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Susceptibility gene for familial acute myeloid leukemia associated with loss of 5q and/or 7q is not localized on the commonly deleted portion of 5q

The molecular mechanism for the occurrence of leukemia in multiple members of a family has not been fully elucidated but data support the contribution of highly penetrant mutations in leukemia susceptibility genes. We have investigated the genetic etiology of an unusual three‐generation family with apparent autosomal dominant transmission of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) accompanied by somatic loss of the long arm of chromosome 5 and/or loss of heterozygosity (LOH) analysis and fluorescence in situ hybridization (FISH) of leukemia cells have been performed, confirming acquired hemi‐ and homozygous deletion of the long arm of chromosome 5. However, the chromosome lost in the observed LOH event is from the affected parent, in contradiction to the expectation for a two‐hit hypothesis involving a tumor suppressor gene. Furthermore, genetic linkage has been performed at 5q31–33 as well as other loci (21q22 and 16q21–23.2) previously implicated in familial leukemia. In this family, linkage analysis excludes loci at 5q31–33 and 21q22, but localization to 16q21–23.2 cannot be excluded. We observed a maximum multipoint LOD score of 1.19 between marker D16S265 and D16S503 at 16q22 (P = 0.03), suggesting possible linkage to this locus. Considering this family and the previous 16q‐linked family together, the linkage of a leukemia susceptibility gene to 16q22 achieved an LOD score of 3.63 at D16S265 with Θ = 0. Thus, somatic deletion of the long arm of chromosome 5 appears as a necessary but surprisingly noncausative event for onset of AML and MDS in this family, thereby confirming a multistep etiology in which chromosome 5 plays an important secondary role. Genes Chromosomes Cancer 28:164–172, 2000. © 2000 Wiley‐Liss, Inc.