PHILADELPHIA (Thurs., Mar. 22, 2007) -- In today's online edition of Genome Research, a husband-and-wife research team from Thomas Jefferson University report the discovery of a gene that, when mutated, may suppress colorectal cancer. To conduct the study, the researchers used a strain of mice that develop polyps, or small growths of tissue, in the digestive tract--the harbingers of cancer. When these mice possessed one copy of the mutated gene, the incidence of small intestinal and colon polyps were reduced by about 90%.
"This gene may give us a novel target to aid in the diagnosis, prevention, and/or treatment of cancer," says Dr. Arthur Buchberg, one of the co-senior authors on the report.
The gene is called Atp5a1, and encodes an essential component of the cell's energy-production machinery. Mice with two copies of mutated Atp5a1 die early in embryonic development--probably due to insufficient energy. The identification of a gene critical for energy production in the cell opens up an array of potential new targets for therapy.
The research team identified a duplication of DNA--only four bases in length--in a critical part of the Atp5a1 gene. This mutation, which results in decreased levels of Atp5a1 gene expression, is the first mutation identified in the mouse Atp5a1 gene. In trypanosomes (tiny parasitic protozoa that cause African sleeping sickness), the loss of Atp5a1 gene function leads to death. To date, no mutations in the human ATP5A1 gene have been identified--further supporting its essential role in the cell.
"In humans, ATP5A1 is located on chromosome 18, in a region that often exhibits genetic alterations in colon tumors," says Dr. Linda Siracusa, the other co-senior investigator on the project. "A better understanding of the biological function of ATP5A1 will provide insights concerning its potential role in human cancer."
Colorectal cancer is currently ranked as the second leading cause of cancer death in the United States. But scientific progress in cancer research is challenged by the array of environmental and genetic influences on tumor initiation, development, and progression in the human population. Therefore, scientists have turned to mouse models, which have nearly identical genetic backgrounds and are housed in controlled conditions.
The scientists used a strain of mice called Min (multiple intestinal neoplasia). Min mice carry mutations in the Apc gene, which causes the development of intestinal tumors. Inactivation of the corresponding gene (APC) in humans is considered a key event in the development of colorectal cancer.
Tumor development is regulated by modifier genes, which may function to enhance or suppress tumor initiation, growth and/or progression. Atp5a1 is a modifier gene, and it is located on the same chromosome as Apc in mice. Interestingly, the results suggest that the mutant Atp5a1 gene caused the death of tumor cells, primarily when it was present on the same chromosome as the mutant Apc gene.
Amy Baran, a doctoral student in Dr. Siracusa's laboratory, and Karen Silverman, a former doctoral student and postdoctoral fellow in Dr. Buchberg's laboratory, are co-first authors on the paper.
About the article:
The manuscript will be published online ahead of print on Thursday, March 22, 2007. Its full citation is as follows: Baran, A.A., Silverman, K.A., Zeskand, J., Koratkar, R., Palmer, A., McCullen, K., Curran, W.J., Bocker Edmonston, T., Siracusa, L.D., and Buchberg, A.M. 2007. The Modifier of Min 2 (Mom2) locus: embryonic lethality of a mutation in the Atp5a1 gene suggests a novel mechanism of polyp suppression. Genome Res. doi:10.1101/gr.6089707
About Genome Research:
Genome Research (www.genome.org) is an international, continuously published, peer-reviewed journal published by Cold Spring Harbor Laboratory Press. Launched in 1995, it is one of the five most highly cited primary research journals in genetics and genomics.
About Cold Spring Harbor Laboratory Press:
Cold Spring Harbor Laboratory Press is an internationally renowned publisher of books, journals, and electronic media, located on Long Island, New York. It is a division of Cold Spring Harbor Laboratory, an innovator in life science research and the education of scientists, students, and the public. For more information, visit www.cshlpress.com.