[Explanation of enigmas of the Lynch syndrome thanks to a new carcinogenesis model characterized by an unorthodox initiation process].
The genotype-phenotype relationship of Lynch syndrome displays many enigmatic features which cannot be explained satisfactorily by the prevailing concepts of carcinogenesis and genetic predisposition to cancer. We propose here a new model of carcinogenesis divided into two and only two evolutive phases: a) a preliminary phase starting with the counter-selective loss of mismatch repair function, in which most clones with the RER mutator phenotype are eliminated through apoptosis or an accelerated ageing process; b) an explosive phase that is initiated only if mutations blocking apoptosis and senescence, rapidly acquired during the short life span of the non-transformed RER+ clones, eventually rescue one mismatch repair-deficient cell that gives rise to the malignant clone. Carcinogenesis is proposed here to progress irreversibly and very rapidly once initiated. We shall show how this model provides a meaningful etiologic and pathogenic interpretation of all the curious features of Lynch syndrome.
Janin
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Unité d'oncologie médicale, Hôpital Laënnec, Paris, France.
D000236:Adenoma / Q000235:genetics / Q000473:pathology; D000328:Adult; D017668:Age of Onset; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D016922:Cellular Senescence / Q000235:genetics; D002648:Child; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology; D003111:Colonic Polyps / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000453:epidemiology / Q000235:genetics / Q000473:pathology*; D004260:DNA Repair / Q000235:genetics*; D018450:Disease Progression; D017491:Genes, APC; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D051379:Mice; D018895:Microsatellite Repeats; D008875:Middle Aged; D008954:Models, Biological; D016296:Mutagenesis; D009928:Organ Specificity; D010641:Phenotype; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology; D012306:Risk