title: Characterization of cryptic rearrangements, deletion, complex variants of PML, RARA in acute promyelocytic leukemia.
abstract: Acute promyelocytic leukemia (APL) is characterized by a reciprocal translocation t(15;17)(q22;q21) leading to the disruption of Promyelocytic leukemia (PML) and Retionic Acid Receptor Alpha (RARA) followed by reciprocal PML-RARA fusion in 90% of the cases. Fluorescence in situ hybridization (FISH) has overcome the hurdles of unavailability of abnormal and/or lack of metaphase cells, and detection of cryptic, submicroscopic rearrangements. In the present study, besides diagnostic approach we sought to analyze these cases for identification and characterization of cryptic rearrangements, deletion variants and unknown RARA translocation variants by application of D-FISH and RARA break-apart probe strategy on interphase and metaphase cells in a large series of 200 cases of APL. Forty cases (20%) had atypical PML-RARA and/or RARA variants. D-FISH with PML/RARA probe helped identification of RARA insertion to PML. By application of D-FISH on metaphase cells, we documented that translocation of 15 to 17 leads to 17q deletion which results in loss of reciprocal fusion and/or residual RARA on der(17). Among the complex variants of t(15;17), PML-RARA fusion followed by residual RARA insertion closed to PML-RARA on der(15) was unique and unusual. FISH with break-apart RARA probe on metaphase cells was found to be a very efficient strategy to detect unknown RARA variant translocations like t(11;17)(q23;q21), t(11;17)(q13;q21) and t(2;17)(p21;q21). These findings proved that D-FISH and break-apart probe strategy has potential to detect primary as well as secondary additional aberrations of PML, RARA and other additional loci. The long-term clinical follow-up is essential to evaluate the clinical importance of these findings.
authors.affiliation: Cancer Cytogenetics Laboratory, Tata Memorial Hospital, Mumbai, India.
authors.forename: Pratibha Kadam
authors.initials: PK
authors.lastname: Amare
authors.forename: Chanda
authors.initials: C
authors.lastname: Baisane
authors.forename: Reena
authors.initials: R
authors.lastname: Nair
authors.forename: Hari
authors.initials: H
authors.lastname: Menon
authors.forename: Shripad
authors.initials: S
authors.lastname: Banavali
authors.forename: Sharayu
authors.initials: S
authors.lastname: Kabre
authors.forename: Sumit
authors.initials: S
authors.lastname: Gujral
authors.forename: P
authors.initials: P
authors.lastname: Subramaniam
references.citation: Cancer Genet Cytogenet. 2000 Jul 1;120(1):80-2
references.pmid: 10913680
references.citation: Nat Genet. 1997 Sep;17(1):109-13
references.pmid: 9288109
references.citation: Blood. 1999 Jun 15;93(12):4131-43
references.pmid: 10361110
references.citation: Cancer Genet Cytogenet. 2008 Apr 1;182(1):27-32
references.pmid: 18328947
references.citation: Cancer Genet Cytogenet. 2005 Jun;159(2):129-36
references.pmid: 15899384
references.citation: Cancer Genet Cytogenet. 2000 Jun;119(2):162-4
references.pmid: 10867154
references.citation: Cancer Genet Cytogenet. 2003 Sep;145(2):144-51
references.pmid: 12935927
references.citation: Cancer Genet Cytogenet. 1998 Apr 1;102(1):15-8
references.pmid: 9530334
references.citation: Pediatr Hematol Oncol. 2008 Sep;25(6):582-97
references.pmid: 18728978
references.citation: Leukemia. 1998 Dec;12(12):1866-80
references.pmid: 9844917
references.citation: Leukemia. 2002 Oct;16(10):1927-32
references.pmid: 12357344
references.citation: Cancer Genet Cytogenet. 1991 Feb;51(2):167-81
references.pmid: 1993302
references.citation: Cancer Genet Cytogenet. 1990 Nov 1;50(1):109-17
references.pmid: 2253178
references.citation: Leuk Res. 2005 May;29(5):517-26
references.pmid: 15755504
references.citation: Cancer Genet Cytogenet. 2001 Dec;131(2):125-34
references.pmid: 11750052
references.citation: Oncol Rep. 2007 Apr;17(4):799-805
references.pmid: 17342318
references.citation: Blood. 1997 Dec 15;90(12):4876-85
references.pmid: 9389704
references.citation: Br J Haematol. 1996 Sep;94(3):557-73
references.pmid: 8790159
references.citation: Blood. 2005 Mar 15;105(6):2281-6
references.pmid: 15572595
references.citation: Pediatr Hematol Oncol. 1998 May-Jun;15(3):243-8
references.pmid: 9615322
references.citation: J Clin Oncol. 2008 May 1;26(13):2212-4
references.pmid: 18445847
references.citation: Blood. 1995 Feb 15;85(4):1083-94
references.pmid: 7849296
references.citation: Cancer Genet Cytogenet. 2002 Apr 1;134(1):55-9
references.pmid: 11996797
references.citation: Am J Hematol. 1999 Feb;60(2):87-93
references.pmid: 9929098