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Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers
K W Kinzler1, M C Nilbert, B Vogelstein
1Molecular Genetics Laboratory, Johns Hopkins Oncology Center, Baltimore, MD 21231.
Abstract:
Recent studies have suggested the existence of a tumor suppressor gene located at chromosome region 5q21. DNA probes from this region were used to study a panel of sporadic colorectal carcinomas. One of these probes, cosmid 5.71, detected a somatically rearranged restriction fragment in the DNA from a single tumor. Further analysis of the 5.71 cosmid revealed two regions that were highly conserved in rodent DNA. These sequences were used to identify a gene, MCC (mutated in colorectal cancer), which encodes an 829-amino acid protein with a short region of similarity to the G protein-coupled m3 muscarinic acetylcholine receptor. The rearrangement in the tumor disrupted the coding region of the MCC gene. Moreover, two colorectal tumors were found with somatically acquired point mutations in MCC that resulted in amino acid substitutions. MCC is thus a candidate for the putative colorectal tumor suppressor gene located at 5q21. Further studies will be required to determine whether the gene is mutated in other sporadic tumors or in the germ line of patients with an inherited predisposition to colonic tumorigenesis.
Insights
Researchers identified the MCC gene, a potential tumor suppressor, in colorectal cancer. Mutations and rearrangements in MCC were found in tumors, suggesting its role in colon tumorigenesis.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- A tumor suppressor gene is suspected at chromosome region 5q21, implicated in colorectal cancer development.
- Sporadic colorectal carcinomas are a focus for identifying genetic alterations contributing to cancer.
Purpose of the Study:
- To identify and characterize the putative tumor suppressor gene at chromosome region 5q21.
- To investigate the role of the identified gene in sporadic colorectal carcinomas.
Main Methods:
- Utilized DNA probes from chromosome region 5q21 to analyze colorectal tumor DNA.
- Employed cosmid 5.71 to detect somatic rearrangements and identify conserved sequences.
- Sequenced and analyzed the identified gene, MCC (mutated in colorectal cancer).
Main Results:
- A somatically rearranged restriction fragment was detected in one tumor using cosmid 5.71.
- Identified the MCC gene, encoding an 829-amino acid protein with similarity to a G protein-coupled receptor.
- Found two colorectal tumors with somatic point mutations in MCC, leading to amino acid substitutions.
Conclusions:
- The MCC gene is a strong candidate for the colorectal tumor suppressor gene at 5q21.
- Somatic mutations and rearrangements in MCC occur in colorectal cancer.
- Further research is needed to confirm MCC's role in sporadic tumors and inherited cancer predisposition.