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Whole-genome inform...
Whole-genome informed circulating tumor DNA analysis by multiplex digital PCR for disease monitoring in B-cell lymphomas : a proof-of-concept study
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- Haider, Zahra (författare)
- Karolinska Institutet
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- Wasterlid, Tove (författare)
- Karolinska Institutet
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- Spångberg, Linn Deleskog (författare)
- Karolinska Inst, Dept Med, Div Clin Epidemiol, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden.
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- Rabbani, Leily (författare)
- Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
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- Jylha, Cecilia (författare)
- Karolinska Institutet
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- Thorvaldsdottir, Birna (författare)
- Karolinska Institutet
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- Skaftason, Aron (författare)
- Karolinska Institutet
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- Awier, Hero Nikdin (författare)
- Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden.
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- Krstic, Aleksandra (författare)
- Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden.
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- Gellerbring, Anna (författare)
- KTH,Science for Life Laboratory, SciLifeLab,Skolan för kemi, bioteknologi och hälsa (CBH)
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- Lyander, Anna (författare)
- KTH,Genteknologi,Science for Life Laboratory, SciLifeLab
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- Hägglund, Moa (författare)
- KTH,Science for Life Laboratory, SciLifeLab,Skolan för kemi, bioteknologi och hälsa (CBH)
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- Jeggari, Ashwini (författare)
- KTH,Skolan för kemi, bioteknologi och hälsa (CBH),Science for Life Laboratory, SciLifeLab
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- Rassidakis, Georgios (författare)
- Karolinska Institutet
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- Sonnevi, Kristina (författare)
- Karolinska Institutet
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- Sander, Birgitta (författare)
- Karolinska Institutet
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- Rosenquist, Richard (författare)
- Karolinska Institutet
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- Tham, Emma (författare)
- Karolinska Institutet
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- Smedby, Karin E. (författare)
- Karolinska Institutet
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Karolinska Institutet Karolinska Inst, Dept Med, Div Clin Epidemiol, Stockholm, Sweden;Karolinska Univ Hosp, Stockholm, Sweden. (creator_code:org_t)
- Frontiers Media SA, 2023
- 2023
- Engelska.
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Ingår i: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 13
- Relaterad länk:
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https://doi.org/10.3...
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https://urn.kb.se/re...
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https://doi.org/10.3...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- IntroductionAnalyzing liquid biopsies for tumor-specific aberrations can facilitate detection of measurable residual disease (MRD) during treatment and at follow-up. In this study, we assessed the clinical potential of using whole-genome sequencing (WGS) of lymphomas at diagnosis to identify patient-specific structural (SVs) and single nucleotide variants (SNVs) to enable longitudinal, multi-targeted droplet digital PCR analysis (ddPCR) of cell-free DNA (cfDNA). MethodsIn 9 patients with B-cell lymphoma (diffuse large B-cell lymphoma and follicular lymphoma), comprehensive genomic profiling at diagnosis was performed by 30X WGS of paired tumor and normal specimens. Patient-specific multiplex ddPCR (m-ddPCR) assays were designed for simultaneous detection of multiple SNVs, indels and/or SVs, with a detection sensitivity of 0.0025% for SV assays and 0.02% for SNVs/indel assays. M-ddPCR was applied to analyze cfDNA isolated from serially collected plasma at clinically critical timepoints during primary and/or relapse treatment and at follow-up. ResultsA total of 164 SNVs/indels were identified by WGS including 30 variants known to be functionally relevant in lymphoma pathogenesis. The most frequently mutated genes included KMT2D, PIM1, SOCS1 and BCL2. WGS analysis further identified recurrent SVs including t(14;18)(q32;q21) (IGH::BCL2), and t(6;14)(p25;q32) (IGH::IRF4). Plasma analysis at diagnosis showed positive circulating tumor DNA (ctDNA) levels in 88% of patients and the ctDNA burden correlated with baseline clinical parameters (LDH and sedimentation rate, p-value <0.01). While clearance of ctDNA levels after primary treatment cycle 1 was observed in 3/6 patients, all patients analyzed at final evaluation of primary treatment showed negative ctDNA, hence correlating with PET-CT imaging. One patient with positive ctDNA at interim also displayed detectable ctDNA (average variant allele frequency (VAF) 6.9%) in the follow-up plasma sample collected 2 years after final evaluation of primary treatment and 25 weeks before clinical manifestation of relapse. ConclusionIn summary, we demonstrate that multi-targeted cfDNA analysis, using a combination of SNVs/indels and SVs candidates identified by WGS analysis, provides a sensitive tool for MRD monitoring and can detect lymphoma relapse earlier than clinical manifestation.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
Nyckelord
- cell-free DNA (cfDNA)
- whole genome sequence (WGS)
- liquid biopsy
- lymphoma
- measurable (minimal) residual disease (MRD)
- droplet digital (ddPCR)
- CtDNA
- IGH-BCL2 translocation
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Haider, Zahra
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Wasterlid, Tove
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Spångberg, Linn ...
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Rabbani, Leily
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Jylha, Cecilia
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Thorvaldsdottir, ...
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Skaftason, Aron
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Awier, Hero Nikd ...
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Krstic, Aleksand ...
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Gellerbring, Ann ...
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Lyander, Anna
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Hägglund, Moa
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Jeggari, Ashwini
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Rassidakis, Geor ...
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Sonnevi, Kristin ...
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Sander, Birgitta
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Rosenquist, Rich ...
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Tham, Emma
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Smedby, Karin E.
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