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Albrecht, Lea Jessica; Höwner, Anna; Griewank, Klaus; Lueong, Smiths S.; von Neuhoff, Nils; Horn, Peter A.; Sucker, Antje; Paschen, Annette; Livingstone, Elisabeth; Ugurel, Selma; Zimmer, Lisa; Horn, Susanne; Siveke, Jens T.; Schadendorf, Dirk; Váraljai, Renáta; Roesch, Alexander

Circulating cell‐free messenger RNA enables non‐invasive pan‐tumour monitoring of melanoma therapy independent of the mutational genotype

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  • Media type: E-Article
  • Title: Circulating cell‐free messenger RNA enables non‐invasive pan‐tumour monitoring of melanoma therapy independent of the mutational genotype
  • Contributor: Albrecht, Lea Jessica; Höwner, Anna; Griewank, Klaus; Lueong, Smiths S.; von Neuhoff, Nils; Horn, Peter A.; Sucker, Antje; Paschen, Annette; Livingstone, Elisabeth; Ugurel, Selma; Zimmer, Lisa; Horn, Susanne; Siveke, Jens T.; Schadendorf, Dirk; Váraljai, Renáta; Roesch, Alexander
  • Published: Wiley, 2022
  • Published in: Clinical and Translational Medicine, 12 (2022) 11
  • Language: English
  • DOI: 10.1002/ctm2.1090
  • ISSN: 2001-1326
  • Origination:
  • Footnote:
  • Description: AbstractBackgroundPlasma‐derived tumour‐specific cell‐free nucleic acids are increasingly utilized as a minimally invasive, real‐time biomarker approach in many solid tumours. Circulating tumour DNA of melanoma‐specific mutations is currently the best studied liquid biopsy biomarker for melanoma. However, the combination of hotspot genetic alterations covers only around 80% of all melanoma patients. Therefore, alternative approaches are needed to enable the follow‐up of all genotypes, including wild‐type.MethodsWe identifiedKPNA2,DTL,BACE2andDTYMKmessenger RNA (mRNA) upregulated in melanoma versus nevi tissues by unsupervised data mining (N = 175 melanoma,N = 20 normal skin,N = 6 benign nevi) and experimentally confirmed differential mRNA expression in vitro (N = 18 melanoma,N = 8 benign nevi). Circulating cell‐free RNA (cfRNA) was analysed in 361 plasma samples (collected before and during therapy) from 100 melanoma patients and 18 healthy donors. Absolute cfRNA copies were quantified on droplet digital PCR.ResultsKPNA2,DTL,BACE2andDTYMKcfRNA demonstrated high diagnostic accuracy between melanoma patients’ and healthy donors’ plasma (AUC > 86%,p < .0001). cfRNA copies increased proportionally with increasing tumour burden independently of demographic variables and even remained elevated in individuals with radiological absence of disease. Re‐analysis of single‐cell transcriptomes revealed a pan‐tumour origin of cfRNA, including endothelial, cancer‐associated fibroblasts, macrophages and B cells beyond melanoma cells as cellular sources. Low baseline cfRNA levels were associated with significantly longer progression‐free survival (PFS) (KPNA2HR = .54,p = .0362;DTLHR = .60,p = .0349) and overall survival (KPNA2HR = .52,p = .0237;BACE2HR = .55,p = .0419;DTYMKHR = .43,p = .0393). Lastly, we found that cfRNA copies significantly increased during therapy in non‐responders compared to responders regardless of therapy and mutational subtypes and that the increase ofKPNA2(HR = 1.73,p = .0441) andDTYMK(HR = 1.82,p = .018) cfRNA during therapy was predictive of shorter PFS.ConclusionsIn sum, we identified a new panel of cfRNAs for a pan‐tumour liquid biopsy approach and demonstrated its utility as a prognostic, therapy‐monitoring tool independent of the melanoma mutational genotype.
  • Access State: Open Access