Integrated genomic DNA/RNA profiling of hematologic malignancies in the clinical setting

Abstract

Key Points Novel clinically available comprehensive genomic profiling of both DNA and RNA in hematologic malignancies. Profiling of 3696 clinical hematologic tumors identified somatic alterations that impact diagnosis, prognosis, and therapeutic selection.

Prognostic tumor sequencing panels frequently identify germ line variants associated with hereditary hematopoietic malignancies

“…Tumor-only sequencing cannot identify hereditary variants without paired normal tissue. 4,5,14 However, many patients in this study were unable to provide germ line samples secondary to death, travel constraints, or lack of follow-up. Therefore, an ideal diagnostic workflow would include counseling and culturing of skin fibroblasts at the time of initial bone marrow biopsy.…”

“…4,5 These panels may identify variants in genes associated with HHMs, 4,6 but tumor-only sequencing cannot differentiate between acquired and germ line variants. We hypothesized that we could identify some patients with HHMs using tumor-only NGS panels, and we determined the frequency at which this occurs.…”

Diagnosis and classification of hematologic malignancies on the basis of genetics

“…Moreover, increased discovery of clinically important mutations and structural variations not detectable by cytogenetics, FISH, or small gene panels (such as copynumber changes, amplifications, deletions, and gene fusions) begets the need for means to comprehensively evaluate molecular alterations of a variety of types in clinical practice. To this end, a number of targeted DNA-sequencing [174][175][176][177] and combined DNA/RNA-sequencing 178,179 panels evaluating recurrently altered genes across hematopoietic malignancies have been described, some of which are commercially available (reviewed recently by Kuo and Dong, 180 Meldrum et al, 181 and Kanagal-Shamanna et al 182 ) and allow use of formalin-fixed paraffinembedded specimens. Further improvements in next-generation sequencing technologies (reviewed by Sheikine et al 183 ) are expected to allow evaluation of mutations across the entire coding regions of hundreds to thousands of genes while also providing information on copy-number status and gene fusions in a clinically relevant timeframe.…”

Mutation load and an effector T-cell gene signature may distinguish immunologically distinct and clinically relevant lymphoma subsets

“…The laboratory and computational methods employed in the FoundationOne Heme (F1H) DNA assay have been described in detail previously. 6,[17][18][19] Briefly, data were generated from the D2 bait set of the F1H test, targeting 406 genes over an ;1.20-Mb region (1 198 160 base pairs). This nextgeneration sequencing platform profiles somatic mutations using high coverage (.5003) exome sequencing of 467 cancer-related genes.…”