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Genome-wide single-nucleotide polymorphism arrays in endometrial carcinomas associate extensive chromosomal instability with poor prognosis and unveil frequent chromosomal imbalances involved in the PI3-kinase pathway

Abstract

Endometrial cancer is one of the tumor types in which either chromosomal instability (CIN) or microsatellite instability (MSI) may occur. It is known to possess mutations frequently in the Ras-PI3K (phosphatidylinositol 3′-kinase) pathway. We performed a comprehensive genomic survey in 31 endometrial carcinomas with paired DNA for chromosomal imbalances (25 by the 50K and 6 by the 250K single-nucleotide polymorphism (SNP) array), and screened 25 of the 31 samples for MSI status and mutational status in the Ras-PI3K pathway genes. We detected five or more copy number changes (classified as CIN-extensive) in 9 (29%), 1 to 4 changes (CIN-intermediate) in 17 (55%) and no changes (CIN-negative) in 5 (16%) tumors. Positive MSI was less common in CIN-extensive tumors (14%), compared with CIN-intermediate/negative tumors (50%), and multivariate analysis showed that CIN-extensive is an independent poor prognostic factor. SNP array analysis unveiled copy number neutral LOH at 54 loci in 13 tumors (42%), including four at the locus of PTEN. In addition to eight (26%) tumors with PTEN deletions, we detected chromosomal imbalances of NF1, K-Ras and PIK3CA in four (13%), four (13%) and six (19%) tumors, respectively. In all, 7 of the 9 CIN-extensive tumors harbor deletions in the loci of PTEN and/or NF1, whereas all the 10 MSI-positive tumors possess PTEN, PIK3CA and/or K-Ras mutations. Our results showed that genomic alterations in the Ras-PI3K pathway are remarkably widespread in endometrial carcinomas, regardless of the type of genomic instability, and suggest that the degree of CIN is a useful biomarker for prognosis in endometrial carcinomas.

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Acknowledgements

We thank Hiroko Meguro, Akira Watanabe, Jennifer Okada, Toshiharu Yasugi, Kei Kawana, Takahide Arimoto, Akira Tsuchiya, Osamu Hiraike-Wada, Kenbun Sone, Yuichiro Miyamoto, Haruko Hiraike, Katsuyuki Adachi, Shiho Miura and Ayako Tomio for support and assistance. This work was supported by the Ministry of Education, Science, Sports and Culture Grant Number: Scientific Research (S) 16101006, Scientific Research on Priority Areas 17015008, Ministry of Education, Culture, Sports, Science and Technology of Japan on Priority Area; Grant Number: 20014007, and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST) (to H Aburatani); by the Grant-in-Aid for Scientific Research (C), Grant Number 19599005 and the Grant-in-Aid for Young Scientists (B), Grant Number 21791544 from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to K Oda); by the Grant-in-Aid for Scientific Research on Priority Areas ‘Applied Genomics’, Grant Number 20018005, from the Ministry of Education, Culture, Sports, Science and Technology of Japan and Industrial Technology Research Grant Program from New Energy and Industrial Technology Development Organization (NEDO) of Japan (to S Ishikawa).

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Murayama-Hosokawa, S., Oda, K., Nakagawa, S. et al. Genome-wide single-nucleotide polymorphism arrays in endometrial carcinomas associate extensive chromosomal instability with poor prognosis and unveil frequent chromosomal imbalances involved in the PI3-kinase pathway. Oncogene 29, 1897–1908 (2010). https://doi.org/10.1038/onc.2009.474

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