Microsatellite instability at selected tetranucleotide repeats is associated with p53 mutations in non-small cell lung cancer

Microsatellite alterations are useful clonal markers for the early detectio n of cancer. An increase in microsatellite instability has been observed at certain tetranucleotide repeat markers (AAAG(n)) in lung, head and neck, a nd bladder cancer. However, the genetic mechanism underlying these elevated microsatellite alterations at selected tetranucleotide repeat (EMAST) tumo rs is still unknown. The p53 gene plays an important role in maintaining ge nome integrity by repairing damaged DNA, Therefore, we tested 88 non-small cell lung cancers with a panel of 13 microsatellite markers previously show n to exhibit frequent instability and also performed p53 sequence analysis in these tumors. Thirty-one of these 88 cancers (35%) demonstrated a novel allele [EMAST(+)] in greater than or equal to 1 of these 13 microsatellite markers. p53 mutations were detected in 50 of 88 (57%) cancers and were sig nificantly (P = 0.001) more common in EMAST(+) tumors (25 of 31; 81 PC) tha n in EMAST(-) tumors (25 of 57; 44%). Among squamous cell cancers, p53 muta tions were detected significantly (P = 0.04) more frequently in EMAST(+) tu mors (17 of 19; 89%) than in EMAST(-) tumors (10 of 18; 55%), Similarly, am ong primary adenocarcinomas, p53 mutations were present in 67% of the EMAST (+) tumors and in 35% of EMAST(-) adenocarcinomas, None of the 31 EMAST(+) tumors demonstrated high frequency microsatellite instability when examined with a reference panel of five mono- and dinucleotide markers, Primary lun g cancers with microsatellite alterations at selected tetranucleotide repea ts have a high frequency of p53 mutations and do not display a phenotype co nsistent with defects in mismatch repair.