Genome-Wide Single-Nucleotide Polymorphism Array Analysis Improves Prognostication of Acute Lymphoblastic Leukemia/Lymphoma

Abstract

Chromosomal abnormalities are important for the risk stratification of acute lymphoblastic leukemia/lymphoma (ALL). However, approximately 30% of pediatric and 50% of adult patients lack abnormalities with clinical relevance by traditional cytogenetic analysis. We integrated cytogenetic, fluorescence in situ hybridization, and whole-genome single-nucleotide polymorphism array results from 60 consecutive clinical ALL cases. By cytogenetic and/or fluorescence in situ hybridization analyses, recurring abnormalities with clinical relevance were observed in 33 B-cell ALL (B-ALL), including t(9;22), hyperdiploidy, KMT2A translocation, ETV6-RUNX1, intrachromosomal amplification of chromosome 21, near haploidy or low hypodiploidy, and t(8;22). Single-nucleotide polymorphism array analysis found additional aberrations with prognostic or therapeutic implication in 21 B-ALL and two T-cell ALL, including IKZF1 deletion, intrachromosomal amplification of chromosome 21 (one case with a normal karyotype), low hypodiploidy (two cases with a normal karyotype), and one case each with fusion genes ETV6-NTRK3, CRLF2-P2RY8, NUP214-ABL1, and SET-NUP214. IKZF1 deletion was noted in nine B-ALL with t(9;22), one B-ALL with t(4;11), five B-ALL with a normal karyotype, and three B-ALL with nonrecurring karyotypic abnormalities. Combining single-nucleotide polymorphism array with chromosome and fluorescence in situ hybridization assays, the detection rate for clinically significant abnormal results increased from 56% to 75%. Whole-genome single-nucleotide polymorphism array analysis detects cytogenetically undetectable clinically significant aberrations and should be routinely applied at diagnosis of ALL. Chromosomal abnormalities are important for the risk stratification of acute lymphoblastic leukemia/lymphoma (ALL). However, approximately 30% of pediatric and 50% of adult patients lack abnormalities with clinical relevance by traditional cytogenetic analysis. We integrated cytogenetic, fluorescence in situ hybridization, and whole-genome single-nucleotide polymorphism array results from 60 consecutive clinical ALL cases. By cytogenetic and/or fluorescence in situ hybridization analyses, recurring abnormalities with clinical relevance were observed in 33 B-cell ALL (B-ALL), including t(9;22), hyperdiploidy, KMT2A translocation, ETV6-RUNX1, intrachromosomal amplification of chromosome 21, near haploidy or low hypodiploidy, and t(8;22). Single-nucleotide polymorphism array analysis found additional aberrations with prognostic or therapeutic implication in 21 B-ALL and two T-cell ALL, including IKZF1 deletion, intrachromosomal amplification of chromosome 21 (one case with a normal karyotype), low hypodiploidy (two cases with a normal karyotype), and one case each with fusion genes ETV6-NTRK3, CRLF2-P2RY8, NUP214-ABL1, and SET-NUP214. IKZF1 deletion was noted in nine B-ALL with t(9;22), one B-ALL with t(4;11), five B-ALL with a normal karyotype, and three B-ALL with nonrecurring karyotypic abnormalities. Combining single-nucleotide polymorphism array with chromosome and fluorescence in situ hybridization assays, the detection rate for clinically significant abnormal results increased from 56% to 75%. Whole-genome single-nucleotide polymorphism array analysis detects cytogenetically undetectable clinically significant aberrations and should be routinely applied at diagnosis of ALL. Identification of recurring cytogenetic abnormalities has had a major effect on risk classification of acute lymphoblastic leukemia/lymphoma (ALL).1Pui C.H. Evans W.E. Treatment of acute lymphoblastic leukemia.N Engl J Med. 2006; 354: 166-178Crossref PubMed Scopus (1543) Google Scholar, 2Moorman A.V. Ensor H.M. Richards S.M. Chilton L. Schwab C. Kinsey S.E. Vora A. Mitchell C.D. Harrison C.J. Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial.Lancet Oncol. 2010; 11: 429-438Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar, 3Toft N. Birgens H. Abrahamsson J. Bernell P. Griskevicius L. Hallbook H. Heyman M. Holm M.S. Hulegardh E. Klausen T.W. Marquart H.V. Jonsson O.G. Nielsen O.J. Quist-Paulsen P. Taskinen M. Vaitkeviciene G. Vettenranta K. Asberg A. Schmiegelow K. Risk group assignment differs for children and adults 1-45 yr with acute lymphoblastic leukemia treated by the NOPHO ALL-2008 protocol.Eur J Haematol. 2013; 90: 404-412Crossref Scopus (107) Google Scholar, 4Marks D.I. Paietta E.M. Moorman A.V. Richards S.M. Buck G. DeWald G. Ferrando A. Fielding A.K. Goldstone A.H. Ketterling R.P. Litzow M.R. Luger S.M. McMillan A.K. Mansour M.R. Rowe J.M. Tallman M.S. Lazarus H.M. T-cell acute lymphoblastic leukemia in adults: clinical features, immunophenotype, cytogenetics, and outcome from the large randomized prospective trial (UKALL XII/ECOG 2993).Blood. 2009; 114: 5136-5145Crossref PubMed Scopus (276) Google Scholar Current therapeutic protocols consider a number of these abnormalities when assigning patients to the high- or low-risk categories. For example, hyperdiploidy (>50 chromosomes) and ETV6-RUNX1 fusion gene confer the most favorable prognosis, whereas near haploidy, low hypodiploidy or near triploidy, t(9;22), and KMT2A (MLL) translocation are associated with poor prognosis in B-cell ALL (B-ALL).1Pui C.H. Evans W.E. Treatment of acute lymphoblastic leukemia.N Engl J Med. 2006; 354: 166-178Crossref PubMed Scopus (1543) Google Scholar, 2Moorman A.V. Ensor H.M. Richards S.M. Chilton L. Schwab C. Kinsey S.E. Vora A. Mitchell C.D. Harrison C.J. Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial.Lancet Oncol. 2010; 11: 429-438Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar, 3Toft N. Birgens H. Abrahamsson J. Bernell P. Griskevicius L. Hallbook H. Heyman M. Holm M.S. Hulegardh E. Klausen T.W. Marquart H.V. Jonsson O.G. Nielsen O.J. Quist-Paulsen P. Taskinen M. Vaitkeviciene G. Vettenranta K. Asberg A. Schmiegelow K. Risk group assignment differs for children and adults 1-45 yr with acute lymphoblastic leukemia treated by the NOPHO ALL-2008 protocol.Eur J Haematol. 2013; 90: 404-412Crossref Scopus (107) Google Scholar In T-cell ALL (T-ALL), t(11;14)(p13;q11), del(17p), and a complex karyotype are associated with a poor overall survival.4Marks D.I. Paietta E.M. Moorman A.V. Richards S.M. Buck G. DeWald G. Ferrando A. Fielding A.K. Goldstone A.H. Ketterling R.P. Litzow M.R. Luger S.M. McMillan A.K. Mansour M.R. Rowe J.M. Tallman M.S. Lazarus H.M. T-cell acute lymphoblastic leukemia in adults: clinical features, immunophenotype, cytogenetics, and outcome from the large randomized prospective trial (UKALL XII/ECOG 2993).Blood. 2009; 114: 5136-5145Crossref PubMed Scopus (276) Google Scholar Karyotype and fluorescence in situ hybridization (FISH) analyses are the standard cytogenetic assays for identifying genomic abnormalities. However, because of inadequate specimens and absent or few mitotic cells, approximately 16% to 30% of the ALL cases yield no or inadequate cytogenetic results. Among those with a cytogenetic result, 15% to 25% have a normal karyotype.2Moorman A.V. Ensor H.M. Richards S.M. Chilton L. Schwab C. Kinsey S.E. Vora A. Mitchell C.D. Harrison C.J. Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial.Lancet Oncol. 2010; 11: 429-438Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar, 5Moorman A.V. Harrison C.J. Buck G.A. Richards S.M. Secker-Walker L.M. Martineau M. Vance G.H. Cherry A.M. Higgins R.R. Fielding A.K. Foroni L. Paietta E. Tallman M.S. Litzow M.R. Wiernik P.H. Rowe J.M. Goldstone A.H. Dewald G.W. Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial.Blood. 2007; 109: 3189-3197Crossref PubMed Scopus (566) Google Scholar, 6Pullarkat V. Slovak M.L. Kopecky K.J. Forman S.J. Appelbaum F.R. Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia: results of Southwest Oncology Group 9400 study.Blood. 2008; 111: 2563-2572Crossref PubMed Scopus (171) Google Scholar Recent application of whole-genome single-nucleotide polymorphism (SNP) arrays, multiplex ligation-dependent probe amplification, and next-generation sequencing has revealed a plethora of submicroscopic genomic abnormalities that specifically target genes involved in key signaling pathways and are associated with patient outcome.7Moorman A.V. The clinical relevance of chromosomal and genomic abnormalities in B-cell precursor acute lymphoblastic leukaemia.Blood Rev. 2012; 26: 123-135Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 8Mullighan C.G. The molecular genetic makeup of acute lymphoblastic leukemia.Hematology Am Soc Hematol Educ Program. 2012; 2012: 389-396PubMed Google Scholar, 9Mullighan C.G. Goorha S. Radtke I. Miller C.B. Coustan-Smith E. Dalton J.D. Girtman K. Mathew S. Ma J. Pounds S.B. Su X. Pui C.H. Relling M.V. Evans W.E. Shurtleff S.A. Downing J.R. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia.Nature. 2007; 446: 758-764Crossref PubMed Scopus (1382) Google Scholar, 10Schwab C.J. Chilton L. Morrison H. Jones L. Al-Shehhi H. Erhorn A. Russell L.J. Moorman A.V. Harrison C.J. Genes commonly deleted in childhood B-cell precursor acute lymphoblastic leukemia: association with cytogenetics and clinical features.Haematologica. 2013; 98: PubMed Scopus Google Scholar, A.V. A. Schwab C. Chilton L. A. S. J. Kinsey S.E. Mitchell C.D. N. Vora A. Harrison C.J. integrated cytogenetic and genomic classification risk stratification in pediatric acute lymphoblastic PubMed Scopus Google Scholar, C.G. Su X. J. Radtke I. Miller C.B. Ma J. C. G. M. Relling M.V. Shurtleff S.A. Pui C.H. M. Downing J.R. of IKZF1 and prognosis in acute lymphoblastic leukemia.N Engl J Med. 2009; PubMed Scopus Google Scholar, L. A. M. A. E. K. of IKZF1 and are associated with poor prognosis in a of pediatric B-cell precursor acute lymphoblastic leukemia and Scopus Google Scholar For example, submicroscopic of genes and have observed in and of and have associated with an array analysis of number aberrations and of and is to important the complex and genomic for array analysis a of and when specimens are or are In have for genomic abnormalities in ALL and to risk and of therapeutic C.G. Goorha S. Radtke I. Miller C.B. Coustan-Smith E. Dalton J.D. Girtman K. Mathew S. Ma J. Pounds S.B. Su X. Pui C.H. Relling M.V. Evans W.E. Shurtleff S.A. Downing J.R. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia.Nature. 2007; 446: 758-764Crossref PubMed Scopus (1382) Google Scholar, 10Schwab C.J. Chilton L. Morrison H. Jones L. Al-Shehhi H. Erhorn A. Russell L.J. Moorman A.V. Harrison C.J. Genes commonly deleted in childhood B-cell precursor acute lymphoblastic leukemia: association with cytogenetics and clinical features.Haematologica. 2013; 98: PubMed Scopus Google Scholar, A.V. A. Schwab C. Chilton L. A. S. J. Kinsey S.E. Mitchell C.D. N. Vora A. Harrison C.J. integrated cytogenetic and genomic classification risk stratification in pediatric acute lymphoblastic PubMed Scopus Google Scholar, C.G. Su X. J. Radtke I. Miller C.B. Ma J. C. G. M. Relling M.V. Shurtleff S.A. Pui C.H. M. Downing J.R. of IKZF1 and prognosis in acute lymphoblastic leukemia.N Engl J Med. 2009; PubMed Scopus Google Scholar, L. A. M. A. E. K. of IKZF1 and are associated with poor prognosis in a of pediatric B-cell precursor acute lymphoblastic leukemia and Scopus Google Scholar, N. S. M. M. M. K. G. Miller J. M. M. of pediatric acute lymphoblastic by polymorphism genomic 2008; 111: PubMed Scopus Google Scholar these have routinely for ALL by clinical results of cytogenetics, and whole-genome array assays in 60 consecutive clinical ALL cases from a We found that array the detection rate of genomic abnormalities by cytogenetics and by