locus in eight out of 31 (26%) tumors; one with homozygous deletions (HD), four with CNN LOH and three with LOH without gain of the opposite allele. In addition to one HD (3%) and three LOH (10%) at NF1 locus, we found gains at the loci of PIK3CA (3q26.3) in four (13%) tumors and K-Ras (12p12.1) in four (13%) tumors. Taken together, we detected 12 (39%) tumors with one or more CNAs involved in the Ras/PI3K pathway. All the four tumors with NF1 deletions coexist with other CNAs involved in the Ras/PI3K pathway (Table). [Conclusion]: Our data unveiled CNN LOH of PTEN and homozygous deletions of PTEN and NF1, which had not been reported by conventional CGH analysis. Various types of CNAs might play roles in activation of the Ras/PI3K pathway and targeting the Ras-PI3K pathway might be effective in endometrial carcinomas with the Ras-PI3K related CNAs.Table.Coexistent CN alterations in the Ras/PI3K pathwayPTEN (Loss)PIK3CA (Gain)K-Ras (Gain)NF1 (Loss)LOH Gain LOH LOH Gain LOHLOHGain HDLOHGainGainLOH 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 3139.