Comparison of DNA copy number changes in malignant mesothelioma, adenocarcinoma and large-cell anaplastic carcinoma of the lung

Abstract

Summary The differential diagnosis of mesothelioma, primary adenocarcinomas and pleural metastases frequently causes problems. We have used the comparative genomic hybridization (CGH) technique on 34 malignant mesotheliomas and 30 primary lung carcinomas (adenocarcinoma, including bronchoalveolar carcinoma and large-cell anaplastic carcinoma) to compare their copy number changes and to evaluate the use of CGH to distinguish between these two types of tumour. In mesothelioma, gains of genetic material occurred as frequently as losses, whereas gains predominated over losses in carcinoma. In mesothelioma, the most frequent changes were losses in 4q, 6q and 14q and gains in 1 5q and 7p, whereas gains in 8q, 1 q, 7p, 5p and 6p were the most common changes in carcinoma. Amplification of KRAS2 was detected in two adenocarcinomas by Southern blot analysis. CGH showed gains in 12p in the same tumours. Statistically significant differences between the two types of tumour were detected in chromosomes X, 1, 2p, 4, 8q, 1 Oq, 1 2p, 1 4q, 1 5q and 1 8q. When comparing the frequency of gains and losses between mesothelioma and lung carcinoma using discriminant analysis, the sensitivity of CGH to differentiate mesotheliomas from lung carcinomas was 81% and the specificity 77%. The differences in DNA copy number changes between the two types of tumour suggest that they are genetically different tumour entities. Although CGH cannot be used as a definitive discriminatory method, we were able to distinguish between mesothelioma and lung carcinoma in a large proportion of the abnormal cases.

Deletions at 14q in malignant mesothelioma detected by microsatellite marker analysis

“…In eight of the tumours (nos 1, 2, 3, 4, 10, 13, 14 and 15) we were able to compare the allelotyping results with previous CGH data of 14q (Björkqvist et al, 1997(Björkqvist et al, , 1998. Loss of genetic material at 14q was found by CGH in tumour nos 1, 3, 4 and 15.…”

“…Fifty-six per cent of the tumours displayed a deletion. The percentage is much higher than that (24%) observed in primary tumours by CGH (Kivipensas et al, 1996;Björkqvist et al, 1997Björkqvist et al, , 1998. However, this is not unexpected due to the small partial deletions observed by allelotyping in some of the tumours and because of the resolution limitation of the CGH method (Kallioniemi et al, 1994).…”

“…Tumours homozygous for a specific locus were defined as uninformative. LOH was observed in heterozygous samples when one of the alleles in the tumour D14S72 D14S1003 D14S283 D14S972 D14S64 D14S80 D14S1060 D14S75 D14S269 D14S66 D14S63 D14S258 D14S277 D14S77 D14S71 D14S284 D14S76 D14S74 D14S68 D14S81 D14S65 D14S78 Björkqvist et al (1998) respectively; i,j cases 4 and 14 in Björkqvist et al (1997) respectively; k genetic distance between markers in cM; s s = Retained heterozygosity; s = LOH; s ss = Al; -= Uninformative; ND = Not determined; X = no data Table 1 Pattern and frequency of loss of heterozygosity (LOH) and allelic imbalance (AI) detected with 23 microsatellite markers at 14q in 18 primary mesothelioma tumours Tumour a DNA was reduced in intensity relative to the remaining allele and the alleles in the normal DNA. Other intensity differences were interpreted merely as AIs.…”

“…However, no aberration specific to mesothelioma has been detected. Comparative genomic hybridization (CGH) analyses on primary mesothelioma tumours and cell lines have revealed that loss of genetic material at chromosome 14q is one of the most frequently occurring aberrations (Kivipensas et al, 1996;Björkqvist et al, 1997Björkqvist et al, , 1998Balsara et al, 1999). In this study we further verify the frequency and pattern of deletions at 14q in primary mesothelioma tumours using polymerase chain reaction (PCR) and 23 microsatellite markers spanning the whole of the long arm of chromosome 14.…”

Genomic gain at 6p21: a new cryptic molecular rearrangement in secondary myelodysplastic syndrome and acute myeloid leukemia

“…[29][30][31][32][33][34][35] In the U937-I cell line, with its unbalanced 6p translocation at karyotype, 18 we detected a cryptic 6p21 duplication/amplification spanning the DNA segment from the BAK/6p21 gene to RUNX2/6p21, which is partially overlapping Table 4 6p gains in eight sAML/MDS. (each black line indicates the overrepresented region.…”