Presentation of an unorthodox model of carcinogenesis initiation providinga simple pathogenic explanation to all the enigmas of Lynch syndrome.

The genotype-phenotype relationship of Lynch syndrome displays many enigmat ic features which cannot be explained satisfactorily by the prevailing conc epts of carcinogenesis and genetic predisposition to cancer. We propose her e a new model of carcinogenesis divided into two and only two evolutive pha ses: a) a preliminary phase starting with the counter-selective loss of mis match repair function, in which most clones with the RER mutator phenotype are eliminated through apoptosis or an accelerated ageing process; b) an ex plosive phase that is initiated only if mutations blocking apoptosis and se nescence, rapidly acquired during the short life span of the non-transforme d RER+ clones, eventually rescue one mismatch repair-deficient cell that gi ves rise to the malignant clone. Carcinogenesis is proposed here to progres s irreversibly and very rapidly once initiated. We shall show how this mode l provides a meaningful etiologic and pathogenic interpretation of all the curious features of Lynch syndrome. (C) 1999 Academie des sciences/Editions scientifiques et medicales Elsevier SAS.