July 30, 2012
UNC scientists are part of an international team reporting results from the Cancer Genome Atlas project’s large-scale study of colon and rectal cancer tissue specimens showing that the pattern of genomic alterations in these tissues is the same regardless of anatomic location or origin within the colon or the rectum.
Initially, the TCGA Research Network studied colon tumors as distinct from rectal tumors. However, in multiple types of genomic analyses, colon and rectal cancer results were nearly indistinguishable, leading researchers to conclude that these two cancer types can be grouped as one.
The study also found that colorectal tumors with very high levels of genetic errors were generally more aggressive. The study, funded by the National Cancer Institute and the National Human Genome Research Institute, both parts of the National Institutes of Health, was published online in the July 19, 2012, issue of the journal Nature.
Todd Auman, PhD, a UNC member of the study’s writing team, says, “The comprehensive genomic profiling of colon and rectal cancers reported in this study has enabled us to identify potential signaling pathways which could be targets for selective chemotherapeutics. In addition, the data provided in this study will serve as a rich resource for other colorectal cancer researchers to explore in the future.” Auman is a research assistant professor in the UNC Eshelman School of Pharmacy.
He explains UNC’s role in the project, “All of the gene expression data used in this study, both from microarrays and RNA sequencing, was generated at UNC. We also conducted the analysis that grouped the colorectal cancers into three distinct classes based on gene expression profiles.”
There is a known association between aggressiveness of colorectal tumors and the phenomenon of hypermutation, in which the rate of genetic mutation is abnormally high because normal DNA repair mechanisms are disrupted. In this study, 16 percent of the specimens were found to be hypermutated. Three-fourths of these cases exhibited microsatellite instability, which often is an indicator for poor prognosis. Microsatellites are repetitive sections of DNA in the genome. If mutations occur in the genes responsible for maintaining those regions of the genome, the microsatellites may become longer or shorter and this is called MSI.
In 2012, it is estimated that more than 143,000 people in the United States will be diagnosed with colorectal cancer and that 51,500 are likely to die from the disease. Colorectal cancer is the fourth most common cancer in men, after non-melanoma skin, prostate and lung cancer. It is also the fourth most common cancer in women, after non-melanoma skin, breast and lung cancer.
The researchers observed that in the 224 colorectal cancer specimens examined, 24 genes were mutated in a significant numbers of cases. In addition to genes found through prior research efforts, (e.g., APC, ARID1A, FAM123B/WTX, TP53, SMAD4, PIK3CA and KRAS), the scientists identified other genes (ARID1A, SOX9 andFAM123B/WTX) as potential drivers of this cancer when mutated. It is only through a study of this scale that these three genes could be implicated in this disease.
The research network also identified the genes ERBB2 and IGF2 as mutated in colorectal cancer and potential drug targets. These genes are involved in regulating cell proliferation and were observed to be frequently overexpressed in colorectal tumors. This finding points to a potential drug therapy strategy in which inhibition of the products of these genes would slow progression of the cancer.
A key part of this study was the analysis of signaling pathways. Signaling pathways control gene activity during cell development and regulate the interactions between cells as they form organs or tissues. Among other findings, the TCGA Research Network identified new mutations in a particular signaling cascade called the WNT pathway. According to the researchers, this finding will improve development of WNT signaling inhibitors, which show initial promise as a class of drugs that could benefit colorectal cancer patients.
In addition to examining the WNT pathway, the investigators also identified RTK/RAS and AKT-PI3K as pathways that are altered in a substantial set of colorectal tumors, which may show promise for targeting therapies for colorectal cancer. Because of these findings, drug developers may now be able to narrow their scope of investigation with an expectation of producing more focused therapeutic approaches, noted the researchers.
Other UNC coauthors include Katherine Hoadley, PhD; Ying Du, PhD; Matthew Wilkerson, PhD; Yan Shi, PhD ; Christina, Liquori, PhD; Shaowu Meng, PhD; Ling Li, MS; Yidi J. Turman, BS; Michael Topal, PhD; Donghui Tan, MS; Scot Waring, PhD; Elizabeth Buda, MS; Jesse Walsh, MS; Corbin Jones, PhD; Piotr Mieckowski, PhD; Darshan Singh, PhD; Junyian Wu, MS; Anisha Gulabani, BE; Peter Dolina, MBA, BA; Tom Bodenheimer, MS; Alan Hoyle, B; Janae Simons, BS; Matthew Soloway, BS; Lisle Mose, B; Stuart Jefferys, PhD; Saianand Balu, MSC, MS; Brian O’Connor, PhD; Jan Prins, PhD; Derek Chiang, PhD; Neil Hayes, MD, MPH; Joel Tepper, MD; and Charles Perou, PhD.
Authors are with one or more UNC academic units: UNC Lineberger Comprehensive Cancer Center, the Institute or Pharmacogenetics and Individualized Therapy, the Carolina Center for Genome Science, and the Departments of Genetics, Pathology and Laboratory Medicine, Biology, Computer Science, and Internal Medicine.
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