Whole-Genome Sequencing Provides Timely Diagnosis

August 2011, Vol 2, No 5 - In the Literature

Whole-genome sequencing (WGS) has traditionally been an important tool in nonclinical research. Recently, however, the potential clinical value of the technique was demonstrated in a patient with acute promyelocytic leukemia (APL) that was hard to identify (Welch JS, et al. JAMA. 2011;305: 1577-1584).

The patient, a 39-year-old woman with acute myeloid leukemia (AML) in first remission after induction therapy with cytarabine, idarubicin, and etoposide, had been referred to the investigators for consideration of allogeneic stem-cell transplantation. A bone marrow biopsy revealed no morphologic evidence of AML, however, and routine metaphase cytogenetic testing and fluorescence in situ hybridization failed to detect the pathogenic X-RARA fusion gene. Reverse transcription polymerase chain reaction testing also revealed no evidence of PML-RARA, the gene that identifies APL.

Because timely diagnosis and treatment are crucial to ensuring an optimal outcome inAML, the investigators’ primary goal was to establish an accurate diagnosis and administer appropriate therapy—either consolidation therapy with chemotherapy or allogeneic stem-cell transplantation, depending on the diagnosis—within a period of 6 to 8 weeks.

Within 7 weeks, using massively parallel paired-end sequencing, they had detected and validated a novel insertional fusion that created a classic PML-RARA bcr3 variant, thereby confirming APL. The patient was then administered consolidation therapy with all-trans retinoic acid and remains in first remission 15 months after her first presentation.

Although other laboratory methods are available for detecting potential pathogenic RARA rearrangements, those are labor- and resource-intensive, say the investigators, and demonstrate success rates inadequate for clinical practice.

The use of WGS identified the oncogene to facilitate a life-saving change of therapy. For routine use for patients with cancer, diagnostic WGS is currently cost-prohibitive ($40,000 for each tumor per normal pair), although its cost has been decreasing rapidly in the past several years.

Because the cumulative costs of molecular testing have been increasing, the decreasing cost of WGS may be enough to encourage its use as a diagnostic and risk assessment tool.