Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in 
Western countries, is a heterogeneous disease with variable clinical 
presentation and evolution. Two major molecular subtypes can be distinguished, 
characterized respectively by a high or low number of somatic hypermutations in 
the variable region of immunoglobulin genes. The molecular changes leading to 
the pathogenesis of the disease are still poorly understood. Here we performed 
whole-genome sequencing of four cases of CLL and identified 46 somatic mutations 
that potentially affect gene function. Further analysis of these mutations in 
363 patients with CLL identified four genes that are recurrently mutated: notch 
1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 
(MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant 
in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 
mutations are mainly detected in patients with unmutated immunoglobulins. The 
patterns of somatic mutation, supported by functional and clinical analyses, 
strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are 
oncogenic changes that contribute to the clinical evolution of the disease. To 
our knowledge, this is the first comprehensive analysis of CLL combining 
whole-genome sequencing with clinical characteristics and clinical outcomes. It 
highlights the usefulness of this approach for the identification of clinically 
relevant mutations in cancer.