Genomic Disruption of the Histone Methyltransferase SETD2 in Chronic Lymphocytic Leukemia

• Published in: Blood 2015-12, Vol.126 (23), p.365-365
• Main Authors: Rose-Zerilli, Matthew John Jerome, Parker, Helen, Larrayoz, Marta, Clifford, Ruth, Blakemore, Stuart, Edelmann, Jennifer, Gibson, Jane, Wang, Jun, Ljungstrom, Viktor, Chaplin, Tracy, Roghanian, Ali, Davis, Zadie, Parker, Anton, Tausch, Eugen, Ntoufa, Stavroula, Ramos, Sara, Robbe, Pauline, Steele, Andrew J, Packham, Graham, Rodriguez, Ana E., Brown, Lee, McNicholl, Feargal, Forconi, Francesco, Pettitt, Andrew R, Hillmen, Peter, Dyer, Martin J.S., Cragg, Mark S, Young, Bryan D, Chelala, Claude, Rosenquist, Richard, Stamatopoulos, Kostas, Stilgenbauer, Stephan, Knight, Samantha, Schuh, Anna, Oscier, David, Strefford, Jonathan C
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.V126.23.365.365

Histone methyltransferases (HMTs) are important epigenetic regulators of gene transcription and have been found disrupted at the genomic level in a spectrum of human tumors including hematological malignancies. In CLL, recurring genomic lesions targeting chromatin modifiers are emerging in the literature (Puente 2015, Nature) but their biological and clinical significance remain uncertain. We studied 802 CLL patients, divided into a discovery [n=261, sampled pre-treatment] and two validation cohorts [n=541, 431 pre-treatment and 110 ultra-high risk], using high-resolution SNP-arrays [n=572, Affymetrix SNP6.0 and HumanOmniS-8] and high-throughput re-sequencing [n=320, Haloplex and TruSeq] to identify genomic lesions targeting HMT genes. In our discovery cohort, we identified nine novel regions of copy-number changes; the prime finding was a recurrent deletion of chromosome 3p in 4% of patients between genomic positions 47.12-47.36Mb. This region included SETD2, KIF9 and KLHL18 (Fig 1A), with SETD2 being the most significantly under-expressed gene (p=0.001) in 3p-deleted [n=6] versus non-deleted cases [n=8]. Further validation in two independent cohorts showed that SETD2 deletions were enriched in ultra high-risk CLL and associated with loss of TP53 (p=0.003), genomic complexity (in TP53 wild-type cases, p=0.01) and chromothripsis. Next, we screened for somatic mutations in SETD2 using targeted re-sequencing and identified non-synonymous mutations in four (4.5%) discovery cases (p.D99G, p.W1306X, p.Q1545K, p.E1955Q), and 7/231 (3%) in the pre-treatment validation cases (p.A50T, p.P167L, p.E670K, p.M1742L, p.M1889T (x2), p.I2295M) (Fig 1B). Mutations were somatic in all samples tested [n=5]. To study the clonal nature of the SETD2 deletions, we assigned each genomic CNA with a relative copy-number by normalizing CNA intensity values from array features, and could infer that the 3p deletion was in the dominant clonal population in 14/21 cases with data available for analysis. Employing either the ABSOLUTE algorithm for our discovery cohort or manually correcting for tumor sample purity and local copy-number changes in our validation cohort, we observed that 10/11 SETD2 mutations exhibited a clonal cell fraction. These data strongly imply that SETD2 aberrations represent early clonal events in the pathobiology of CLL. Next, we extended our gene expression analysis to include additional wild-type, deleted, and mutated patients, showing reduced expression both in