A group of investigators from the Howard Hughes Medical Institute took a look at breast and colon cancers, and deciphered some common pathways that are being utilized for carcinogenesis :
An extensive study of the DNA in cancerous cells has uncovered a large number of genes likely to contribute to the development and progression of breast and colorectal cancer. The study suggests that each breast and colon tumor is unique and may arise through mutations in many different combinations of genes.
Despite the inherent complexity of the diseases, the new studies show that most of the approximately 280 candidate cancer genes identified by the researchers are involved in a much smaller number of biochemical pathways – as few as 15. Studies of these pathways are already producing new ways to diagnose and treat cancer…
“Most or all of the major pathways that contribute to at least these two kinds of cancer have been discovered,” said Bert Vogelstein, a Howard Hughes Medical Institute investigator at the Kimmel Cancer Center at Johns Hopkins, who led the study. “We need to start thinking about cancer in terms of these pathways instead of individual genes, because that’s a more accurate view of how cancers originate.”
The team isolated DNA from 11 breast and 11 colorectal tumors. They then compared the DNA sequences of all of the RefSeq genes in those cells to gene sequences derived from the Reference Sequence compiled by the Human Genome Project. RefSeq is a compendium of 18,191 genes that represents the gold-standard in the field and is estimated to contain more than 90 percent of the coding information in the human genome.
More than nine percent of the genes (1,718 of 18,191) sequenced in the tumors had at least one DNA change in either a breast or colorectal cancer that altered the protein encoded by the gene. But the majority of these DNA changes were what the researchers called “passenger” mutations that were not involved in the development of the tumor. The team therefore applied statistical and bioinformatics techniques to prioritize the mutations, highlighting genes that were most likely to be causally involved in tumorigenesis (“driver” mutations). In this way, they identified 280 candidate cancer genes that were most likely to be drivers and ranked them on the basis of a variety of criteria.
When the team laid out all 18,000 or so human genes on a two-dimensional grid, the mutation frequency data for the candidate cancer genes formed a few “mountains” amidst a large number of “hills.” The mountains represented genes that are mutated in a large percentage of breast and colorectal tumors — typically more than 20 percent — while the hills are mutated in fewer than five percent of tumors. An average of about 15 candidate cancer genes were mutated in each colorectal and breast tumor, respectively.
“The take-home message is that there are a few mountains and many hills, so the low-frequency mutations dominate the landscape,” said Laura Wood, an M.D./Ph.D. student at Johns Hopkins who is the lead author of the paper. “That really wasn’t expected when we embarked on this project a few years ago. We all expected to find more mountains hiding out there, and we didn’t.”