Abstract
BackgroundIntrachromosomal amplification of chromosome 21 (iAMP21) results from breakage-fusion-bridge cycles and chromothripsis is a distinct marker of a subgroup of B cell acute lymphoblastic leukemia (B-ALL) cases associated with a poor prognosis. iAMP21 accounts for 2% of pediatric B-ALL and occurs predominantly in older children or adolescents. ETV6-RUNX1 fusion, resulting from t(12;21)(p13;q22), is associated with an excellent outcome in younger children with B-ALL. Coexistence of iAMP21 with ETV6-RUNX1 fusion is extremely rare with limited clinical information available.ResultsWe report the case of an 18-year old Caucasian man diagnosed with ETV6-RUNX1 fusion positive B-ALL. He was treated with intensive chemotherapy and achieved remission for 6 months before relapse, 15 months after the initial diagnosis. G-band karyotyping and Fluorescence in situ hybridization (FISH) analyses performed on bone marrow revealed complex abnormalities: 41,X,-Y,der(3)t(3;20)(p11.2;q11.2),-4,t(5;22)(q32;q11.2),del(9)(p13),dic(9;17)(p13;p11.2),t(12;21)(p13;q22),der(14)t(14;17)(p11.2;q11.2),der(17;22)(q11.2;q11.2),-20,add(21)(q22),-22[4]/46,XY[15] with an iAMP21 and an ETV6-RUNX1. Additional molecular studies confirmed ETV6-RUNX1 fusion and with a TP53 mutation. High-resolution single nucleotide polymorphism microarray (SNP array) revealed the iAMP21 to be chromothripsis of 21q and subsequent metaphase FISH further delineated complex genomic aberrations. Although the patient received intensive chemotherapy with allogenic stem cell transplant, he died 26 months after initial diagnosis. We searched the literature and identified six cases showing coexisting iAMP21 and ETV6-RUNX1. The median age for these six patients was 10 years (range, 2–18) and males predominated. The median overall survival (OS) was 28 months.ConclusionsPatients with B-ALL associated with both iAMP21 and ETV6-RUNX1 tend to be older children or adolescents and have a poor prognosis.
Highlights
Intrachromosomal amplification of chromosome 21 results from breakage-fusion-bridge cycles and chromothripsis is a distinct marker of a subgroup of B cell acute lymphoblastic leukemia (B-ALL) cases associated with a poor prognosis. iAMP21 accounts for 2% of pediatric B-ALL and occurs predominantly in older children or adolescents
The latest revision to the World Health Organization (WHO) classification of B-cell lymphoblastic leukemia/ lymphoma (B-ALL) has added B-ALL with intrachromosomal amplification of chromosome 21 as an entity in the group of B-ALL with recurrent genetic abnormalities [1]. iAMP21 is a distinct marker that can be readily detected by metaphase Fluorescence in situ hybridization (FISH) [2] and is caused by breakage-fusion-bridge cycles and chromothripsis, which is a phenomenon reported in cancer genomes, resulted from tens to hundreds of genomic rearrangements occur in a cellular crisis
We describe a patient with B-ALL associated with both iAMP21 with ETV6-RUNX1 that we have characterized extensively by using molecular and cytogenetic methods
Summary
Intrachromosomal amplification of chromosome 21 (iAMP21) results from breakage-fusion-bridge cycles and chromothripsis is a distinct marker of a subgroup of B cell acute lymphoblastic leukemia (B-ALL) cases associated with a poor prognosis. iAMP21 accounts for 2% of pediatric B-ALL and occurs predominantly in older children or adolescents. Intrachromosomal amplification of chromosome 21 (iAMP21) results from breakage-fusion-bridge cycles and chromothripsis is a distinct marker of a subgroup of B cell acute lymphoblastic leukemia (B-ALL) cases associated with a poor prognosis. IAMP21 is a distinct marker that can be readily detected by metaphase FISH [2] and is caused by breakage-fusion-bridge cycles and chromothripsis, which is a phenomenon reported in cancer genomes, resulted from tens to hundreds of genomic rearrangements occur in a cellular crisis. Patients with iAMP21 often show low platelet and low white blood cell counts (WBC) [5–8]. These patients have a relapse rate that is three times higher than other B-ALL patients are and patients often require intensified therapy, in older children or adolescents with B-ALL [9]
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