PMID- 21505136
OWN - NLM
STAT- MEDLINE
DCOM- 20110421
LR  - 20211020
IS  - 1538-3598 (Electronic)
IS  - 0098-7484 (Print)
IS  - 0098-7484 (Linking)
VI  - 305
IP  - 15
DP  - 2011 Apr 20
TI  - Use of whole-genome sequencing to diagnose a cryptic fusion oncogene.
PG  - 1577-84
LID - 10.1001/jama.2011.497 [doi]
AB  - 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.
FAU - Welch, John S
AU  - Welch JS
AD  - Department of Medicine, Washington University, St Louis, Missouri, USA.
FAU - Westervelt, Peter
AU  - Westervelt P
FAU - Ding, Li
AU  - Ding L
FAU - Larson, David E
AU  - Larson DE
FAU - Klco, Jeffery M
AU  - Klco JM
FAU - Kulkarni, Shashikant
AU  - Kulkarni S
FAU - Wallis, John
AU  - Wallis J
FAU - Chen, Ken
AU  - Chen K
FAU - Payton, Jacqueline E
AU  - Payton JE
FAU - Fulton, Robert S
AU  - Fulton RS
FAU - Veizer, Joelle
AU  - Veizer J
FAU - Schmidt, Heather
AU  - Schmidt H
FAU - Vickery, Tammi L
AU  - Vickery TL
FAU - Heath, Sharon
AU  - Heath S
FAU - Watson, Mark A
AU  - Watson MA
FAU - Tomasson, Michael H
AU  - Tomasson MH
FAU - Link, Daniel C
AU  - Link DC
FAU - Graubert, Timothy A
AU  - Graubert TA
FAU - DiPersio, John F
AU  - DiPersio JF
FAU - Mardis, Elaine R
AU  - Mardis ER
FAU - Ley, Timothy J
AU  - Ley TJ
FAU - Wilson, Richard K
AU  - Wilson RK
LA  - eng
GR  - P01 CA101937-07/CA/NCI NIH HHS/United States
GR  - U54 HG003079-08/HG/NHGRI NIH HHS/United States
GR  - K99 HL103975/HL/NHLBI NIH HHS/United States
GR  - P01 CA101937/CA/NCI NIH HHS/United States
GR  - U54 HG003079/HG/NHGRI NIH HHS/United States
GR  - R01 CA083962/CA/NCI NIH HHS/United States
PT  - Case Reports
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - JAMA
JT  - JAMA
JID - 7501160
RN  - 0 (Nuclear Proteins)
RN  - 0 (Oncogene Proteins, Fusion)
RN  - 0 (Promyelocytic Leukemia Protein)
RN  - 0 (RARA protein, human)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Retinoic Acid Receptor alpha)
RN  - 0 (Transcription Factors)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 143220-95-5 (PML protein, human)
SB  - IM
CIN - JAMA. 2011 Apr 20;305(15):1596-7. PMID: 21505140
CIN - JAMA. 2011 Aug 10;306(6):610; author reply 610-1. PMID: 21828321
MH  - Adult
MH  - Chromosome Breakpoints
MH  - Chromosomes, Human, Pair 15/genetics
MH  - Chromosomes, Human, Pair 17/genetics
MH  - Gene Fusion
MH  - Genome, Human
MH  - Humans
MH  - Introns
MH  - Leukemia, Promyelocytic, Acute/*genetics/therapy
MH  - Male
MH  - Nuclear Proteins/*genetics
MH  - Oncogene Proteins, Fusion/*genetics
MH  - Promyelocytic Leukemia Protein
MH  - Receptors, Retinoic Acid/*genetics
MH  - Retinoic Acid Receptor alpha
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - *Sequence Analysis, DNA
MH  - Transcription Factors/*genetics
MH  - Tumor Suppressor Proteins/*genetics
PMC - PMC3156695
MID - NIHMS299367
EDAT- 2011/04/21 06:00
MHDA- 2011/04/22 06:00
PMCR- 2011/08/16
CRDT- 2011/04/21 06:00
PHST- 2011/04/21 06:00 [entrez]
PHST- 2011/04/21 06:00 [pubmed]
PHST- 2011/04/22 06:00 [medline]
PHST- 2011/08/16 00:00 [pmc-release]
AID - 305/15/1577 [pii]
AID - 10.1001/jama.2011.497 [doi]
PST - ppublish
SO  - JAMA. 2011 Apr 20;305(15):1577-84. doi: 10.1001/jama.2011.497.