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150 Abstracts/Lung Cancer I4 (1996) 149-179
Epidemiology and etiology
Genetic susceptibility to lung cancer as determined by lymphocytic chromosome analysis Dave BJ, Hopwood VL, King TM, Ziang H, Spitz MR, Pathak S. Cellular Genetics Laboratory. Texas Univ. M.D. Anderson Can. Ctr.. Box 181. 1515 Holcombr Boulevard, Houston, TX 77030. Cancer Epidemiol Biomarkers Prev 1995;4: 743-9.
Chromosomal anomalies were analyzed in the lymphocyte cultures among 96 untreated lung cancer patients and 74 clinically normal comparison subjects. The analysis revealed that > 15% of the lung cancer patients showed structural or numerical rearrangements in chromosomes I, 3, 5,7,9, 12, 14, and 21. A case control comparison showed that these aberrations were significantly higher in chromosome 7 [oddsratio(OR)=2.32; 95% confidence interval(Cl). 1.14and4.82], chromosome9(OR=2.61;95%CI, 1.27and5.48),chromosome lZ(OR =4. IO; 95%Cl, 1.40 and 14.54). and chromosome 21 (OR= 7.75; 95% Cl, I .73 and 70.80) of the patients than in the controls. However, only chromosome 9 (OR= 3.57; 95% CI, 1.33 and9.46) and chromosome 21 (OR=6.94;95%Cl,3.lSand9.98)retainedsignificanceaAerstratifing on smoking status. Among the lung cancer patients, the breakpoints cluster in specific regions ofsome ofthese chromosomes. These regions are lpl3-q21, 3p21-q13, 7pl2-q12. 7q22, 7q32, 9pl3-ql3, 12~13. 14ql 1. and 14q32. The distribution of lung cancer patients, according to histological types. showed that aberrations in chromosomes I, 7. and 9 dominated the scenario of chromosomal changes in non-small cell lung carcinomas. Thus, the dataon lymphocytic chromosomal rearrange- ments in lung cancer patients not only indicate the importance of specificgeneticchangesintheetiologyoflungcancerbutalsoemphaslzes the putative rule of such analysis in determining primary genetic abnormalities in the large heterogeneous group of lung cancers.
p53 and K-ras in radon-associated lung adenocarcinoma McDonald JW, Taylor JA, Watson MA, Saccomanno G, Devereux TR. Epidemiology Branch. NIEHS, P.O. Box 12233, Research Triangle Park, NC 27709. Cancer Epidemiol Biomarkers Prev 1995;4:791-3.
Mutations in the ~53 tumor suppressor gene and the K-ras proto- oncogene are common genetic defects in lung cancer. Analysis of the patterns of damage in these genes may provide important insights into the mechanisms by which environmental mutagens initiate cancer. Previously, our laboratory found that a rare ~53 codon 249 mutation (AGG(ARG) toATG(MET)transversion) waspresent in3 l%ofaseries of 52 large and squamous cell lung cancers from uranium miners, suggesting that this mutation might be a marker for radon exposure. In the current study, we analyzed 23 lung adenocarcinomas from the same cohort of highly exposed uranium miners. These tumors failed to show the codon 249 transversion, but 9 (39%) of 23 contained 1 or more mutations within hotspots in the K-ras gene. The results suggest that there is histological tissue-type specificity for the codon 249 mutation; although this mutation was common in squamous and large cell tumors From very highly exposed uranium miners, it is rare in adenocarcinomas from the same cohort of miners.
Role of genetic factors in bronchial cancer. Based upon a case of anaplastic lung carcinoma in identical twins Nores JM, Dalayeun JFChebat J, Dieudonne P, Remy JM. Department qflnternal Medicine, University o/Paris. Hopital Raymond Poincare. F-92380 Garches. Hum Gent 1995;96:483-4.
Having observed homozygotic identical twin brothers suffering simultaneously from anaplastic bronchial cancer leading rapidly to death in both cases, the authors assessedthe frequency ofsuch cases. The available literature failed to reveal any identical observations, although four cases of twins suffering from bronchial cancer featuring different histologies (three epidermoidal and one bronchiolar-alveolar) were noted. Statistics show that, in the area where the observed twins were living, anaplastic cancer occurs each year in 0.39% of53-year-old men. The case of these twins therefore supports the idea of the role of genetic factors in the determination of bronchial cancer.
Somatic genetic changes in lung cancer and precancerous lesions Sundaresan V, Heppell-Patton LA, Coleman LN, Miozzo M, Sozzi G, Ball R et al. MRC C/in. Oncol./Radiotherap. Unir. MCR Centre. Hills Road. Cambtidge CB2 2QH. Ann Oncol 1995;6:Suppl l:S27-32.
Background: Morphological abnormalities of the bronchial epithe- lium are associated with lung cancer development and are considered likely torepresent thepreneoplastic stage ofthe disease. The association of these lesions with different histological types of lung cancer was reviewed in a series of 97 samples. Lesions associated with squamous cell carcinomas provided the best samples for further study. The objective of this study was to describe the somatic genetic changes which occur in these preinvasive lesions. Among the various candidate somatic genetic changes, loss of heterozygosity on chromosome 3 and changes to the ~53 gene were selected as being the most informative. It was demonstrated that these genetic changes, characteristic of fully invasive lung tumours, also occur at the premalignant stage of the disease. In an attempt to take a less directed approach to the comparison of invasive and preinvasive lesions, karyotype analysis was performed on short-term cultures of bronchial cells adjacent to the bronchial margin obtained from patients undergoing lung tumour resection. One such karyotype had a deletion to chromosome 3 (de1 3~13-14) as the single abnormality. Conclusion: It was concluded that genetic damage to ~53 and chromosome 3 is involved in the preinvasive stage of lung cancer, and that damage to chromosome 3 is a particularly early event.
P53 polymorphisms and haplotypes in lung cancer Birgander R, Sjalander A, Rannug A, AIexantie A-K, Sundberg MI, Seidegard J et al. Department of Medical Genetics, Umea Universiry. Llutea. Carcinogenesis 1995;16:2233-6.
Anassociationbetween the BstUl l-l (Pro-Pro) genotype ofthe ~53 codon 72 polymorphism and lung cancer has previously been reported by Kawajiri et al. A reanalysis of the data by Kawajiri et al. revealed no significant difference between patients and controls with respect to allelefiequencies,andtheincreasedfrequencyofBstUI l-l homozygotes was mostly ascribable to a deviation from the Hardy-Weinberg equilibrium. In an attempt to replicate the results by Kawajiri et al. we have studied three ~53 polymorphisms (BstU I and Msp I RFLPs in exon 4 and intron 6 respectively and a 16 bp duplication in intron 3) and their haplotypes in Swedish lung cancer patients and controls. The results concerning the codon 72 polymorphism were largely negative. Thus there was no significant association between lung cancer and the BstU I 1-l type, andonly amarginal difference (P = 0.044) withrespect to the BstU l allele frequency when lung cancer patients were compared with patientswithchronicobstructivepulmonarydisease(COPD). However, when the analysis was based onhaplotype frequencies larger differences appeared and it was found that only BstU I 1 (pro) alleles linked to 16 bp 1 alleles were associated with lung cancer. Pro alleles linked to the 16 bp duplication appeared instead to confer some protection against cancer. Thus the codon 72 alleles need not be functionally involved in lung cancer, but may rather be markers in linkage disequilibrium with other cancer susceptibility sites on ~53.