Insulin growth factor 1 receptor expression is associated with NOTCH1 mutation, trisomy 12 and aggressive clinical course in chronic lymphocytic leukaemia

Francesco Maura; Laura Mosca; Sonia Fabris; Giovanna Cutrona; Serena Matis; Marta Lionetti; Luca Agnelli; Marzia Barbieri; Marianna D'Anca; Martina Manzoni; Monica Colombo; Carlotta Massucco; Daniele Reverberi; Massimo Gentile; Anna Grazia Recchia; Sabrina Bossio; Fiorella Ilariucci; Caterina Musolino; Francesco Di Raimondo; Agostino Cortelezzi; Fortunato Morabito; Manlio Ferrarini; Antonino Neri

doi:10.1371/journal.pone.0118801

Insulin growth factor 1 receptor expression is associated with NOTCH1 mutation, trisomy 12 and aggressive clinical course in chronic lymphocytic leukaemia

PLoS One. 2015 Mar 18;10(3):e0118801. doi: 10.1371/journal.pone.0118801. eCollection 2015.

Authors

Francesco Maura¹, Laura Mosca¹, Sonia Fabris¹, Giovanna Cutrona², Serena Matis³, Marta Lionetti¹, Luca Agnelli¹, Marzia Barbieri¹, Marianna D'Anca¹, Martina Manzoni¹, Monica Colombo³, Carlotta Massucco³, Daniele Reverberi⁴, Massimo Gentile⁵, Anna Grazia Recchia⁵, Sabrina Bossio⁵, Fiorella Ilariucci⁶, Caterina Musolino⁷, Francesco Di Raimondo⁸, Agostino Cortelezzi¹, Fortunato Morabito⁴, Manlio Ferrarini³, Antonino Neri¹

Affiliations

¹ Department of Clinical Sciences and Community Health, University of Milano and Hematology 1 CTMO, Foundation IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy.
² SS Molecular Diagnostics, IRCCS S. Martino-IST, Genova, Italy.
³ Scientific Direction IRCCS S. Martino-IST, Genova, Italy.
⁴ Department of Pathology IRCCS S. Martino-IST, Genova, Italy.
⁵ U.O.C. di Ematologia, Azienda Ospedaliera di Cosenza, Cosenza, Italy.
⁶ Division of Hematology, A.O. Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy.
⁷ Division of Haematology, University of Messina, Messina, Italy.
⁸ Department of Biomedical Sciences, Division of Hematology, University of Catania and Ferrarotto Hospital, Catania, Italy.

Abstract

IGF1R is emerging as an important gene in the pathogenesis of many solid and haematological cancers and its over-expression has been reported as frequently associated with aggressive disease and chemotherapy resistance. In this study we performed an investigation of the role of IGF1R expression in a large and representative prospective series of 217 chronic lymphocytic leukaemia (CLL) patients enrolled in the multicentre O-CLL1 protocol (clinicaltrial.gov #NCT00917540). High IGF1R gene expression was significantly associated with IGHV unmutated (IGHV-UM) status (p<0.0001), high CD38 expression (p<0.0001), trisomy 12 (p<0.0001), and del(11)(q23) (p=0.014). Interestingly, higher IGF1R expression (p=0.002) characterized patients with NOTCH1 mutation (c.7541_7542delCT), identified in 15.5% of cases of our series by next generation sequencing and ARMS-PCR. Furthermore, IGF1R expression has been proven as an independent prognostic factor associated with time to first treatment in our CLL prospective cohort. These data suggest that IGF1R may play an important role in CLL biology, in particular in aggressive CLL clones characterized by IGHV-UM, trisomy 12 and NOTCH1 mutation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Chromosomes, Human, Pair 12 / genetics*
Clinical Trials as Topic
Gene Expression Regulation, Neoplastic*
Humans
Leukemia, Lymphocytic, Chronic, B-Cell / diagnosis
Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
Leukemia, Lymphocytic, Chronic, B-Cell / pathology
Mutation*
Neoplasm Staging
Prognosis
RNA, Messenger / genetics
RNA, Messenger / metabolism
Receptor, IGF Type 1
Receptor, Notch1 / genetics*
Receptors, Somatomedin / genetics*
Trisomy / genetics*

Substances

IGF1R protein, human
RNA, Messenger
Receptor, Notch1
Receptors, Somatomedin
Receptor, IGF Type 1

Associated data

GEO/GSE51529
ClinicalTrials.gov/NCT00917540

Grants and funding

This work was supported by Associazione Italiana Ricerca sul Cancro (AIRC, AN-IG10136, MF464 IG10492, and FM-RG6432), AIRC–Special Program Molecular Clinical Oncology (5 per Mille, grant 9980, 2010-15; Antonino Neri, Manlio Ferrarini, and Fortunato Morabito), Ricerca Finalizzata from the Italian Ministry of Health 2006 (Giovanna Cutrona, Fortunato Morabito, and Manlio Ferrarini) and 2007 (Giovanna Cutrona), Fondo Investimento per la Ricerca di Base (grant RBIP06LCA9; Manlio Ferrarini), progetto Compagnia San Paolo (G.C.). Sabrina Bossio was supported by fellowships from the AIRC. Marta Lionetti was supported by a fellowship from the Fondazione Italiana Ricerca sul Cancro (FIRC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.