Gene Alterations

Loss or gain of gene function can result from singlegene mutations, chromosomal translocations (unbalanced or balanced), and epigenetic alterations, such as silencing of gene expression by hypermethylation. The net result is either gain of an oncogene function or loss of tumor-suppressor gene function. Tumor-suppressor gene function in a recessive fashion that requires loss of both alleles.18 Haploinsufficiency (loss of a single gene copy) can result in reduction of the gene products and a predisposition to malignancies.19

The RAS gene family is the most studied in MDS. Ten to forty percent of patients with MDS have RAS mutations. The most common mutation is a single base change at codon 12 of the N-RAS family. The resultant mutated N-RAS protein retains an active GTP form, promoting continuous signaling to the nucleus. N-RAS mutations carry a higher risk of AML transformation and portend a worse prognosis.

Other gene mutations described in MDS include P53 tumor suppression gene (5-10% of cases);20 FLT3 oncogene receptor tyrosine kinase (5% of cases);21 P15 ink4b, a tumor suppressor gene that is transcriptionaly repressed through promoter silencing by hypermethyla-tion (can be present in up to 50% of high-grade MDS).22 The abnormality is seen with the 7q- syndrome and is associated with shorter survival.23 Microsatellite instability (MSI) resulting from defective mismatch repair genes (MMR) has been described particularly in therapy related MDS (t-MDS).24 Table 38.1 lists a few of the described genes that are altered in MDS.

Certain co-existing gene mutations may increase the individual susceptibility to develop MDS; the NQO1 gene mutation increases the risk for t-MDS in both the homozygotic and heterozygotic states. NQO1 is a quinone oxireductase required for detoxifying benzene derivatives.25'26

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