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 alteration 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 cell lung cancer (NSCLC) patients. A highly significant association between p53 mutations and deletions on 3p, 5q, 9p, 11p and 17p was found. There was also a significant correlation between deletions at these loci. 86% of the tumours 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 without deletions at the corresponding loci (P< 0.0001). Data were also examined in relation to smoking status of the patients and histology of the tumours. The frequency of deletions was significantly higher among smokers as compared to non-smokers. This difference was significant for the 3p21.3 (hMLH1 locus), 3p14.2 (FHIT locus), 5q11-13 (hMSH3 locus) and 9p21 (D9S157 locus). Tumours with deletions at the hMLH1 locus had higher levels of hydrophobic DNA adducts. Deletions were more common in squamous cell carcinomas than in adenocarcinomas. Covariate analysis revealed that histological type and p53 mutations were significant and independent parameters for predicting LOH status at several loci. In the pathogenesis of NSCLC exposure to tobacco carcinogens in addition to clonal selection may be the driving force in these alterations.
Zienolddiny
S
S
Department of Toxicology, National Institute of Occupational Health, P.O. Box 8149 Dep., Oslo, N-0033, Norway.
Ryberg
D
D
Arab
M O
MO
Skaug
V
V
Haugen
A
A
D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000209:etiology / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000235:genetics; D002352:Carrier Proteins; D018736:DNA Adducts; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D006801:Humans; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics*; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000070957:MutL Protein Homolog 1; D000074081:MutS Homolog 3 Protein; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins; D018807:Polymorphism, Single-Stranded Conformational; D012907:Smoking / Q000009:adverse effects*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018736:DNA Adducts; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000070957:MutL Protein Homolog 1; D000074081:MutS Homolog 3 Protein; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; C501486:MLH1 protein, human; C078444:MSH3 protein, human; C421109:multidrug resistance-associated protein 1