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BTK and PLCG2 remai...
BTK and PLCG2 remain unmutated in one-third of patients with CLL relapsing on ibrutinib
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- Bonfiglio, Silvia (författare)
- IRCCS Osped San Raffaele, Ctr Omics Sci, Milan, Italy.;IRCCS Osped San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy.
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- Sutton, Lesley-Ann (författare)
- Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
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- Ljungström, Viktor, 1986- (författare)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Cancerprecisionsmedicin,Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden
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visa fler...
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- Capasso, Antonella (författare)
- IRCCS Osped San Raffaele, Strateg Res Program CLL, Milan, Italy.
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- Pandzic, Tatjana (författare)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Cancerprecisionsmedicin
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- Weström, Simone (författare)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Cancerprecisionsmedicin
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- Foroughi-Asl, Hassan (författare)
- Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
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- Skaftason, Aron (författare)
- Karolinska Institutet,Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
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- Gellerbring, Anna (författare)
- Sci Life Lab, Clin Genom Stockholm, Solna, Sweden.;Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.
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- Lyander, Anna (författare)
- KTH,Genteknologi,Science for Life Laboratory, SciLifeLab,Sci Life Lab, Clin Genom Stockholm, Solna, Sweden.;Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.;KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Stockholm, Sweden.
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- Gandini, Francesca (författare)
- IRCCS Osped San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy.
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- Gaidano, Gianluca (författare)
- Univ Piemonte Orientale, Dept Translat Med, Div Hematol, Novara, Italy.
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- Trentin, Livio (författare)
- Univ Padua, Dept Med Hematol & Clin Immunol, Padua, Italy.
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- Bonello, Lisa (författare)
- AOU Citta Salute & Sci, Mol Pathol Unit, Turin, Italy.;Univ Torino, Dept Mol Biotechnol & Hlth Sci, Turin, TO, Italy.
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- Reda, Gianluigi (författare)
- Fdn IRCCS Ca Granda Osped Maggiore Policlin, Dept Hematol, Milan, Italy.
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- Bodor, Csaba (författare)
- HCEMM SU Mol Oncohematol Res Grp, Budapest, Hungary.;Semmelweis Univ, Dept Pathol & Expt Canc Res 1, Budapest, Hungary.
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- Stavroyianni, Niki (författare)
- G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece.
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- Tam, Constantine S. (författare)
- Alfred Hlth, Dept Hematol, Melbourne, Vic, Australia.;Monash Univ, Cent Clin Sch, Melbourne, Vic, Australia.
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- Marasca, Robert (författare)
- Univ Modena & Reggio Emilia, Dept Med & Surg Sci, Hematol Unit, Modena, Italy.
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- Forconi, Francesco (författare)
- Univ Southampton, Fac Med, Sch Canc Sci, Southampton, England.;Univ Hosp Natl Hlth Serv Trust, Dept Hematol, Southampton, England.
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- Baliakas, Panagiotis, 1977- (författare)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Cancerprecisionsmedicin
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- Ringshausen, Ingo (författare)
- Univ Cambridge, Dept Hematol, Cambridge, England.
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- Kaksic, Ozren (författare)
- Dubrava Univ Hosp, Zagreb, Croatia.
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- Frustaci, Anna Maria (författare)
- ASST Grande Osped Metropolitano Niguarda, Niguarda Canc Ctr, Dept Hematol, Milan, Italy.
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- Iyengar, Sunil (författare)
- Royal Marsden Hosp, Dept Haematooncol, London, England.
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- Coscia, Marta (författare)
- Univ Torino, Dept Mol Biotechnol & Hlth Sci, Turin, TO, Italy.;AOU Citta Salute & Sci Torino, Div Hematol, Turin, Italy.
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- Mulligan, Stephen P. (författare)
- Univ Sydney, Royal North Shore Hosp, Dept Haematol, Sydney, Australia.
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- Ysebaert, Loic (författare)
- Inst Univ Canc Oncopole Toulouse, Dept Hematol, Toulouse, France.
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- Strugov, Vladimir (författare)
- Almazov Natl Med Res Ctr, St Petersburg, Russia.
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- Pavlovsky, Carolina (författare)
- FUNDALEU, Clin Res Ctr, Buenos Aires, Argentina.
