title: 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.
abstract: 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 theta = 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.
authors.affiliation: Section of Hematology/Oncology, University of Chicago, Illinois 60637, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Gao
authors.forename: M
authors.initials: M
authors.lastname: Horwitz
authors.forename: D
authors.initials: D
authors.lastname: Roulston
authors.forename: F
authors.initials: F
authors.lastname: Hagos
authors.forename: N
authors.initials: N
authors.lastname: Zhao
authors.forename: E J
authors.initials: EJ
authors.lastname: Freireich
authors.forename: H M
authors.initials: HM
authors.lastname: Golomb
authors.forename: O I
authors.initials: OI
authors.lastname: Olopade
mesh_terms: D000208:Acute Disease; D000328:Adult; D002872:Chromosome Deletion; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics* / Q000378:metabolism*; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000473:pathology*; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D010375:Pedigree