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Genetic lesions associated with chronic lymphocytic leukemia chemo-refractoriness

2014; Elsevier BV; Volume: 123; Issue: 15 Linguagem: Inglês

10.1182/blood-2013-10-534271

1528-0020

Monica Messina, Ilaria Del Giudice, Hossein Khiabanian, Davide Rossi, Sabina Chiaretti, Silvia Rasi, Valeria Spina, Antony B. Holmes, M Marinelli, Giulia Fabbri, Alfonso Piciocchi, Francesca Romana Mauro, Anna Guarini, Gianluca Gaïdano, Riccardo Dalla‐Favera, Laura Pasqualucci, Raúl Rabadán, Robin Foà,

Advanced Breast Cancer Therapies

Fludarabine refractoriness (FR) represents an unsolved clinical problem of chronic lymphocytic leukemia (CLL) management. Although next-generation sequencing studies have led to the identification of a number of genes frequently mutated in FR-CLL, a comprehensive evaluation of the FR-CLL genome has not been reported. Toward this end, we studied 10 FR-CLLs by combining whole-exome sequencing and copy number aberration (CNA) analysis, which showed an average of 16.3 somatic mutations and 4 CNAs per sample. Screening of recurrently mutated genes in 48 additional FR-CLLs revealed that ~70% of FR-CLLs carry ≥1 mutation in genes previously associated with CLL clinical course, including TP53 (27.5%), NOTCH1 (24.1%), SF3B1 (18.9%), and BIRC3 (15.5%). In addition, this analysis showed that 10.3% of FR-CLL cases display mutations of the FAT1 gene, which encodes for a cadherin-like protein that negatively regulates Wnt signaling, consistent with a tumor suppressor role. The frequency of FAT1-mutated cases was significantly higher in FR-CLL than in unselected CLLs at diagnosis (10.3% vs 1.1%, P = .004), suggesting a role in the development of a high-risk phenotype. These findings have general implications for the mechanisms leading to FR and point to Wnt signaling as a potential therapeutic target in FR-CLL.