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- Walewska, Reneta (författare)
- Univ Hosp Dorset, Dept Mol Pathol, Bournemouth, England.
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- Österborg, Anders (författare)
- Karolinska Institutet,Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.
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- Cortese, Diego (författare)
- Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
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- Ranghetti, Pamela (författare)
- IRCCS Osped San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy.
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- Baliakas, Panagiotis, 1977- (författare)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Cancerprecisionsmedicin
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- Stamatopoulos, Kostas (författare)
- Karolinska Institutet,Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.
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- Scarfò, Lydia (författare)
- IRCCS Osped San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy.;IRCCS Osped San Raffaele, Strateg Res Program CLL, Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy.
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- Rosenquist, Richard (författare)
- Karolinska Institutet,Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Clin Genet, Stockholm, Sweden.
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- Ghia, Paolo (författare)
- IRCCS Osped San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy.;IRCCS Osped San Raffaele, Strateg Res Program CLL, Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy.
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IRCCS Osped San Raffaele, Ctr Omics Sci, Milan, Italy;IRCCS Osped San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy. Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. (creator_code:org_t)
- 2023-01-25
- 2023
- Engelska.
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 7:12, s. 2794-2806
- Relaterad länk:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://doi.org/10.1...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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https://urn.kb.se/re...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- Patients with chronic lymphocytic leukemia (CLL) progressing on ibrutinib constitute an unmet need. Though Bruton tyrosine kinase (BTK) and PLCG2 mutations are associated with ibrutinib resistance, their frequency and relevance to progression are not fully understood. In this multicenter retrospective observational study, we analyzed 98 patients with CLL on ibrutinib (49 relapsing after an initial response and 49 still responding after ≥1 year of continuous treatment) using a next-generation sequencing (NGS) panel (1% sensitivity) comprising 13 CLL-relevant genes including BTK and PLCG2. BTK hotspot mutations were validated by droplet digital polymerase chain reaction (ddPCR) (0.1% sensitivity). By integrating NGS and ddPCR results, 32 of 49 relapsing cases (65%) carried at least 1 hotspot BTK and/or PLCG2 mutation(s); in 6 of 32, BTK mutations were only detected by ddPCR (variant allele frequency [VAF] 0.1% to 1.2%). BTK/PLCG2 mutations were also identified in 6 of 49 responding patients (12%; 5/6 VAF <10%), of whom 2 progressed later. Among the relapsing patients, the BTK-mutated (BTKmut) group was enriched for EGR2 mutations, whereas BTK-wildtype (BTKwt) cases more frequently displayed BIRC3 and NFKBIE mutations. Using an extended capture-based panel, only BRAF and IKZF3 mutations showed a predominance in relapsing cases, who were enriched for del(8p) (n = 11; 3 BTKwt). Finally, no difference in TP53 mutation burden was observed between BTKmut and BTKwt relapsing cases, and ibrutinib treatment did not favor selection of TP53-aberrant clones. In conclusion, we show that BTK/PLCG2 mutations were absent in a substantial fraction (35%) of a real-world cohort failing ibrutinib, and propose additional mechanisms contributing to resistance.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
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Bonfiglio, Silvi ...
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Sutton, Lesley-A ...
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Ljungström, Vikt ...
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Capasso, Antonel ...
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Pandzic, Tatjana
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Weström, Simone
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visa fler...
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Foroughi-Asl, Ha ...
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Skaftason, Aron
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Gellerbring, Ann ...
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Lyander, Anna
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Gandini, Frances ...
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Gaidano, Gianluc ...
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Trentin, Livio
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Bonello, Lisa
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Reda, Gianluigi
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Bodor, Csaba
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Stavroyianni, Ni ...
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Tam, Constantine ...
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Marasca, Robert
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Forconi, Frances ...
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Baliakas, Panagi ...
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Ringshausen, Ing ...
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Kaksic, Ozren
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Frustaci, Anna M ...
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Iyengar, Sunil
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Coscia, Marta
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Mulligan, Stephe ...
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Ysebaert, Loic
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Strugov, Vladimi ...
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Pavlovsky, Carol ...
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Walewska, Reneta
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Österborg, Ander ...
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Cortese, Diego
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Ranghetti, Pamel ...
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Stamatopoulos, K ...
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Scarfò, Lydia
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Rosenquist, Rich ...
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Ghia, Paolo
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