CONSTITUTIONAL TRISOMY 8 AS FIRST MUTATION IN MULTISTEP CARCINOGENESIS - CLINICAL, CYTOGENETIC AND MOLECULAR-DATA ON 3 CASES

Three patients, with constitutional trisomy 8 mosaicism (CT8M), who de veloped a malignancy are reported. The diagnoses were refractory anaem ia, acute lymphoblastic leukaemia, and idiopathic myelofibrosis. In th e child with acute leukaemia, the CT8M was diagnosed at birth due to s evere dysmorphisms and malformations; the other two patients showed a milder phenotype, and the CT8M was diagnosed only after the finding of trisomy 8 in neoplastic cells. The review of eight similar, previousl y reported cases and the clinical, cytogenetic, and molecular studies performed in our patients led us to make the following observations: ( I) CT8M predisposes to neoplasms, preferentially to myelo- or lymphopr oliferative diseases; (2) a gene dosage effect for glutathione reducta se in red blood cells was seen in two of our patients; (3) the wide ph enotypic variation of CT8M was confirmed: trisomy 8 in neoplastic cell s of phenotypically near-normal cases may be misinterpreted as acquire d; and (4) molecular studies suggested a postzygotic origin of the tri somy in our three cases, with the supernumerary chromosome being of pa ternal origin in one case and of maternal origin in the other two. We postulate that the trisomy 8 in neoplasms may often occur by mitotic n ondisjunction in an early embryonic multipotent cell and that what is usually interpreted as an acquired trisomy 8 may in fact be CT8M. The constitutional trisomy 8 would act as a pathogenetically important fir st mutation in multistep carcinogenesis, Whenever trisomy 8 is found i n malignancies, the patient should be reevaluated clinically to exclud e CT8M, and CT8M patients should be monitored for the possible develop ment of malignancies. (C) 1996 Wiley-Liss, Inc.