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Study IDs Chromosomal Instabilities Linked to Poor Colorectal Cancer Outcomes

NEW YORK (GenomeWeb News) – In a paper scheduled to appear online this week in the Proceedings of the National Academy of Sciences, researchers from Israel and the US began characterizing the chromosomal instabilities associated with the transition from normal tissue to colorectal cancer. Along the way, they found specific chromosomal and gene expression changes heralding poor colorectal cancer outcomes.

The team, which included investigators from Israel's Weizmann Institute of Science, Weill Cornell Medical College, the Broad Institute, Memorial Sloan-Kettering Cancer Center, and Princeton University, used gene expression and SNP arrays to assess chromosomal instabilities in hundreds of samples, from normal tissue to advanced colorectal cancer and various stages in between.

In so doing, they identified characteristic chromosomal abnormalities that occur during colorectal cancer development and progression — and biological pathways affected by such changes. Together, their results suggest some chromosomal abnormalities occur early in some colorectal cancers and may help determine patient outcomes.

The study was different from previous colorectal studies in its scope and size, senior author Eytan Domany, a bioinformatics researcher at the Weizmann Institute of Science, told GenomeWeb Daily News, since he and his colleagues evaluated a large number of samples representing colorectal cancer at every stage.

The progression from normal tissue to benign and malignant colorectal tumors involves a range of genetic changes, including large chromosomal changes and relatively small amplifications and deletions, called microsatellite instabilities.

About 85 percent of colorectal cancer patients have chromosomal instabilities, Domany explained. That, coupled with an interest in finding personalized, biomarkers for predicting cancer outcomes, spurred the group to look for chromosomal instabilities that were linked to colorectal cancer development and progression.

Using 130 Affymetrix 50 k SNP arrays and 299 Affymetrix U133A gene expression arrays, the researchers evaluated colorectal cancer at every stage — from normal epithelial tissues to benign adenomas to stage 1-4 malignant adenocarcinomas and metastatic cancers.

"Data that were collected from patients at a variety of clinical stages allowed us to associate chromosomal changes with survival and disease progression and to identify genetic and biochemical pathways that are affected by these aberrations," the authors wrote.

The project involved key contributions from several research centers, Domany emphasized. Co-author Philip Paty, a MSKCC surgeon, collected the tissue samples over several years. Researchers from MSKCC, Princeton, and Cornell, respectively, did the pathology work, gene expression analyses, and SNP arrays. Meanwhile, co-lead author Michal Sheffer, a graduate student in Domany's lab, performed data integration and analyses for the project.

Using the Broad Institute's Genomic Identification of Significant Targets in Cancer algorithm, the researchers identified amplifications and deletions that were significantly more common in the tumor samples. For example, they detected broad amplifications — which affected more than half of a chromosomal arm — on the X-chromosome and chromosomes 7, 8, 13, and 20, and broad deletions on chromosomes 4, 8, 14, 15, 17, 18, 20, and 22.

Interestingly, the team reported that the group of individuals with deletions on chromosome arms 18q, 8p, 4p, or 15q tended to have poor outcomes whereas the group with no such deletions usually had good outcomes, characterized as disease-free survival for five years or longer.

Meanwhile, the transition from benign adenomas to stage 1 tumors frequently corresponded to copy number changes involving chromosome arms14q, 20q, 20p, and/or 8q, with more than 90 percent of tumors carrying 8q amplifications.

When the researchers looked at how such chromosomal instabilities affected biological pathways they identified copy number and gene expression changes affecting genes involved in several known cancer-related pathways. But they also detected expression and copy number changes for genes not previously implicated in cancer. For instance, their results suggest copy number alterations that decreased the expression of genes in an oxidative phosphorylation pathway were linked to poor outcomes.

Looking at both copy number changes and gene expression data also allowed the team to predict copy number changes based on RNA profiling and gene expression data, Domany explained.

Another goal of the study was to determine whether chromosomal instabilities are involved in causing colorectal cancer or whether they are a byproduct of other malignant changes in the cell. Based on their results so far, Domany said the team has reason to believe chromosomal instabilities are driving at least some colorectal cancer development.

"At least for colorectal cancer, some of the aberrations occur early in the process and there's a good chance it's causative," Domany said. While this may not be true of all cancers, he added, recognizing chromosomal abnormalities as an early event in cancer development may eventually help target this type of cancer.

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