Kallikreins stepwise scoring reveals three subtypes of papillary thyroid cancer with prognostic applications

Background: Papillary thyroid cancer (PTC) is the most common type of thyroid cancer. Unlike most cancers, its incidence has dramatically increased in the last decades mainly due to the overdiagnosis of indolent PTCs. The adequate risk stratification is crucial to avoid the overtreatment of low-risk patients as well as the undertreatment of high-risk patients, but the current markers are still insufficient. Kallikreins (KLKs) are emergent biomarkers in cancer, but their involvement in PTC is unknown. Methods: We analysed the DNA methylation (HumanMethylation arrays) and gene expression (RNA-Seq) of KLKs, BRAF and RAS mutations and clinical data from four published thyroid cancer datasets including normal and tumour tissues (n = 73, n = 475, n = 20, n = 82), as discovery, training and validation series. We used the C4.5 classification algorithm to generate a decision tree. Disease-free survival was estimated using Kaplan-Meier and Cox approaches. Specific analyses were performed using real-ti...