Ha-ras hypervariable alleles in myelodysplasia

Abstract

The somatic mutation of one of the ras oncogenes is now considered to be a critical step in the pathogenesis of many tumours^1,2. Circumstantial evidence also suggests that some individuals may be genetically predisposed to malignancy³ and a general method used to analyse such disease susceptibility is the study of restriction fragment length polymorphisms (RFLPs) at particular loci^4,5. The Harvey ras (Ha-ras) locus includes a hypervariable region (HVR) which consists of a series of 28-base-pair (bp) tandem repeats 3′ to the gene⁶. This arrangement gives rise to alleles of a wide range of sizes, making such genetic analysis possible. A previous study reported that white blood cell DNA from cancer patients frequently showed allelic restriction fragments at the Ha-ras locus which were found only rarely in normal unaffected individuals, and it was concluded that the inheritance of such unusual alleles may be linked to a susceptibility to cancer⁷. As this conclusion has major implications we sought to investigate whether this association could be confirmed in patients with myelodysplasia, a common haematological malignancy reported to have the highest frequency of rare alleles⁷. The Ha-ras alleles were characterized in normal healthy individuals and compared with those found in patients with myelodysplasia (MDS). Our results, reported here, show that the distribution of Ha-ras alleles in myelodysplastic patients is not significantly different from that in normal individuals.