PROGNOSTIC VALUE OF REPLICATION ERRORS ON CHROMOSOMES 2P AND 3P IN NON-SMALL-CELL LUNG-CANCER

As chromosomes 2p and 3p are frequent targets for genomic instability in lung cancer, we have addressed whether alterations of simple (CA), DNA repeats occur in non-small-cell lung cancer (NSCLC) at early stage s. We have analysed by polymerase chain reaction (PCR) assay replicati on errors (RER) and loss of heterozygosity (LOH) at microsatellites ma pped on chromosomes 2p and 3p in 64 paired tumour-normal DNA samples f rom consecutively resected stage [, II or [IIA NSCLC. DNA samples were also examined for K-ras and p53 gene mutations by PCR-single-stranded conformational polymorphism (PCR-SSCP) analysis and cyclic sequencing , as well as their relationship with clinical outcome. Forty-two of th e 64 (66%) NSCLC patients showed RER at single or multiple loci. LOH w as detected in 23 tumours (36%). Among patients with stage I disease, the 5-year survival rate was 80% in those whose tumours had no evidenc e of RER and 26% in those with RER (P = 0.005). No correlation was est ablished between RER phenotype and LOH, K-ras or p53 mutations. RER re mained a strong predictive factor (hazard ratio for death, 2.89; 95% c onfidence interval, 2.23-3.79; P = 0.002) after adjustment for all oth er evaluated factors, including p53, K-ras, LOH, histological type, tu mour differentiation and TNM stage, suggesting that microsatellite ins tability on chromosomes 2p and 39 may play a role in NSCLC progression through a different pathway from the traditional tumour mechanisms of oncogene activation and/or tumour-suppressor gene inactivation.