and additional prognostic and therapeutic by cytogenetics and by cytogenetics, and results that whole-genome should be standard of for ALL in array analysis of standard clinical for patients with ALL. We cytogenetic, and array results for consecutive ALL cases from the at the of and consecutive patients had array results and had cytogenetic and/or analysis was in two patients with analysis was in patients with B-ALL and two patients with was by the at the of were from and/or standard with normal were analysis was probe including KMT2A ETV6-RUNX1 and for and for pediatric patients with B-ALL and and KMT2A for adults with B-ALL and most patients with of the array results were by analysis commonly in the clinical cytogenetics and results were to the for were a with the was from or the to the Genome-wide array analysis was the with approximately to the protocols L. Miller S. J. fluorescence in situ hybridization, and genomic array of leukemia with Full Text Full Text PDF Scopus Google Scholar array data were by the of two the and the number and were by genomic were on the of the were to of number in including the of genomic for and of number were from the results. or or including a clinically significant gene or the clinical significant and of are of 60 consecutive ALL cases were and in the for clinical array analysis. Among were from pediatric patients to were from adults to and were from adults to patients were B-ALL and abnormalities were found in of patients and abnormalities were found in of patients recurring abnormalities with clinical relevance were observed in 33 patients with abnormalities hyperdiploidy, KMT2A translocation, ETV6-RUNX1 intrachromosomal amplification of chromosome 21 near haploidy or low hypodiploidy, and additional nine B-ALL and cases had chromosome abnormalities with normal karyotype was observed in nine B-ALL and one B-ALL and the cases had normal results. B-ALL was inadequate for cytogenetic and ETV6-RUNX1 fusion was observed by analysis. cytogenetic results were for two patients with and one of was to have amplification by analysis array of and in 60 of case with fusion had ETV6-RUNX1 karyotype and/or with prognostic IKZF1 of three cases with had IKZF1 case with fusion had IKZF1 cytogenetics, and array recurring with clinical fluorescence in situ single-nucleotide case with fusion had ETV6-RUNX1 of three cases with had IKZF1 The case with fusion had IKZF1 in a fluorescence in situ single-nucleotide array results were observed in 60 ALL cases. aberrations with prognostic or therapeutic implication were found in cases. submicroscopic that involved the IKZF1 hyperdiploidy, low hypodiploidy or of low hypodiploidy, and the fusion genes CRLF2-P2RY8, ETV6-NTRK3, NUP214-ABL1, and SET-NUP214. Combining array results with those from chromosome and assays, the detection rate for clinically results increased from 56% to deletion of the IKZF1 gene was in B-ALL cases and The deletion from to and most had a In deletion of to or the gene was observed in three and deletion of to to to to and was observed in one case had two for the IKZF1 a deletion of and a deletion of to had deletion of to cases and had of on and the cases had of Among the cases with an IKZF1 deletion, five had a normal karyotype to two had to two had nonrecurring chromosomal abnormalities to one had the and nine had the to In the five cases with a normal karyotype, an IKZF1 deletion or with submicroscopic array aberrations was observed in each had a deletion of at results in of the gene to of a fusion gene with an IKZF1 deletion in the of are for sequencing to or For example, case had a fusion is with the nonrecurring translocation found by karyotype analysis of hypodiploidy with to or near to of low hypodiploidy was in B-ALL cases by array to and had a normal karyotype, whereas cases and had abnormal The array revealed that case had of to to and and for and to The were by analysis