DNA hypermethylation biomarkers to predict response to cisplatin treatment, radiotherapy or chemoradiation: the present state of art

Abstract

Concurrent platinum-based chemoradiation significantly improved survival of advanced stage cervical patients over radiotherapy alone. However, the 5-year overall survival is still only 66%. Presently, no biomarkers are available to select those cervical cancer patients that might benefit from concurrent platinum-based chemoradiation therapy. DNA methylation is a well-established contributor to the regulation of gene transcription, predominantly causing transcriptional silencing. Differences in promoter hypermethylation patterns and subsequent silencing, could contribute to the variety of responses observed in clinical practice. Several clinical trials on various malignancies reported a better response when Decitabine was administered prior to or in combination with standard therapy. This sensitization is thought to be due to re-expression of tumor suppressor genes. However, not all patients might benefit from demethylating agents, since re-expression of oncogenes could render patients more resistant. In this review, we summarized the present state of art regarding hypermethylated genes and their affected signaling pathways that are associated with outcome after cisplatin treatment, radiotherapy or chemoradiation. Since only few studies were reported in cervical cancer, other malignancies were reviewed as well. From the data presented in this review, we conclude that, in order to select patients that benefit most optimally from demethylating strategies, a comprehensive screening of a large panel of methylation markers, associated with both good as well as poor clinical outcome have to be investigated. Since such panels are not available at this moment, global methylation screening approaches are required to profile such methylated genes. Such methylated gene profiles might be very useful to optimize personalized treatment planning not only in cervical cancer but also in other malignancies.