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Malignant pleural mesothelioma (MM) is a rare tumour with high mortality, which can exhibit various morphologies classified as epithelioid, biphasic and sarcomatoid subtypes. To investigate the molecular changes in these tumours, we studied gene expression patterns by combined use of cDNA arrays and tumour tissue microarrays (TMA). Deregulation of the expression of 588 cancer-related genes was screened in 16 MM comprising all three subtypes and compared with references, i.e. normal mesothelial cell lines and pleural mesothelium. Array data were analysed using three statistical methods; principal component analysis (PCA), permutation test and receiver operating characteristic (ROC) curves. Eleven genes were verified by real-time RT–PCR. Genes encoding two adhesion molecules [COL1A2 and integrin β4 (ITGB4)] and a chemokine (INP10) were up-regulated in MM compared with both the cell lines and pleural mesothelium. There was a type-specific up-regulation of semaphorin E, ITGB4 and P-cadherin in epithelioid MM, matrix metalloproteinase 9 (MMP9) and tissue-type plasminogen activator (tPA) in sarcomatoid MM and neural cell adhesion molecule L1 (L1CAM) and INP10 in biphasic MM. Immunohistochemistry on TMA containing 47 MM (26 epithelioid, 15 sarcomatoid and six biphasic) was performed for five proteins, ITGB4, P-cadherin, tPA, INP10 and L1CAM. INP10 expression was increased in MM in general compared with normal mesothelium, while increased expression of P-cadherin, L1CAM and ITGB4 was more specific in MMs exhibiting an epithelioid growth pattern. The over-expression of tPA was more frequent in epithelioid MM despite higher mRNA levels in sarcomatoid and biphasic MM. We conclude that several proteins, associated with cell adhesion either directly (ITGB4, L1CAM, P-cadherin) or as a regulatory factor (INP10), are differentially expressed in MM. In particular, INP10, ITGB4 and COL1A2 were up-regulated in MM compared with both reference sample types, suggesting a relationship with development of these tumours.

The highly polymorphic N-acetyltransferases (NAT1 and NAT2) are involved in both activation and inactivation reactions of numerous carcinogens, such as tobacco derived aromatic amines. The potential effect of the NATgenotypes in individual susceptibility to lung cancer was examined in a hospital based case–control study consisting of 392 Caucasian lung cancer patients 152 adenocarcinomas, 173 squamous cell carcinomas (SCC) and 67 other primary lung tumours and 351 controls. In addition to the wild-type allele NAT14, seven variant NAT1alleles (NAT13, 10, 11, 14, 15, 17and 22)were analysed. A new method based on the LightCycler (Roche Diagnostics Inc.) technology was applied for the detection of the polymorphic NAT1sites at nt 1088 and nt 1095. The NAT2polymorphic sites at nt 481, 590, 803 and 857 were detected by polymerase chain reaction-restriction fragment length polymorphism or LightCycler. Multivariate logistic regression analyses were performed taking into account levels of smoking, age, gender and occupational exposure. An increased risk for adenocarcinoma among the NAT1 putative fast acetylators odds ratio (OR) 1.92 (1.16–3.16) was found but could not be detected for SCC or the total case group. NAT2genotypes alone appeared not to modify individual lung cancer risk, however, individuals with combined NAT1fast and NAT2slow genotype had significantly elevated adenocarcinoma risk OR 2.22 (1.03–4.81) compared to persons with other genotype combinations. These data clearly show the importance of separating different histological lung tumour subtypes in studies on genetic susceptibility factors and implicate the NAT110allele as a risk factor for adenocarcinoma.

Oxidative damage is implicated in several chronic diseases including cancer. 8-Hydroxyguanine (8-oxoG) is one of the major promutagenic DNA lesions, which is produced by reactive oxygen species, causes G:C to T:A transversions and is excised by OGG1, an 8-oxoG specific DNA glycosylase/AP−Lyase. In a nested case-control study, gDNA from 105 Caucasian primary non-small cell lung cancer cases and 105 matched controls was screened for 6 possible new polymorphic sites in the human OGG1 gene, detected previously mainly in tumour tissue. The previously described Ser³²⁶Cys polymorphism was found to be common (allele frequency 0.22) in Caucasians. However, no major difference in Ser³²⁶Cys genotype distribution could be detected between cases and controls. Two 5`-end polymorphisms previously found in Japanese as well as Arg¹³¹Gln could not be detected in this population. An Ala⁸⁵Ser polymorphism was found in 2 controls, whereas Arg⁴⁶Gln was detected in only 1 case. As the hOGG1 gene is mapped (3p26.2) to a region frequently lost in primary lung tumours, the frequency of loss of heterozygosity (LOH) was investigated. Forty-three percent of the studied lung tumours exhibited loss of one of the hOGG1 alleles. The wt Ser³²⁶ allele was not predominantly lost in our sample set, which suggests a minor role of this polymorphism in tumourgenesis. Our results show that LOH at the hOGG1 gene locus is a very common occurrence in lung tumourgenesis, possibly leading to increased mutational damage due to ROS in smokers. However, the hOGG1 polymorphisms studied are probably not major contributors to individual lung cancer susceptibility in Caucasians. Int. J. Cancer 88:932–937, 2000. © 2000 Wiley-Liss, Inc.