DETROIT, June 8 – For decades, cancer has been believed to be caused by a sequential accumulation of common gene mutations, with the identification, characterization and targeting of common genetic alterations and their defined pathways dominating the field. A Wayne State University researcher is challenging this notion, however, with evidence that the general mechanism of cancer occurs at the level of the genome, not the gene.
Henry Heng, Ph.D., associate professor in WSU’s Center for Molecular Medicine and Genetics and resident of Detroit, published a study in a recent edition of the Journal of Cellular Biochemistry that represents an important illustration of the evolutionary mechanism of cancer. The paper, which was co-authored by a team from WSU’s Center for Molecular Medicine and Genetics, describes the correlation between changes at the genome level and cancer progression.
“Considering cancer as an evolutionary process is vital to both basic research and clinical applications,” Heng said. “Unfortunately, most previous efforts have focused on individual cancer genes, which represent only a small part of the evolutionary story of cancer. A growing body of evidence suggests that no distinguishable pattern can be discerned from single gene studies. Instead, it appears that finding a general mechanism will require us looking to the system as a whole – the genome.”
Despite the impressive amount of data accumulated from studies of gene mutations, epigenetic dysregulation and pathway alterations, an overwhelming amount of diverse molecular information has offered only a limited understanding of the general mechanism. To solve this paradox, Heng’s group applied the newly established genome theory to describe how somatic cells evolve within individual patients. Using cell culture and animal models, they identified three key components of somatic cell evolution that are responsible for cancer formation: increased dynamics induced by stress, elevated genetic and epigenetic heterogeneity, and natural selection mediated by genome alteration. Results of the study showed a correlation between cancer progression events – immortalization, transformation, metastasis and drug resistance – and changes at the genome level. No common pattern of gene mutations was discovered. In fact, cancer risk was found to be associated with higher levels of genetic diversity.
The findings provide supporting evidence for the genome theory of cancer evolution, which was established by Heng in a paper published in a 2009 edition of BioEssays. According to the theory, most genetic information cannot be defined at the gene level because the function of an individual gene is dependent on the genome context – its position relative to other genes and environmental factors. The theory is supported by previous discoveries that cancer progression requires evolution of the genome as a whole, or macroevolution. Other support includes the lack of common mutations that have been discovered, despite the ever-increasing amount of sequenced cancer genes.
“Decades of cancer research have been conducted by searching for ‘silver bullet’ genes that are common among cancer patients that can be targeted for treatment and prevention, yet no consistent pattern of gene mutations has been found,” Heng said. “Genetic changes at the genome level, however, exist universally in cancer, particularly in the late stages.”
As a result of this and previous findings, Heng said, the field of cancer research should begin to shift its search for evolutionary mechanisms to the genome level. “With the genome theory of cancer evolution, we hope to initiate a new direction in cancer research that focuses on the genome,” he said. “We believe this shift will yield a new platform to fight cancer.”
To view the paper’s abstract, visit http://www.ncbi.nlm.nih.gov/pubmed/20213744?otool=waynelib&dopt=Abstract
Wayne State University is one of the nation’s pre-eminent public research universities in an urban setting. Through its multidisciplinary approach to research and education, and its ongoing collaboration with government, industry and other institutions, the university seeks to enhance economic growth and improve the quality of life in the city of Detroit, state of Michigan and throughout the world. For more information on research at Wayne State University, visit http://www.research.wayne.edu.