Mechanisms Underlying Losses of Heterozygosity in Human Colorectal Cancers

Losses of heterozygosity are the most common molecular genetic alteration observed in human cancers. However, there have been few systematic studies to understand the mechanism(s) responsible for losses of heterozygosity in such tumors. Here we report a detailed investigation of the five chromosomes...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2001-02, Vol.98 (5), p.2698-2702
Main Authors: Thiagalingam, Sam, Laken, Steve, James K. V. Willson, Markowitz, Sanford D., Kinzler, Kenneth W., Vogelstein, Bert, Lengauer, Christoph
Format: Article
Language:English
Subjects:
Alleles
Aneuploidy
Biological Sciences
Cancer
Cell lines
Cells
Chromosome Deletion
Chromosomes
Colorectal cancer
Colorectal Neoplasms - genetics
Colorectal Neoplasms - pathology
Genes
Humans
In Situ Hybridization, Fluorescence
Loss of Heterozygosity
Medical research
Mitotic recombination
Tumor Cells, Cultured
Tumors
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Summary:Losses of heterozygosity are the most common molecular genetic alteration observed in human cancers. However, there have been few systematic studies to understand the mechanism(s) responsible for losses of heterozygosity in such tumors. Here we report a detailed investigation of the five chromosomes lost most frequently in human colorectal cancers. A total of 10,216 determinations were made with 88 microsatellite markers, revealing 245 chromosomal loss events. The mechanisms of loss were remarkably chromosome-specific. Some chromosomes displayed complete loss such as that predicted to result from mitotic nondisjunction. However, more than half of the losses were associated with losses of only part of a chromosome rather than a whole chromosome. Surprisingly, these losses were due largely to structural alterations rather than to mitotic recombination, break-induced replication, or gene conversion, suggesting novel mechanisms for the generation of much of the aneuploidy in this common tumor type.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.051625398