Neoplasia, Ageing, and Genetic Instability due to Defective Caretaker Genes

Neoplasia, ageing, and genetic instability due to defective caretaker genes * Sir, In all human populations, cancer prevalence and ge-nomic instability increase as a function of age, suggesting that loss of genetic homeostasis contributes to car-cinogenesis. Loss of genetic homeostasis is reflected by the accumulation of chromosome damage and DNA alterations which result from age-dependent decrease of efficiency and fidelity of our genomic maintenance systems. Chromosomal rearrangements reflect errors of recombinational types of DNA repair which, in a variety of leukemias and lymphomas, give rise to chimeric proteins with altered functions. A number of cancer prone conditions are caused by biallelic in-activation of caretaker genes, e.g. TP53, WRN, ATM, BLM and the FANC family of genes, including BRCA2. At the cellular level, inactivation of caretaker genes leads to chromosomal instability, reflecting inability to properly recognize and/or repair genetic damage caused by exogenous (e.g. ionizing radiation, chemicals) or endogenous (e.g. reactive oxygen species) agents. Chromosomal alterations are strikingly different among caretaker gene syndromes, indicating involvement of the respective genes in different genomic maintenance functions (e.g. NER, HR, NHEJ, etc.). While ATM defects yield specific chromosomal rearrangements involving chromosomes 7 and 14, BLM defects result in sharply increased sister chromatid exchange rates, and WRN helicase defects cause " var-iegated translocation mosaicism " (VTM [1–3]). VTM is characterized by the emergence of multiple chro-mosomal rearrangements in a clonal fashion, mostly side by side with diploid cells. During propagation in vitro, a given VTM cell clone may expand or disappear over time (clonal succession and clonal attenuation). The phenomenon of VTM may contribute to the early occurrence of mostly mesenchymal tumors in Werner syndrome patients. A highly instructive example of the adverse effects of genetic instability is Fanconi anemia (FA), a cancer prone multisystem disorder caused by biallelic mutations in one of at least 13 different genes, including BRCA2, PALB2 and BRIP1 [4]. FA patients display a variable pattern of congenital anomalies, but also a myriad of progeroid features (pigmentary changes, premature occurrence of endocrine dysfunction, osteo-porosis, squamous cell carcinomas of the aerodiges-tive tract and the anogenital region). FA cells show a characteristic pattern of spontaneous and induced chromosomal instability (chromatid-type lesions and multiradial exchanges between non-homologous chromosomes), while primary aneuploidy is rare. As a consequence of impaired homologous recombination repair, FA cells are defective in the removal of DNA-interstrand crosslinks and stalled replication forks. This renders FA cells exquisitely sensitive towards DNA-crosslinking agents …