TY  - JOUR
T1  - USe of whole-genome sequencing to diagnose a cryptic fusion oncogene
AU  - Welch JS, Westervelt P, Ding L, et al
Y1  - 2011/04/20
N1  - 10.1001/jama.2011.497
JO  - JAMA
SP  - 1577
EP  - 1584
VL  - 305
IS  - 15
N2  - Context 
                  Whole-genome sequencing is becoming increasingly available for research purposes, but it has not yet been routinely used for clinical diagnosis.Objective 
                  To determine whether whole-genome sequencing can identify cryptic, actionable mutations in a clinically relevant time frame.Design, Setting, and Patient 
                  We were referred a difficult diagnostic case of acute promyelocytic leukemia with no pathogenic X-RARA fusion identified by routine metaphase cytogenetics or interphase fluorescence in situ hybridization (FISH). The case patient was enrolled in an institutional review board–approved protocol, with consent specifically tailored to the implications of whole-genome sequencing. The protocol uses a “movable firewall” that maintains patient anonymity within the entire research team but allows the research team to communicate medically relevant information to the treating physician.Main Outcome Measures 
                  Clinical relevance of whole-genome sequencing and time to communicate validated results to the treating physician.Results 
                  Massively parallel paired-end sequencing allowed identification of a cytogenetically cryptic event: a 77-kilobase segment from chromosome 15 was inserted en bloc into the second intron of the RARA gene on chromosome 17, resulting in a classic bcr3 PML-RARA fusion gene. Reverse transcription polymerase chain reaction sequencing subsequently validated the expression of the fusion transcript. Novel FISH probes identified 2 additional cases of t(15;17)–negative acute promyelocytic leukemia that had cytogenetically invisible insertions. Whole-genome sequencing and validation were completed in 7 weeks and changed the treatment plan for the patient.Conclusion 
                  Whole-genome sequencing can identify cytogenetically invisible oncogenes in a clinically relevant time frame.
SN  - 0098-7484
M3  - doi: 10.1001/jama.2011.497
UR  - http://dx.doi.org/10.1001/jama.2011.497
ER  -