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  • Brieghel, ChristianRigshosp, Dept Hematol, Copenhagen, Denmark. (author)

The Number of Signaling Pathways Altered by Driver Mutations in Chronic Lymphocytic Leukemia Impacts Disease Outcome

  • Article/chapterEnglish2020

Publisher, publication year, extent ...

  • AMER ASSOC CANCER RESEARCH,2020
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:uu-409837
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-409837URI
  • https://doi.org/10.1158/1078-0432.CCR-18-4158DOI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:143337055URI

Supplementary language notes

  • Language:English
  • Summary in:English

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Classification

  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • Purpose: Investigation of signaling pathways altered by recurrent gene mutations and their clinical impact in a consecutive cohort of patients with newly diagnosed chronic lymphocytic leukemia (CLL). The heterogeneous clinical course and genetic complexity of CLL warrant improved molecular prognostication. However, the prognostic value of recurrent mutations at the time of diagnosis remains unclear. Experimental Design: We sequenced samples from 314 consecutive, newly diagnosed patients with CLL to investigate the clinical impact of 56 recurrently mutated genes assessed by next-generation sequencing. Results: Mutations were identified in 70% of patients with enrichment among IGHV unmutated cases. With 6.5 years of follow-up, 15 mutated genes investigated at the time of diagnosis demonstrated significant impact on time to first treatment (TTFT). Carrying driver mutations was associated with shorter TTFT and poor overall survival. For outcome from CLL diagnosis, the number of signaling pathways altered by driver mutations stratified patients better than the number of driver mutations. Moreover, we demonstrated gradual impact on TTFT with increasing number of altered pathways independent of CLL-IPI risk. Thus, a 25-gene, pathway-based biomarker assessing recurrent mutations refines prognostication in CLL, in particular for CLL-IPI low- and intermediate-risk patients. External validation emphasized that a broad gene panel including low burden mutations was key for the biomarker based on altered pathways. Conclusions: We propose to include the number of pathways altered by driver mutations as a biomarker together with CLL-IPI in prospective studies of CLL from time of diagnosis for incorporation into clinical care and personalized follow-up and treatment.

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • da Cunha-Bang, CasparRigshosp, Dept Hematol, Copenhagen, Denmark. (author)
  • Yde, Christina WestmoseRigshosp, Ctr Genom Med, Copenhagen, Denmark. (author)
  • Schmidt, Ane YdeRigshosp, Ctr Genom Med, Copenhagen, Denmark. (author)
  • Kinalis, Savvas (author)
  • Nadeu, FerranInst Invest Biomed August Pi & Sunyer IDIBAPS, Lymphoid Neoplasms Program, Barcelona, Spain.;Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain. (author)
  • Andersen, Michael AsgerRigshosp, Dept Hematol, Copenhagen, Denmark. (author)
  • Jacobsen, Line OffenbachRigshosp, Ctr Genom Med, Copenhagen, Denmark. (author)
  • Andersen, Mette KlarskovRigshosp, Dept Clin Genet, Copenhagen, Denmark. (author)
  • Pedersen, Lone BredoRigshosp, Dept Hematol, Copenhagen, Denmark. (author)
  • Delgado, JulioInst Invest Biomed August Pi & Sunyer IDIBAPS, Lymphoid Neoplasms Program, Barcelona, Spain.;Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain.;Hosp Clin Barcelona, Dept Hematol, Barcelona, Spain. (author)
  • Baumann, TychoHosp Clin Barcelona, Dept Hematol, Barcelona, Spain. (author)
  • Mattsson, MattiasUppsala universitet,Hematologi,Experimentell och klinisk onkologi(Swepub:uu)matma431 (author)
  • Mansouri, LarryKarolinska Institutet (author)
  • Rosenquist, RichardKarolinska Institutet (author)
  • Campo, EliasInst Invest Biomed August Pi & Sunyer IDIBAPS, Lymphoid Neoplasms Program, Barcelona, Spain.;Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain.;Hosp Clin Barcelona, Dept Hematol, Barcelona, Spain.;Univ Barcelona, Barcelona, Spain. (author)
  • Nielsen, Finn CiliusRigshosp, Ctr Genom Med, Copenhagen, Denmark. (author)
  • Niemann, Carsten UtoftRigshosp, Dept Hematol, Copenhagen, Denmark. (author)
  • Rigshosp, Dept Hematol, Copenhagen, Denmark.Rigshosp, Ctr Genom Med, Copenhagen, Denmark. (creator_code:org_t)

Related titles

  • In:Clinical Cancer Research: AMER ASSOC CANCER RESEARCH26:6, s. 1507-15151078-04321557-3265

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