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large-scale genomic losses

Friday 29 August 2008

Extensive genomic deletions affecting multiple genes are frequent in tumors, making it difficult to identify which lost gene contributes to the development of the cancer.

The classic approach to identifying a tumor-suppressor gene compares multiple tumors with a specific chromosomal deletion to determine the minimal genomic region that is lost in all cases.

Candidate genes from this region are then screened for deletions, mutations, or epigenetic modifications that inactivate the remaining allele.

This strategy has identified important tumor-suppressor genes such as RB1 (band 13q14.2), TP53 (17p13.1), APC (5q21-q22), NF1 (17q11.2), PTEN (10q23.3), and ATM (11q22-q23).

For many recurrent genomic losses, however, such as 1p deletions (Ip LOH) in neuroblastoma, 3p deletions (3p LOH) in lung cancer, and 7q deletions (7q LOH) in myeloid cancers, the critical genes are unknown.

Regardless of whether the respective disease genes have been identified, some deletions have proved to be of great value for determining the prognosis and guiding treatment decisions, as exemplified by 5q deletions (5q LOH) in acute myeloid leukemia; 11q deletions (11q LOH), 13q deletions (13q LOH), and 17p deletions (17p LOH) in chronic lymphocytic leukemia; and the concurrent 1p deletions (1p LOH) and 19q deletions (19q LOH) in anaplastic oligodendroglioma.

RNA interference screening

For example, RNA interference screening in combination with high-resolution DNA copy-number analysis identified the REST gene as a suppressor of epithelial-cell transformation that maps to a segment of band 4q12 that is frequently deleted in colon cancer.

Array-based SNP genotyping

The power of array-based SNP genotyping as a tool for gene discovery in cancers associated with genomic losses is demonstrated by recent studies that revealed deletions of PAX5 (9p13) and IKZF1 (7p13-p11.1) in approximately 30% of children with B-progenitor acute lymphoblastic leukemia and in more than 80% of patients with BCR-ABL1–positive acute lymphoblastic leukemia, respectively.

References

- Fröhling S, Döhner H. Chromosomal abnormalities in cancer. N Engl J Med. 2008 Aug 14;359(7):722-34. PMID: #18703475#