Field Change in Bladder Carcinogenesis: The Concept of Forerunner Genes
S Lee, SK Lee, S Zhang, J Bondaruk, T Majewski, W Chung, L Xiao, C Guo, JP Issa, M Bar-Eli, K Baggerly, B Czerniak. The University of Texas M D Anderson Cancer Center, Houston, TX
Background: Analysis of genomic imbalances can guide us to those chromosomal regions that contain genes playing a role in tumor development. In sporadic epithelial cancers that develop from microscopically recognizable in situ conditions the early events maybe deduced from the geographic relationship between genomic imbalance and precursor in situ conditions.
Design: Using whole-organ histologic and genetic mapping approach, we matched the clonal allelic losses in distinct chromosomal regions to specific phases of bladder neoplasia and produced a detailed genetic map of human bladder cancer development. The genetic changes mapped to six regions at 3q22–q24, 5q22–q31, 9q21–q22, 10q26, 13q14, and 17p13, which may be critical for the development of bladder cancer. In addition, we performed high-resolution mapping within one region on chromosome 13q14, containing the model tumor suppressor gene RB1, and defined a minimal deleted region associated with clonal expansion of in situ neoplasia. These analyses identified novel target genes, termed forerunner (FR) genes, involved in early phases of cancer development.
Results: The functional studies focused on the two nearest candidate FR genes flanking RB1. These were ITM2B, which encodes a mitochondrial membrane protein with a BH3 domain, and CHC1L, which encodes a GEF protein for the ras-related GTPase. Surprisingly, a third candidate FR gene, P2RY5 was actually located within intron 17 of RB1 and encodes a G-protein-coupled receptor. ITM2B and P2RY5 modulated cell survival and were silenced by methylation or point mutations, respectively. We also showed 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. Our recent studies of another candidate FR gene, ARL11 encoding ADP-ribosylation factor-like tumor suppressor protein 1, have identified an unexpected link between the recessive events in the 13q14 region and up-regulation of one of the most important oncogenic pathways, namely the ras signaling.
Conclusions: The FR genes represent a new class of genes mapping near critical model tumor suppressors, such as RB1, whose loss of function drives incipient clonal expansion of phenotypically normal cells facilitating the subsequent inactivation of tumor suppressors and malignant transformation.
Wednesday, March 24, 2010 9:30 AM
Poster Session V # 211, Wednesday Morning