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Background: Disease progression and therapeutic resistance are hallmarks of advanced stage prostate cancer (PCa), which remains a major cause of cancer-related mortality around the world. Longitudinal studies, coupled with the use of liquid biopsies, offer a potentially new and minimally invasive platform to study the dynamics of tumour progression. Our aim was to investigate the dynamics of personal DNA methylomic profiles of metastatic PCa (mPCa) patients, during disease progression and therapy administration., Results: Forty-eight plasma samples from 9 mPCa patients were collected, longitudinally, over 13-21 months. After circulating cell-free DNA (cfDNA) isolation, DNA methylation was profiled using the Infinium MethylationEPIC BeadChip. The top 5% most variable probes across time, within each individual, were utilised to study dynamic methylation patterns during disease progression and therapeutic response. Statistical testing was carried out to identify differentially methylated genes (DMGs) in cfDNA, which were subsequently validated in two independent mPCa (cfDNA and FFPE tissue) cohorts. Individual cfDNA global methylation patterns were temporally stable throughout the disease course. However, a proportion of CpG sites presented a dynamic temporal pattern that was consistent with clinical events, including different therapies, and were prominently associated with genes linked to immune response pathways. Additionally, study of the tumour fraction of cfDNA identified > 2000 DMGs with dynamic methylation patterns., Conclusions: Longitudinal assessment of cfDNA methylation in mPCa patients unveiled dynamic patterns associated with disease progression and therapy administration, thus highlighting the potential of using liquid biopsies to study PCa evolution at a methylomic level., (© 2021. The Author(s).)

Because of advances in targeted therapies, the clinical evaluation of cutaneous melanoma is increasingly based on a combination of traditional histopathology and molecular pathology. Therefore, it is necessary to expand our knowledge of the molecular events that accompany the development and progression of melanoma to optimize clinical management. The central objective of this study was to increase our knowledge of the mutational events that complement melanoma progression. High-throughput genotyping was adapted to query 159 known single nucleotide mutations in 33 cancer-related genes across two melanoma cohorts from Ireland (n=94) and Belgium (n=60). Results were correlated with various clinicopathological characteristics. A total of 23 mutations in 12 genes were identified, that is--BRAF, NRAS, MET, PHLPP2, PIK3R1, IDH1, KIT, STK11, CTNNB1, JAK2, ALK, and GNAS. Unexpectedly, we discovered significant differences in BRAF, MET, and PIK3R1 mutations between the cohorts. That is, cases from Ireland showed significantly lower (P<0.001) BRAF(V600E) mutation rates (19%) compared with the mutation frequency observed in Belgian patients (43%). Moreover, MET mutations were detected in 12% of Irish cases, whereas none of the Belgian patients harbored these mutations, and Irish patients significantly more often (P=0.027) had PIK3R1-mutant (33%) melanoma versus 17% of Belgian cases. The low incidence of BRAF(V600E)(-) mutant melanoma among Irish patients was confirmed in five independent Irish cohorts, and in total, only 165 of 689 (24%) Irish cases carried mutant BRAF(V600E). Together, our data show that melanoma-driving mutations vary by demographic area, which has important implications for the clinical management of this disease.