Molecular genetics, natural history and the demise of childhood leukaemia

The patterns of genetic change, clonal evolution, natural history and laten cy are very different in the paediatric leukaemias compared with adult epit helial cancers but are similar to those in other childhood cancers of mesen chymal stem cell origin. This distinction has a biological logic in the con text of the selective pressures for clonal emergence in different developme ntal and cellular contexts and has a major impact on curability. Most child hood leukaemias and some other mesenchymal stem cell tumours are of fetal o rigin and can metastasise without corruption of restraints on cell prolifer ation or bypassing apoptosis. In marked contrast to most invasive or metast atic epithelial carcinomas in adults, these former cancers then retain sens itivity to therapeutic apoptosis. Moreover, their abbreviated and less comp lex evolutionary status is associated with less genetic diversity and insta bility, minimising opportunity for clonal selection for resistance. A minor ity of leukaemias in children and a higher fraction in adults do, however, have genetic alterations that bypass cell cycle controls and apoptosis impo sition. These are the 'bad news' genotypes. The cellular and molecular dive rsity of acute leukaemia impacts also on aetiology. Paediatric acute leukae mias can be initiated prenatally by illegitimate recombination and fusion g ene formation in fetal haemopoiesis. For acute lymphoblastic leukaemia (ALL ) in children, twin studies suggest that a secondary postnatal molecular ev ent is also required. This may be promoted by an abnormal or delayed respon se to common infections. Even for a classic case of a cancer that is intrin sically curable by systematic chemotherapy i.e. childhood ALL, prevention m ay turn out to be the preferred option. (C) 1999 Elsevier Science Ltd. All rights reserved.