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

M. D. Anderson-led team's whole-organ genomic survey depicts journey from normal to malignant cell

HOUSTON ¯ Whole-organ maps that superimpose genetic information over the terrain of cancerous bladders chart the molecular journey from normal cell to invasive cancer, an international research team led by scientists at The University of Texas M. D. Anderson Cancer Center reports online at the journal Laboratory Investigation, a member of the Nature Publishing Group.

By geographically relating an organ’s varied tissues – normal, precancerous and malignant – to their underlying genetic variation or regulation, the team also identified a crucial new category of genes that launches the process of cancer development.

“These ‘forerunner genes’ are the ignition key that starts the engine of carcinogenesis,” said senior author Bogdan Czerniak, M.D., Ph.D., professor in M. D. Anderson’s Department of Pathology.

“Discovery of forerunner genes opens an entirely new field of investigation to identify biomarkers for the early detection and prevention of cancer,” Czerniak said. “Inactivation of these genes occurs during cancer’s invisible stage, when it is undetectable by traditional means.”

The team reports that forerunner genes must be shut down before a major tumor-suppressing gene called RB1 is silenced, paving the way for invasive cancer. By characterizing the genetic aspects of all tissue types in the organ, the researchers illuminated the sequence of events that carries a normal cell through various stages to invasive cancer. In the case of bladder cancer, they identified three “waves” of genetic hits that drive the process.

Czerniak’s unique approach is called whole organ histologic and genetic mapping, which combines genetic information with microscopic study of the organ tissue, or histology.

Biomarkers for detection, prevention, treatment

Czerniak’s mapping techniques and the team’s findings are seminal work, said T. Sudhir Srivastava, Ph.D., chief of the Cancer Biomarkers Research Group, Division of Cancer Prevention of the National Cancer Institute.

“Identifying genes involved in precancerous development has been an arduous task, primarily for lack of a systematic approach to discovering them and the non-availability of quality tumor specimens,” Srivastava said. “Dr. Czerniak has overcome these difficulties by utilizing the resources available at M. D. Anderson and employing the gene-mapping expertise of his group to uniquely characterize chromosomal regions involved in genomic imbalances, particularly those involved in progression of precancerous conditions to clinically aggressive bladder cancer.

“These findings will accelerate the development of clinically useful biomarkers for the early detection, surveillance, and clinical management of bladder cancer,” said Srivastava, who leads the NCI’s Early Detection Research Network, which partially funds Czerniak’s work.

Bladder cancer is the fifth most common cancer in the United States and accounts for 3 percent of cancer deaths annually. It is strongly associated with smoking, which studies show is a factor in half of cases