ALTERATIONS IN TELOMERIC REPEAT LENGTH IN LUNG-CANCER ARE ASSOCIATED WITH LOSS OF HETEROZYGOSITY IN P53 AND RB

In the two-stage model of controlling cellular senescence in cultured human fibro blasts, retinoblastoma (Rb) and p53 proteins may be key fa ctors regulating the mortality stage 1 mechanism. In addition, the cri tical loss of telomeric DNA due to the end-replication problem may res ult in the mortality stage 2 mechanism, Cells which acquire telomerase activity can overcome the M2 mechanism by stabilizing telomere length and thus become immortal (telomere hypothesis). At present it is know n whether cellular immortality is a prerequisite for all human cancers , To investigate this question and the applicability of the two-stage model to human cancers, we analysed the relationship between alteratio ns of telomere length and other genetic changes in lung cancer. Among 60 primary lung cancer tissues, telomere length alterations were obser ved in 16 tumors (26.7%) including 14 with short and two with elongate d telomeres. Ten of them revealed allelic loss of both p53 and Rb gene s, and remaining six showed no abnormalities in both genes. We propose that inactivation of both p53 and Rb genes may promote cell divisions causing telomere shortening in lung cancer as in the two-stage model, while there may be another pathway to overcome both M1 and M2 mechani sms, especially for adenocarcinoma.