Combined physical and genetic map finds cancer's 'ignition key'

Two genes in the region were found to give cells an initial minimum genetic advantage needed to grow into cancer.

A neighboring gene called ITM2B was found to be silenced by methylation, which is the connection of a methyl chemical group to portions of the gene that shuts it down. In bladder cancer tumors and cancer cell lines, this gene was methylated 40 percent of the time.

A gene known as P2RY5 located inside a portion of the RB1 gene was affected by a number of single-nucleotide changes. A case-control study of one of the gene’s variant forms was conducted using blood DNA from 790 bladder cancer patients and 712 controls matched for age and gender. The specific variation was present in 2.78 percent of patients and every patient with the variation who also smoked developed bladder cancer.

The forerunner genes identified in bladder cancer were analyzed for their expression, methylation and sequence in 62 cell lines derived from major groups of common cancers. Of the cell lines tested, forerunner gene expression was reduced in 63 percent of the cases and ITM2B was methylated in 42 percent.

While forerunner genes were downregulated in lung, breast, blood and pediatric malignancies, they were strongly expressed in colon and liver cancers. This makes sense, the researchers note, because those two cancers do not rely on inactivation of RB1 in order to thrive.

Research continues. “It took us 10 years to get where we are now. With the new high-throughput technology now available, we will complete a high-resolution genetic map of the entire genome for bladder cancer in the next two or three years,” Czerniak said.

Funding for this research was provided by several grants from the National Cancer Institute, including M. D. Anderson’s Specialized Program in Research Excellence for bladder cancer.

Other M. D. Anderson co-authors with Czerniak are co-lead authors Tadeusz Majewski and Sangkyou Lee, and Joon Jeong, Dong-Sup Yoon, Andrzej Kram, Mi-Sook Kim, Tomasz Tuziak, Jolanta Bondaruk, Sooyong Lee, and Weon-Seo Park, all of the Department of Pathology; Kuang Tang, Dennis Johnston and Keith Baggerly, all of the Department of Biostatistics; Woonbok Chung, Lanlan Shen, Saira Ahmed and Jean-Pierre Issa, all of the Department of Leukemia; Barton Grossman, Colin Dinney and David McConkey of the Department of Urology; Jain-Hua Zhou and William F. Benedict, both of the Department of Genitourinary Medical Oncology; and Menashe Bar-Eli of the Department of Cancer Biology.

Co-authors also include R. Alan Harris and Steven Scherer of Baylor College of Medicine’s Department of Molecular and Human Genetics and Human Genome Sequencing Center; Carrie Snyder, Patrice Watson and Henry Lynch, all of the Creighton University School of Medicine Department of Preventive Medicine in Omaha, Neb.; Slawomir Filipek of the International Institute of Molecular and Cell Biology, Warsaw, Poland; Steven Narod of the Centre for Research on Women’s Health, Sunnybrook and Women’s College Health Sciences Center, Toronto, Canada; and Adi Gazdar of The University of Texas Southwestern Medical Center Department of Pathology and Hamon Center for Therapeutic Oncology Research in Dallas.