The majority of colorectal tumors sequenced in the first major project of The Cancer Genome Atlas showed that gene mutations disrupted proper activity of a cellular pathway known to play a crucial role in embryogenesis and in cancer, said researchers including those from the Baylor College of Medicine Human Genome Sequencing Center in a report that appears online in the journal Nature.
"The thing that really came across was the WNT signaling pathway," said Dr. Lawrence Donehower, professor of molecular virology and microbiology at BCM, who helped analyze the results. "We knew it was important but so many of the mutations clustered around it, either in the pathway or regulating it."
New genes identified
"The large number of patients in the study enabled us to identify several new genes not previously suspected of playing a role in colorectal cancer." said Dr. David Wheeler, associate professor in the Baylor Human Genome Sequencing Center and a communicating author of the report. "The surprising finding was the confluence of mutations that led to the activation of the MYC pathways," he said.
Both Donehower and Wheeler are members of the NCI-designated Dan L Duncan Cancer Center at BCM.
"MYC is a key driver of proliferation in many stem and progenitor cell types and its continued overexpression would keep the colon cells proliferating and not differentiating," said Donehower.
Wheeler plays a major role in directing the BCM Human Genome Sequencing Center's Cancer Genome Atlas activities. Donehower, an expert in oncogene and tumor suppressor gene biology, spent some months on sabbatical in the BCM Human Genome Sequencing Center that led to their successful collaboration in this project.
Dr. Preethi Gunaratne, associate professor of biology and biochemistry at the University of Houston and of pathology & immunology at BCM, also took part in the work and said, "The new findings from this work will undoubtedly lead to a quantum leap in our understanding of the networks of genetic alterations that cooperate to generate and maintain this cancer."
To carry out the sequencing, researchers from The Cancer Genome Atlas Network compared the exomes of 224 colorectal tumor samples to normal tissues samples from the same people.
The tumors fell into two basic categories the hypermutated cancers found mainly in the right colon and those that were not hypermutated, which could be found throughout the colon and rectum.
A phenomenon known as microsatellite instability is associated with the hypermutated tumors. Microsatellites are repeated sequences of DNA that everyone has. However, these repeats are the same length in individuals. Defects in DNA repair genes, however, can lead to these microsatellites gaining or losing length and becoming unstable. This can lead to the colorectal tumors having a mutation rate that is 10 to 100 times higher than seen in other tumors.
Prior studies have shown that people with these hypermutated tumors have a better prognosis than those whose tumors are mutated at lower rates.
Looking for better treatments
The results of this sequencing may help explain why that is so and point the way to better treatments. Some tumors are even ultramutated, said Wheeler, which has also been seen in some forms of endometrial cancer (affecting the lining of the uterus).
"I think we will get to the point where we don't look at treatment of cancer on an organ by organ basis, but by the commonality of mutations the cancers share. Patients would be treated in a pan-cancer way, depending on the molecular remodeling that has occurred," said Wheeler.
The BCM Human Genome Sequencing Center carried out two-thirds of the sequencing activities while Washington University Sequencing Center in St. Louis, Mo., carried out one-third.
Other BCM researchers who took part include Dr. Richard Gibbs, Donna M. Muzny, Matthew N. Bainbridge, Kyle Chang, Huyen H. Dinh, Jennifer A. Drummond, Gerald Fowler, Christie L. Kovar, Lora R. Lewis, Margaret B. Mogan, Dr. Irene F. Newsham, Dr. Jeffrey G. Reid, Jireh Santibanez, Dr. Eve Shinbrot, Dr. Lisa R. Trevino, Yuan-Qing Dr. Wu, Min Wang, and Dr. Chad J. Creighton. Funding for this work came from the National Institutes of Health.
Other BCM components that took part include the NCI-designated Dan L Duncan Cancer Center.