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In this study, microarray analysis was used to identify tumour-related genes that were down regulated in lung carcinoma. The promoter sequences of the identified genes were analysed for methylation patterns. In lung cancer cell lines, CpG island methylation was frequently detected for TIMP4 (64%), SOX18 (73%), EGF-like domain 7 (56%), CD105 (71%), SEMA2 (55%), RASSF1A (71%), p16 (56%) SLIT2 (100%) and TIMP3 (29%). Methylation was however rarely observed in cell lines for SLIT3 (18%) and DLC1 (18%). In primary lung tumours, methylation of TIMP4 (94%), SOX18 (100%), EGF-like domain 7 (100%), CD105 (69%), SEMA2 (93%), DLC1 (61%), RASSF1A (44%), p16 (47%), SLIT2 (100%) and TIMP3 (13%) was also detected. Methylation of several CpG islands was frequently found in normal lung tissue of cancer patients and this may have been attributed to epigenetic field defect and/or infiltrating tumour cells. Interestingly, inactivation of RASSF1A and p16 correlated well with an extended smoking habit (P=0.02), and exposure to asbestos (P=0.017) or squamous cell carcinoma (P=0.011), respectively. These results have identified genes whose aberrant promoter methylation could play a crucial role in the malignancy of lung carcinoma.

The relationship between DNA content and TNM stage, histology, histological differentiation, survival as well as recurrence was assessed in a study of 215 patients with non-small cell lung cancer (NSCLC) who had undergone complete resection (R0). Cellular DNA content was obtained by image cytometry on paraffinembedded- tumor tissue and by flow cytometry on tumor cell suspension. DNA aneuploidy was measured in 179 (83% out of the 215 NSCLC. The aneuploid/diploid ratio were identical in TNM stage, histology and grading. Only in adenosquamous careionomas the proportion of DNA aneuploid tumors was significantly higher. Aneuploid tumors showed higher recurrence rates (23.2%) during follow-up as diploid tumors (11%). Survival analysis showed that life expectancy of patients with diploid tumors was longer than those with aneuploid carcinomas (5-year survival rate of 69% vs. 49%). The most significant difference was found in patients with adenocarcinoma (5-year survival rate of 100% for diploid tumors vs. 45% for aneuploid tumors). These results suggest that DNA aneuploidy may provide an independent prognostic factor for patients with NSCLC. The study made possible by a grant of the German Ministry lor Research and Technology (BMFT nr. 0 1ZZ9105).