Combined somatic mutation and copy number analysis in the survival of familial CLL

Summary Recurrent large‐scale somatic copy number alterations ( SCNA s), and somatic point mutations can be analysed to stratify patients with chronic lymphocytic leukaemia ( CLL ) into distinct prognostic groups. To investigate the relationship between SCNA s and somatic mutations, we performed whole‐exome sequencing and single nucleotide polymorphism microarray analyses on 98 CLL patients from 40 families with a high burden of CLL . Overall, 69 somatic mutations in 29 CLL driver genes were detected among 45 subjects (46%), with the most frequently mutated genes being TP 53 (8·2%), NOTCH 1 (8·2%) and ATM (5·1%). Additionally, 142 SCNA s from 54 subjects (57%) were detected, including losses of chromosome 13q14 (28·9%), 11q (5·6%), 17p (2·1%), and gain of chromosome 12 (4·2%). We found that patients having both an adverse point mutation in a CLL driver gene and an unfavourable SCNA tended to have poorer survival (Hazard ratio [ HR ] = 3·17, 95% confidence interval [ CI ] = 0·97–10·35; P  = 0·056) than patients having either a point mutation ( HR  = 1·34, 95% CI  = 0·66–2·71; P  = 0·42) or SCNA s ( HR  = 2·65, 95% CI  = 0·77–9·13; P  = 0·12). TP 53 mutation carriers were associated with the poorest overall survival ( HR  = 4·39, 95% CI  = 1·28–15·04; P  = 0·018). Our study suggests that combining SCNA and mutational data could contribute to predicting outcome in familial CLL .