Forerunner genes contiguous to RB1 contribute to the development of in situ neoplasia

Sangkyou Lee, Joon Jeong, Tadeusz Majewski, Steven E. Scherer, Mi Sook Kim, Tomasz Tuziak, Kuang S. Tang, Keith Baggerly, Herbert Barton Grossman, Jain Hua Zhou, Lanlan Shen, Jolanta Bondaruk, Saira S. Ahmed, Susmita Samanta, Philippe Spiess, Xifeng Wu, Slawomir Filipek, David McConkey, Menashe Bar-Eli, Jean Pierre IssaWilliam F. Benedict, Bogdan Czerniak

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37 Citations (Scopus)

Abstract

We used human bladder cancer as a model system and the whole-organ histologic and genetic mapping strategy to identify clonal genetic hits associated with growth advantage, tracking the evolution of bladder cancer from intraurothelial precursor lesions. Six putative chromosomal regions critical for clonal expansion of intraurothelial neoplasia and development of bladder cancer were identified by using this approach. Focusing on one of the regions, which includes the model tumor suppressor RB1, we performed allelotyping of single-nucleotide polymorphic sites and identified a 1.34-Mb segment around RB1 characterized by a loss of polymorphism associated with the initial expansion of in situ neoplasia. This segment contains several positional candidate genes referred to by us as forerunner genes that may contribute to such expansion. We subsequently concentrated our efforts on the two neighbor genes flanking RB1, namely ITM2B and CHC1L, as well as P2RY5, which is located inside RB1. Here, we report that ITM2B and P2RY5 modulated cell survival and were silenced by methylation or point mutations, respectively, and thus by functional loss may contribute to the growth advantage of neoplasia. We also show that homozygous inactivation of P2RY5 was antecedent to the loss of RB1 during tumor development, and that nucleotide substitutions in P2RY5 represent a cancer predisposing factor.

Original languageEnglish
Pages (from-to)13732-13737
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number34
DOIs
Publication statusPublished - 2007 Aug 21

All Science Journal Classification (ASJC) codes

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    Lee, S., Jeong, J., Majewski, T., Scherer, S. E., Kim, M. S., Tuziak, T., Tang, K. S., Baggerly, K., Grossman, H. B., Zhou, J. H., Shen, L., Bondaruk, J., Ahmed, S. S., Samanta, S., Spiess, P., Wu, X., Filipek, S., McConkey, D., Bar-Eli, M., ... Czerniak, B. (2007). Forerunner genes contiguous to RB1 contribute to the development of in situ neoplasia. Proceedings of the National Academy of Sciences of the United States of America, 104(34), 13732-13737. https://doi.org/10.1073/pnas.0701771104