DNA and RNA sequencing performed on panel of genes known to be recurrently mutated, at high sequencing depth in CLL pts at clinical presentation and progression.

59 CLL samples, 29 CLL at initial presentation and at later progression requiring therapy.

Median time between samples: 2.07 years.

Targeted sequencing approach: 1 clonal somatic mutation in 95% of CLL patients, 144 individual mutations, 3 functional rearrangements, and 1 homozygous deletion.

Most common: mutations in NOTCH1 (25%), SF3B1 (19%), and TP53 (14%).

Most commonly mutated genes targeted by somatic mutations in CLL: KRAS (15%) and BRAF (10%).

Mutations activating Notch signaling: 40% of population.

Mutations resulting in constitutive MAP kinase signaling: 36% of population.

Clonal evolution: mutations in DNMT3A, EED, IDH2, IRF4, VHL, and RB1 .

Mutations in NOTCH1, KRAS, TP53, NRAS, and BCOR: more common at disease progression .

Mutations in SF3B1 and XPO1: always retained at disease progression if found earlier.

Utility of clinical grade, high throughput targeted sequencing in CLL.

Identifies targetable genomic alterations.

identify important markers of disease evolution.

Time and cost required still a challenge in implementing genomic strategies in real-time clinical practice.

Study identified: integrated mutation, copy number, and gene fusion events in CLL