the and ETV6-RUNX1 genomic is with of a with had of to and with a with The karyotype of case was because of of the chromosome and of an additional chromosome in a The karyotype was array results that the of the chromosome was a chromosome that was by an translocation and case was with low hypodiploidy with had and by chromosome analysis. array the and the from the was in three B-ALL cases and and and had complex whereas case had a normal analysis the ETV6-RUNX1 amplification of in the of three the was by analysis in the two cases with a complex abnormal were observed for case the genomic of chromosome 21 has intrachromosomal amplification and deletion of chromosome 21 H.M. H. I. M. V. Harrison C.J. genomic alterations and gene in acute lymphoblastic leukemia with intrachromosomal amplification of chromosome A. 2006; PubMed Scopus Google Scholar with was by and had deletion of IKZF1 fusion genes were observed in two B-ALL and and five cases to had aberrations by including the IKZF1 deletion and an deletion at results in fusion had an additional for gene on chromosome by analysis the ETV6-RUNX1 at the of and analysis the revealed that were to chromosome array analysis of a at revealed including a of at with the of the gene and a of on chromosome with the the results a translocation an fusion genes were observed in five of the cases by had a amplification at with the and genes was by analysis the five to nine of were The amplification with these is with an fusion to and C. M. M. N. Harrison C.J. K. S. N. E. S. A. R.P. Moorman A.V. K. A. L. P. I. K. I. J. A. of amplification of the fusion gene in T-cell acute lymphoblastic 2009; PubMed Scopus Google Scholar had a deletion of the of chromosome by chromosome the array including the deletion and an deletion of at The deletion of to and a fusion SET-NUP214. had a complex karyotype with a with an and a with of the The array including a of with a and a of with a to the that the was in the had a deletion of a cytogenetic and case had a normal array an deletion of at in cases. The deletion in a of to of the gene and and to of and a two cases in of of and of by pediatric patients had hyperdiploidy with favorable by chromosome and analyses to The array results revealed with the karyotype in case and additional abnormalities in the cases. additional abnormalities deletion of and deletion of with deletion of in case and of and and and cases had by karyotype and/or that were in of the or KMT2A and one case each for with the and at the translocation were in the cases with and whereas the cases had no aberrations found at the translocation B-ALL with had an additional chromosome in 15% to of the by the additional chromosome was by analysis and array in two cases. these two cases and had fusion in the abnormal cells, with a and no chromosome and no number at or by array analysis. results that the additional were most abnormalities that to a have in ALL risk is the to that cytogenetic, and array results in the clinical of patients with B-ALL and to C.H. Evans W.E. Treatment of acute lymphoblastic leukemia.N Engl J Med. 2006; 354: 166-178Crossref PubMed Scopus (1543) Google Scholar, 2Moorman A.V. Ensor H.M. Richards S.M. Chilton L. Schwab C. Kinsey S.E. Vora A. Mitchell C.D. Harrison C.J. Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial.Lancet Oncol. 2010; 11: 429-438Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar, 3Toft N. Birgens H. Abrahamsson J. Bernell P. Griskevicius L. Hallbook H. Heyman M. Holm M.S. Hulegardh E. Klausen T.W. Marquart H.V. Jonsson O.G. Nielsen O.J. Quist-Paulsen P. Taskinen M. Vaitkeviciene G. Vettenranta K. Asberg A. Schmiegelow K. Risk group assignment differs for children and adults 1-45 yr with acute lymphoblastic leukemia treated by the NOPHO ALL-2008 protocol.Eur J Haematol. 