A novel insertion ins(18;5)(q21.1;q31.2q35.1) in acute myeloid leukemia associated with microdeletions at 5q31.2, 5q35.1q35.2 and 18q12.3q21.1 detected by oligobased array comparative genomic hybridization

2014-09-30 00:01:32

Molecular Cytogenetics; 19 SEPT 2014; DOI:10.1186/s13039-014-0063-x

Eigil Kjeldsen


In acute myeloid leukemia (AML) recurrent nonrandom chromosomal aberrations occur in approximately 55% of the patients. Until now about one hundred different
chromosomal rearrangements have been uncovered in AML. The rearrangements mostly include balanced translocations, inversions, deletions, amplifications, mono-
somies and trisomies. It is well established that cytogenetic analysis is an important prognostic factor that influences therapeutic decision-making and disease outcome because the various chromosomal rearrangements play critical roles in the molecular pathogenesis.

Myeloid malignancies are subdivided into distinct disease entities on the basis of specific cytogenetic or molecular genetic abnormalities. Cytogenetic char-
acterization defines three different risk groups: favorable, intermediate, and adverse. Molecular characterization has revealed that mutations in FLT3 and NPM1
define molecular subgroups with prognostic relevance. AML patients that do not fulfill WHO criteria for other categories are grouped together in the “AML, not otherwise specified (NOS)” category, which do not provide prognostic information. AML is a heterogeneous disease with respect to clinical and biological features. Hence, it is very important to better define less frequent chromosomal rearrangements in AML patients to identify the full spectrum of molecular prognostic factors.

Here we report the characterization of a novel cryptic insertion ins(18;5)(q21.1;q31.2q35.1) in a patient with de novo AML, who, as detected by oligobased high-
resolution array CGH (oaCGH) analysis, also harbored three concurrent submicroscopic microdeletions 5q31.2, 5q35.1q35.2, and 18q12.3q21.1 in his leukemic cells. Two previous AML patients with the translocation t(5;18)(q35;q21), and similar breakpoints as observed in our patient, have been reported. We review these patients and discuss the possibility that the ins(18;5) detected in our present patient is a variant of this rare non-random chromosomal abnormality t(5;18).

Case Presentation

A 37-year-old male Caucasian, previously well, presented with 4–5 weeks of fatigue, increasing paleness and dyspnea. In this period and on admission there were no febrilia, infections, or signs of bleeding except for one occasion of melaena 3 weeks prior to admission. He had an unintended weight loss of five kg from 91 kg. Bone marrow (BM) examination showed marked hypercellularity with medium-sized mononuclear blasts and an 80% proportion of highly proliferative blasts, staining CD4+, CD7+, CD13+, CD43+, CD117+, CD123+, CD34-, HLA-DR+, CD56-, and TdT-. Hematological examination included a total white blood cell count of 4.49 × 109/L, hemoglobin of 5.1 mmol/L and, platelets of 24 × 109/L. Segmented neutrophil count was 0.70 × 109/L. The patient’s father’s cousin and great grandmother in his mother’s line had leukemia. The patient had no comorbidity and had no previous history of being treated with chemotherapy or exposed to radiation. He had been smoking until 3 years prior to his AML diagnosis with an estimated pack years of 15. There was no information on possible occupational hazards.

Our patient entered the AML-17 treatment protocol (Trial reference ISRCTN55675535). This protocol is a randomized multi-arm Phase III study designed by the
AML Working Group of the National Cancer Research Institute (NCRI) and the Hematology Oncology Study Group in Acute Myeloid Leukemia and high risk Myelodysplastic Syndrome (MDS) in adults. In this interventional treatment protocol, AML and high risk MDS patients are randomized to one of five subgroups for induction therapy, then risk assessed, and randomized to FLT3 inhibitor if mutated or high risk chemotherapy with or without mTOR inhibition. According to the protocol our patient was initially treated with DA because of intermediate-risk cytogenetics. Molecular genetic analysis of his bone marrow cells at diagnosis showed an internal tandem duplication mutation in FLT3 (FLT3-ITD) and NPM1wt, and was then assigned to high-risk leukemia. He received FLAG-IDA treatment according to AML-17 and obtained complete remission 28 days after admission as evaluated by pathology, flowcytometry, cytogenetics and molecular genetics.

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Key Words

Acute myeloid leukemia | ins(18;5) | oaCGH analysis | Chromosomal insertion | Microdeletion | Cryptic chromosomal aberration | del(5q) | add(18q)