Research published in Laboratory Investigation implicates portions of six chromosomes, also called forerunner genes.
A group of researchers have identified chromosomal regions that launch cancer development. They documented three waves of genetic hits mainly involving genetic deletions that drive cells from normal to precancerous states.
The first wave leads to widespread expansion of urothelial cells that harbor genetic changes but otherwise appear normal under microscopic analysis. The second wave provides a growth advantage to cells that now have recognizable outward features of dysplasia. The third wave fully transforms the cell’s appearance and features the onset of severe dysplasia or carcinoma in situ, in this case the urothelium.
By superimposing the low-resolution map of genetic variation over the geographic map of the organ’s tissue, the scientists identified regions associated with first-wave and second-wave cells.
Additional analysis narrowed the chromosomal regions to portions of six chromosomes. Genetic losses from at least one of the six regions were found in 98% of bladder cancer patients. In 82% of the cases, two to five chromosomal regions were involved.
The team chose the 13q14 region on chromosome 13, which they knew harbored the tumor-suppressor RB1, for high-resolution genetic analysis to identify candidate genes affecting RB1. This high-resolution genetic analysis pointed to the same section of the chromosome that the whole organ histologic and genetic mapping had identified with expansion of abnormal cells.
Two genes, ITM2B and P2RY5, in the region were found to give cells an initial minimum genetic advantage needed to grow into cancer, hence the investigators termed them forerunner genes. In bladder cancer tumors and cancer cell lines, ITM2B, which neighbors RB1, was methylated 40% of the time. P2RY5, which is located inside a portion of the RB1 gene, was affected by a number of SNPs.
The investigators then tested 62 cell lines derived from major groups of common cancers. They found that forerunner gene expression was reduced in 63% of the cases and ITM2B was methylated in 42%.
The research was conducted by investigators at The University of Texas M. D. Anderson Cancer Center, Baylor College of Medicine, Creighton University School of Medicine, International Institute of Molecular and Cell Biology, Sunnybrook Health Sciences Centre, Women’s College, and The University of Texas Southwestern Medical Center. The study will be published online in Laboratory Investigation.