2013; 90: 404-412Crossref Scopus (107) Google Scholar approximately 30% of pediatric and 50% of adult patients lack abnormalities with clinical relevance for prognosis by traditional cytogenetic analysis. In found 56% of patients with ALL with clinically abnormalities by chromosome and/or By whole-genome array the detection rate for clinically abnormalities increased to 75%. with the rate in a in approximately of childhood ALL cases a recurring chromosomal by or molecular C.G. The molecular genetic makeup of acute lymphoblastic leukemia.Hematology Am Soc Hematol Educ Program. 2012; 2012: 389-396PubMed Google Scholar The IKZF1 gene on chromosome the that and of J. K. with a that is independent of PubMed Scopus Google Scholar, L. and J Haematol. 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Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia: results of Southwest Oncology Group 9400 study.Blood. 2008; 111: 2563-2572Crossref PubMed Scopus (171) Google Scholar the of karyotypic analysis in of ALL. In chromosome aberrations in cases with a normal karyotype and two cases with no karyotypic results. the cytogenetic low hypodiploidy and hypodiploidy has a of and with and most commonly and chromosome 21 most hypodiploidy or near is associated with and poor V. M. S. S. A. C. lymphoblastic leukemia with low karyotype is a clinical and a of Scopus Google Scholar For the standard of detection is by to to the number of the most in or of on a abnormal chromosome 21 of five or C.J. J. A. M. J. S. of genetic abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: from the and of the J Haematol. 2010; PubMed Scopus Google Scholar, C.J. Moorman A.V. Schwab C. M. S. K. J. A. M. N. A. J. A. G. G. Chilton L. P. E. I. M. J. C. Vora A. of intrachromosomal amplification of chromosome 21 cytogenetic and PubMed Scopus Google Scholar array a of amplification and deletion chromosome H.M. H. I. M. V. Harrison C.J. genomic alterations and gene in acute lymphoblastic leukemia with intrachromosomal amplification of chromosome A. 2006; PubMed Scopus Google Scholar with have a poor outcome and rate when treated with standard treated in the is no significant in the outcome these with or C.J. on acute lymphoblastic leukemia a pediatric PubMed Scopus Google Scholar of is for the risk stratification and In the of cytogenetics and/or results with a probe for array analysis should be and submicroscopic number were found to be in the cases by array in 15% to of children with ALL the molecular that to are the and were in from patients with recurring C. C. M. V. V. S. J. A. J. S. P. A. M. J. of childhood acute lymphoblastic leukemia associated with risk Full Text Full Text PDF Scopus Google Scholar, K. C. A. C. G. M. A. M. A. M. A. C. G. and a in childhood acute lymphoblastic Scopus Google Scholar is associated with of or be found with and and additional the relevance of these additional abnormalities to the clinical In the array results the of fusion genes routinely in ALL with clinical implication for prognosis or NUP214-ABL1, ETV6-NTRK3, and The of these recurring fusion genes with of ALL. For example, and fusion genes are to in acute lymphoblastic leukemia.N Engl J Med. PubMed Scopus Google Scholar, cytogenetic in a patient with a T-cell acute lymphoblastic 2009; PubMed Scopus Google Scholar the of fusion is associated with to in and these patients have a poor A. A. A. A. A. E. A. H. C. N. H. E. V. is a fusion associated with in adult PubMed Scopus Google Scholar Current the of clinical for IKZF1 deletion in patients with ALL for and P. S.E. H.M. G. Litzow M. A. A.V. K. C. lymphoblastic Scholar multiplex ligation-dependent probe amplification is in for detection of IKZF1 deletion, the is gene and submicroscopic abnormalities of genomic array IKZF1 and number aberrations that are by chromosome analysis. the array is a to the chromosome and In that array risk stratification and for patients with ALL by additional abnormalities of clinical We that array be routinely applied at diagnosis of ALL. with