Summary

Background: The contribution of the abnormal DNA mismatch repair system to non-small cell lung cancer tumorigenesis is controversial and has not been reported in Jewish Israeli patients. Similarly, the involvement of 3p deletions in NSCLC[1] in the same population has not been assessed.

Objectives: To assess the contribution of the DNA-MMR[2] system to NSCLC pathogenesis by analyzing microsatellite instability, and evaluate loss of heterozygosity at 3p rates in Israeli NSCLC patients.

Methods: Paired DNA from tumorous and non-tumorous tissue was extracted, and genotyping for MSI[3] determination was carried out using the five Bethesda markers and for determining LOH[4] two 3p markers were used. Genotyping was performed using polymerase chain reaction amplification and size separation on an ABI semiautomatic DNA sequencer, and the allelic patterns of tumorous and non-tumorous tissue were compared.

Results: Forty-four NSCLCs from 35 smokers and 9 non-smokers were analyzed, with 26 of the 44 (59%) at stage I disease. Using five microsatellite markers (D17S250, D5S346, D2S123, BAT-25, BAT-26) (known as Bethesda markers) for MSI determination, 6 of the 44 tumors (13.6%) exhibited MSI in at least one marker. Similarly, genotyping for LOH at chromosome 3p was performed using two markers (D3S4103, D3S1234) located at 3p14.2 l. With D3S4103, 33 of the 44 patients successfully analyzed were homozygous and therefore non-informative with respect to LOH. Using D3S1234, 33 of 36 patients (91.7%) were heterozygous, and 23 of these individuals' tumors (69.7%) displayed LOH. Unexpectedly, 4 of 33 tumors (12.1%) genotyped by D3S4103, and 16 of 36 tumors (44.5%) genotyped by D3S1234 showed a pattern of MSI, even though only one of these tumors showed a similar pattern when genotyped with the five consensus markers. Overall, 23 of 44 tumors (52.3%) demonstrated MSI on at least one marker, and 5 of these 23 tumors (21.7%) had MSI on two or more markers.

Conclusions: MSI using 3p markers and not the Bethesda markers occurs at a high rate and in early stages in Jewish NSCLC patients.