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Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers
S Thiagalingam1, C Lengauer, F S Leach
1Johns Hopkins Oncology Center, Baltimore, Maryland 21231, USA.
Abstract:
Chromosome deletions are the most common genetic events observed in cancer. These deletions are generally thought to reflect the existence of a tumour suppressor gene within the lost region. However, when the lost region does not precisely coincide with a hereditary cancer locus, identification of the putative tumour suppressor gene (target of the deletion) can be problematic. For example, previous studies have demonstrated that chromosome 18q is lost in over 60% of colorectal as well as in other cancers, but the lost region could not be precisely determined. Here we present a rigorous strategy for mapping and evaluating allelic deletions in sporadic tumours, and apply it to the evaluation of chromosome 18 in colorectal cancers. Using this approach, we define a minimally lost region (MLR) on chromosome 18q21, which contains at least two candidate tumour suppressor genes, DPC4 and DCC. The analysis further suggested genetic heterogeneity, with DPC4 the deletion target in up to a third of the cases and DCC or a neighbouring gene the target in the remaining tumours.
Insights
Chromosome deletions are common in cancer, often indicating tumor suppressor genes. This study precisely maps deletions on chromosome 18q21 in colorectal cancers, identifying DPC4 and DCC as key targets.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- Chromosome deletions are frequent genetic alterations in cancer development.
- Identifying specific tumor suppressor genes within deleted chromosomal regions is crucial but challenging, especially when deletions don't align with known hereditary cancer loci.
- Chromosome 18q deletions are prevalent in colorectal cancers, yet the precise region and target genes remain undetermined.
Purpose of the Study:
- To develop and apply a rigorous strategy for mapping and evaluating allelic deletions in sporadic tumors.
- To precisely define the minimally deleted region (MLR) on chromosome 18q in colorectal cancers.
- To identify candidate tumor suppressor genes within the MLR on chromosome 18q21.
Main Methods:
- Development of a precise strategy for mapping allelic deletions in sporadic tumors.
- Application of this strategy to analyze chromosome 18 deletions in colorectal cancer samples.
- Identification of a minimally lost region (MLR) on chromosome 18q21.
Main Results:
- A minimally lost region (MLR) on chromosome 18q21 was precisely defined in colorectal cancers.
- The MLR contains at least two candidate tumor suppressor genes: DPC4 and DCC.
- Genetic heterogeneity was observed, with DPC4 being the deletion target in approximately one-third of cases, and DCC or a neighboring gene in the remainder.
Conclusions:
- The study successfully mapped a critical region on chromosome 18q21 frequently deleted in colorectal cancer.
- DPC4 and DCC are identified as strong candidate tumor suppressor genes targeted by these deletions.
- The findings suggest genetic heterogeneity in the deletion targets within chromosome 18q in colorectal tumorigenesis.