Use of Whole-Genome Sequencing to Diagnose a Cryptic Fusion Oncogene

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Abstract
Acute promyelocytic leukemia (APL) is commonly (>90%) associated with PML-RARA (NCBI Entrez Gene 5371 and 5914) fusion transcripts resulting from pathogenic t(15;17) translocations.1,2 Unusual cytogenetic rearrangements (eg, insertions and 3, 4, or even 8-way translocations)2-4 can also lead to PML-RARA formation. Alternative PML-RARA fusions and splice variants exist but are not detected by standard reverse transcription polymerase chain reaction (RT-PCR)5-7; alternative X-RARA fusions also may exist and may be responsive to all- trans retinoic acid (ATRA) (eg, NuMA1-RARA, NPM1-RARA, STAT5B-RARA, PRKAR1A-RARA, FIP1L1-RARA, BCOR-RARA, and the non- RARA translocation NUP98-RARG)1,8-12 or ATRA resistant (PLZF-RARA).1 Timely and accurate diagnosis of APL is essential, because the addition of ATRA to chemotherapy leads to substantially improved outcomes (5-year event-free survival of 69%, compared with 29% in patients receiving chemotherapy alone).13