Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia.
Puente XS, Pinyol M, Quesada V et al.
Editor’s note: The molecular pathogenesis of chronic lymphocytic leukemia (CLL) is poorly understood. In this study, whole-genome sequencing of four different cases of CLL identified a number of recurrent mutations in 46 different genes. To determine if these mutations were truly recurrent, an additional 363 patients with CLL were screened. Four genes were identified that were recurrently mutated in CLL: NOTCH1 (31 of 255 patients), XPO1 (four of 165 patients), MYD88 (nine of 310 patients), and KLHL6 (three of 160 patients). Two different molecular subtypes of CLL have been previously identified on the basis of the degree of somatic hypermutations in the variable region of the immunoglobulin (Ig) genes. MYD88 and KLHL6 were predominant in more favorable prognostic mutated IgH CLL cases whereas NOTCH1 and XPO1 were more frequent in poor prognostic unmutated cases. The NOTCH1 mutations led to deletion of the PEST (proline, glutamic acid, serine, and threonine-rich) domain and increased NOTCH1 signaling.