Kevin Hoang

Survival of Del17p CLL Depends on Genomic Complexity and Somatic Mutation.

Purpose: Chronic lymphocytic leukemia (CLL) with 17p deletion typically progresses quickly and is refractory to most conventional therapies. However, some del(17p) patients do not progress for years, suggesting that del(17p) is not the only driving event in CLL progression. We hypothesize that other concomitant genetic abnormalities underlie the clinical heterogeneity of del(17p) CLL. Experimental Design: We profiled the somatic mutations and copy number alterations (CNA) in a large group of del(17p) CLLs as well as wild-type CLL and analyzed the genetic basis of their clinical heterogeneity. Results: We found that increased somatic mutation number associates with poor overall survival independent of 17p deletion (P = 0.003). TP53 mutation was present in 81% of del(17p) CLL, mostly clonal (82%), and clonal mutations with del(17p) exhibit shorter overall survival than subclonal mutations with del(17p) (P = 0.019). Del(17p) CLL has a unique driver mutation profile, including NOTCH1 (15%), RPS15 (12%), DDX3X (8%), and GPS2 (6%). We found that about half of del(17p) CLL cases have recurrent deletions at 3p, 4p, or 9p and that any of these deletions significantly predicts shorter overall survival. In addition, the number of CNAs, but not somatic mutations, predicts shorter time to treatment among patients untreated at sampling. Indolent del(17p) CLLs were characterized by absent or subclonal TP53 mutation and few CNAs, with no difference in somatic mutation number. Conclusions: We conclude that del(17p) has a unique genomic profile and that clonal TP53 mutations, 3p, 4p, or 9p deletions, and genomic complexity are associated with shorter overall survival. Clin Cancer Res; 23(3); 735–45. ©2016 AACR.

FISHing in the dark: How the combination of FISH and conventional karyotyping improves the diagnostic yield in CpG-stimulated chronic lymphocytic leukemia.

Despite significant advances in molecular genetic approaches, fluorescence in situ hybridization (FISH) remains the gold standard for the diagnostic evaluation of genomic aberrations in patients with chronic lymphocytic leukemia (CLL). Efforts to improve the diagnostic utility of molecular cytogenetic testing have led to the expansion of the traditional 4‐probe CLL FISH panel. Not only do these efforts increase the cost of testing, they remain hindered by the inherent limitations of FISH studies ‐ namely the inability to evaluate genomic changes outside of the targeted loci. While array‐based profiling and next generation sequencing (NGS) have critically expanded our understanding of the molecular pathogenesis of CLL, these methodologies are not routinely used by diagnostic laboratories to evaluate copy number changes or the mutational profile of this disease. Mitogenic stimulation of CLL specimens with CpG‐oligonucleotide (CpG‐ODN) has been identified as a reliable and reproducible means of obtaining a karyotype, facilitating a low‐resolution genome‐wide analysis. Across a cohort of 1255 CpG‐ODN‐stimulated CLL specimens, we describe the clinical utility associated with the combinatorial use of FISH and karyotyping. Our testing algorithm achieves a higher diagnostic yield (∼10%) through the detection of complex karyotypes, well‐characterized chromosomal aberrations not covered by the traditional CLL FISH panel and through the detection of concurrent secondary malignancies. Moreover, the single cell nature of this approach permits the evaluation of emerging new clinical concepts including clonal dynamics and clonal evolution. This approach can be broadly applied by diagnostic laboratories to improve the utility of traditional and molecular cytogenetic studies of CLL. Am. J. Hematol. 91:978–983, 2016.

Rare germline variants in ATM are associated with chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a highly heritable cancer, with a 7.5-fold increased risk in first-degree relatives.1 However, inherited predisposition to CLL remains largely unexplained by traditional linkage or genome-wide association studies. Here, we hypothesized that CLL heritability might arise from rare coding variants not analyzed in previous studies.

Minimal residual disease detected by immunoglobulin sequencing predicts CLL relapse more effectively than flow cytometry

Andrew Aw, Haesook T. Kim, Stacey M. Fernandes, Kevin Hoang, Siddha Kasar, Malek Faham and Jennifer R. Brown Division of Hematology, Department of Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, Canada; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Dana-Farber Cancer Institute, Boston, MA, USA; Adaptive Biotechnologies Corp, South San Francisco, CA, USA; CLL Center and Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA