Since Slaughter s proposal of a genetic field
Since Slaughter’s proposal of a genetic field defect concept for the explanation of the local relapse occurrence, much evidence has accumulated for its confirmation. The last ten years brought evidence that the genetic changes in the field are frequently accompanied by epigenetic aberrations. The epigenetic field defect was observed for oesophageal, lung or stomach cancers. Similarly, epigenetic changes in normal mucosa TPPU derived from surgical margins were detected in head and neck carcinomas.5, 6, 13, 32 However, so far such changes have not been observed specifically in laryngeal cancers. In this paper evidence of a wide-spread occurrence of the aberrations in the profile of DNA methylation in laryngeal cancer patients is presented. Less than ten percent of cancer cases did not show any epigenetic changes in the normal mucosa samples. Gene methylation frequency was only slightly lower in the normal epithelium of epiglottis or trachea than in tumor cells. However, it should be taken into account that all the patients were exposed to similar laryngeal cancer risk factors. As discussed earlier, tobacco and alcohol are associated with the aberrations in the DNA methylation profile. The long-term exposure of patients to these factors could be responsible for the common appearance of epigenetic defects in a large field of upper respiratory tract mucosa. The existence of the epigenetically changed field in laryngeal cancers seems to be confirmed especially by such cases where lack of gene methylation in tumor cells was accompanied by the presence of hypermethylation in the normal epithelial cells although the percentage of patients with such gene methylation pattern was rather low. Similar observations were shown in a group of patients with head and neck carcinomas. The open question is to what extent these molecular changes are a causative factor in the formation of laryngeal squamous cell carcinomas.
In conclusion, it has been demonstrated that the hypermethylation of DAPK, RARbeta, MGMT, RASSF1A and FHIT is common not only in laryngeal cancer cells but also in paired normal epithelial cells from epiglottis or trachea. Moreover, the methylation of MGMT correlates with lymph node metastasis in laryngeal cancer patients. The analysis of the methylation status of the studied genes may have the potential to be used for biomarker purposes. Although such markers probably would not be suitable for LSCC detection however they might become a promising diagnostic tool for the prediction of therapy outcome and local relapse risk. In this regard further studies are necessary.
Conflict of interest statement
Renal cell carcinoma is the third most common urogenital tumor disease with an estimated incidence of 51,000 cases per year in the United States. Although RCC appears to be curable at nonadvanced stage, locally advanced or lymph node positive tumors are likely to become metastatic someday. In metastatic tumor disease surgical resection is optional because immunomodulatory therapies with IFN and interleukin show low response rates. Recently tyrosine kinase inhibitors such as sunitinib or sorafenib were introduced, which are promising therapeutic agents for metastatic kidney tumors., The dilemma of which patient should receive adjuvant therapy still persists and to our knowledge tumor markers that could answer this question are not available. Common events in the tumorigenesis of RCC are cytogenetic changes, including mutations of the gene located on chromosome 3 or trisomies of chromosome 7 and 17. Dulaimi et al reported frequent methylation of the , and tissue inhibitor of metalloproteinase-3 genes, and methylation of the γ-catenin gene seems to correlate with poor prognosis in patients with RCC. Recently we found that the level of methylation of specific genes, as expressed by NIM, is able to differentiate patients with tumor who are at higher risk for recurrence. Although methylation in the promoter region of a gene may lead to transcriptional silencing, this was reported in RCC only for the gene. Wethkamp et al noted that mRNA expression of the gene is still abundant in cases of promoter methylation even at the protein level.