Page 93 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman
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Figure 1. Fluorescence in situ hybridization in high-grade CIN
Typical examples showing a disomy in A) for both 3q26 (green FITC signal) and 3C (red TRITC signal) (case number 197). In B) a tetrasomy (case 192) and in C) an imbalance between 3q26 and 3c (case 218). In the latter case the cells showed a ratio of 3 to 2 signals for 3q26 and 3c respectively, with nuclei with multiple copies for both targets (classified as gain). The arrows point to the nuclei with the typical signal distribution for the cases with no gain (A) and gain (B,C).
Discussion
This is the first study to assess the prognostic value of 3q26 gain as a single genetic marker in the natural prognosis of solely high-grade CIN. The results show that 3q26 gain is found in both women with persistence and regression of high-grade CIN, but that none of the women without 3q26 gain show disease persistence. This results in a high negative predictive value of 3q26 for disease persistence. As such, the absence of 3q26/hTERC gain may potentially be applied to identify those lesions with a high potential of disease regression.
The test performance of hTERC gain in high-grade lesions in our pilot study is comparable to the test performance of hTERC gain in low-grade lesions, as reviewed in the literature. Negative predictive values were consistently high, while positive predictive values were much lower. The mediocre positive predictive value of 3q26/hTERC gain as a prognostic marker for disease persistence and/or progression may indicate that hTERC gain is a contributing, but not critical step in cervical oncogenesis. The development of cervical precancerous lesions and subsequent carcinoma is based on a complex interaction between virus and host, in which viral oncogenic properties and the human immune system influence the cellular processes that lead to cell transformation.[8, 9] In this process, several important molecular events have been identified, among which are viral DNA integration and upregulation of telomerase.[8] However, none of these events have been identified as critical steps or ‘point of no return’. Indeed, upregulation of telomerase is not found in all high-grade CIN lesions or cervical carcinomas.[12] As such, it is unlikely that the prediction of the natural prognosis of CIN lesions will be based on one molecular event, but rather on a combination of viral, host and genetic parameters. Therefore, combining hTERC testing with other predictive biomarkers may lead to a test panel with a better overall test performance.
3q26 as a prognostic biomarker
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