Significance of genetic instability in development and chemosensitivity of malignant tumors

Abstract

We set the aim to examine the alterations of the main mismatch repair genes (hMLH1 and hMSH2) in the predisposition to hereditary colorectal cancer, and the influence of these genes on the therapeutic sensitivity of testicular germ-cell tumors. We investigated mutations of the p53 gene in primary head and neck tumors with the view to outline their prognostic values in the clinical outcome and the therapeutic responsiveness. Germline alterations of the MMR genes result in autosomal dominantly inherited predisposition to hereditary nonpolyposis colon carcinoma (HNPCC). We applied Bethesda guidelines to select patients not fulfilling Amsterdam criteria. Our findings demonstrated that causative mutations coupled with single nucleotide polymorphisms have worse prognostic values. The majority of testicular germ cell tumors (TGCTs) are highly sensitive to cisplatin-based chemotherapy, but a small fraction of cases are resistant to the effects of chemotherapy. Although we found a strong correlation between weak or loss of hMLH1 expression and promoter hypermethylation, reduced expression of MMR proteins and MSI have not proved to be predictive markers for chemotherapeutic resistance of TGCTs. The analysis of p53 gene mutations in head and neck tumors revealed a significant trend between the tumor stage progression and the frequency of missense mutations on the DNA-binding surface. We found that patients with other than missense mutations (nonsense, splice mutations, deletions) had more favorable prognosis. Mutational analysis of surgical margins may be of value in the prediction of local recurrence and in the decision for postoperative therapy.