title: Patients with chronic lymphocytic leukaemia and clonal deletion of both 17p13.1 and 11q22.3 have a very poor prognosis.
abstract: Detection of a 17p13.1 deletion (loss of TP53) or 11q22.3 deletion (loss of ATM), by fluorescence in situ hybridization (FISH), in chronic lymphocytic leukaemia (CLL) patients is associated with a poorer prognosis. Because TP53 and ATM are integral to the TP53 pathway, we hypothesized that 17p13.1- (17p-) and 11q22.3- (11q-) occurring in the same cell (clonal 17p-/11q-) would confer a worse prognosis than either 17p- or 11q-. We studied 2184 CLL patients with FISH (1995-2012) for the first occurrence of 17p-, 11q-, or clonal 17p-/11q-. Twenty (1%) patients had clonal 17p-/11q-, 158 (7%) had 17p- (including 4 with 17p- and 11q- in separate clones), 247 (11%) had 11q-, and 1759 (81%) had neither 17p- nor 11q-. Eleven of 15 (73%) tested patients with clonal 17p-/11q- had dysfunctional TP53 mutations. Overall survival for clonal 17p-/11q- was significantly shorter (1·9 years) than 17p- (3·1 years, P = 0·04), 11q- (4·8 years, P ≤ 0·0001), or neither 17p- nor 11q- (9·3 years, P ≤ 0·0001). Clonal 17p-/11q- thus conferred significantly worse prognosis, suggesting that loss of at least one copy of both TP53 and ATM causes more aggressive disease. Use of an ATM/TP53 combination FISH probe set could identify these very-high risk patients.
authors.affiliation: Department of Laboratory Medicine and Pathology, Cytogenetics Laboratory, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Patricia T
authors.initials: PT
authors.lastname: Greipp
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Smoley
authors.forename: David S
authors.initials: DS
authors.lastname: Viswanatha
authors.forename: Lori S
authors.initials: LS
authors.lastname: Frederick
authors.forename: Kari G
authors.initials: KG
authors.lastname: Rabe
authors.forename: Ruchi G
authors.initials: RG
authors.lastname: Sharma
authors.forename: Susan L
authors.initials: SL
authors.lastname: Slager
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Van Dyke
authors.forename: Tait D
authors.initials: TD
authors.lastname: Shanafelt
authors.forename: Renee C
authors.initials: RC
authors.lastname: Tschumper
authors.forename: Clive S
authors.initials: CS
authors.lastname: Zent
mesh_terms: D000328:Adult; D000368:Aged; D064007:Ataxia Telangiectasia Mutated Proteins / Q000172:deficiency / Q000235:genetics; D002872:Chromosome Deletion; D002880:Chromosomes, Human, Pair 11 / Q000648:ultrastructure*; D002886:Chromosomes, Human, Pair 17 / Q000648:ultrastructure*; D002999:Clone Cells / Q000648:ultrastructure; D005260:Female; D052138:Genes, Neoplasm; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000145:classification / Q000235:genetics* / Q000401:mortality; D008214:Lymphocytes / Q000648:ultrastructure; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics; D011379:Prognosis; D012189:Retrospective Studies; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency
chemical_list: D009363:Neoplasm Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ATM; TP53; chronic lymphocytic leukaemia; fluorescence in situ hybridization (FISH); prognostic factors
references.citation: Blood. 1999 Sep 15;94(6):1840-7
references.pmid: 10477712
references.citation: Hematology Am Soc Hematol Educ Program. 2010;2010:481-8
references.pmid: 21239840
references.citation: Leukemia. 2012 Jul;26(7):1458-61
references.pmid: 22297721
references.citation: Blood. 1995 Mar 15;85(6):1580-9
references.pmid: 7888675
references.citation: Leukemia. 2009 Jan;23(1):117-24
references.pmid: 18843282
references.citation: Blood. 2008 Oct 15;112(8):3322-9
references.pmid: 18689542
references.citation: N Engl J Med. 2000 Dec 28;343(26):1910-6
references.pmid: 11136261
references.citation: Br J Haematol. 2003 Apr;121(2):287-95
references.pmid: 12694251
references.citation: J Clin Oncol. 2010 Oct 10;28(29):4473-9
references.pmid: 20697090
references.citation: Clin Cancer Res. 2009 Feb 1;15(3):995-1004
references.pmid: 19188171
references.citation: J Clin Oncol. 2007 Dec 1;25(34):5448-57
references.pmid: 17968022
references.citation: J Clin Oncol. 2012 Dec 20;30(36):4524-32
references.pmid: 23091097
references.citation: Blood. 1999 Sep 15;94(6):1848-54
references.pmid: 10477713
references.citation: Genes Chromosomes Cancer. 2012 Dec;51(12):1125-32
references.pmid: 22952040