Loss of heterozygosity is related to p53 mutations and smoking in lung cancer

Carcinogenesis results from an accumulation of several genetic alterations. Mutations in the p53 gene are frequent and occur at an early stage of lung carcinogenesis. Loss of multiple chromosomal regions is another genetic al teration frequently found in lung tumours. We have examined the association between p53 mutations, loss of heterozygosity (LOH) at frequently deleted loci in lung cancer, and tobacco exposure in 165 tumours from non-small cel l lung cancer (NSCLC) patients. A highly significant association between p5 3 mutations and deletions on 3p, 5q, 9p, 11p and 17p was found. There was a lso a significant correlation between deletions at these loci. 86% of the t umours with concordant deletion in the 4 most involved loci (3p21, 5q11-13, 9p21 and 17p13) had p53 mutations as compared to only 8% of the tumours wi thout deletions at the corresponding loci (P < 0.0001). Data were also exam ined in relation to smoking status of the patients and histology of the tum ours. The frequency of deletions was significantly higher among smokers as compared to non-smokers. This difference was significant for the 3p21.3 (hM LH1 locus), 3p14.2 (FHIT locus), 5q11-13 (hMSH3 locus) and 9p21 (D9S157 loc us). Tumours with deletions at the hMLH1 locus had higher levels of hydroph obic DNA adducts. Deletions were more common in squamous cell carcinomas th an in adenocarcinomas. Covariate analysis revealed that histological type a nd p53 mutations were significant and independent parameters for predicting LOH status at several loci. In the pathogenesis of NSCLC exposure to tobac co carcinogens in addition to clonal selection may be the driving force in these alterations. (C) 2001 Cancer Research Campaign.