Institution: Montefiore Medical Center
Additional authors:Rizwan Naeem, Christine McMahon, Amit Verma
Session: Therapy-related myeloid neoplasms
HISTORY
A 69 year old Asian female with prior exposure to Agent Orange during the Vietnam War presented with low grade fever and ecchymoses. She was pancytopenic with WBC of 2,900/µL, Hgb of 9.5 g/dL, and platelet count of 20,000/µL. Bone marrow biopsy showed myelodysplastic syndrome (MDS) with increased blasts and a complex karyotype.
DETAILS
Bone Marrow Biopsy - 10% buffered formalin fixed, formic acid-decalcified
Hypercellular marrow (80-90%) with increased blasts and slightly increased monolobated megakaryocytes, consistent with myelodysplastic syndrome (refractory anemia with excess blasts – 2).IMMUNOHISTOCHEMISTRY AND FLOW CYTOMETRY
10-15% CD34+ and/or CD117+ hematopoietic precursor cells are identified by immunostains and flow cytometry. CD61+ small and large, hypolobated, and polylobated megakaryocytes are increased.
CYTOGENETIC FINDINGS
There are multiple numerical and structural anomalies in 19/20 cells, including an interstitial deletion of the long arm of chromosome 5, a homogeneously staining region of 11q23, and monosomy 18. By FISH, EGR1 (5q31) is deleted in 90% of cells, and MLL is amplified in 50% of cells. Metaphase FISH reveals BCR is translocated to the long arm of an unknown chromosome.
MOLECULAR FINDINGS
Agilent 44k oligonucleotide microarray analysis – A large region on chromosome 11q is comprised of adjoining segments with alternating copy number increases and decreases. The copy number increases in 3 segments [.26, .30, .29] are similar. The copy number decreases in 4 segments [.73, .76, .89, .71] are also similar. (Copy number data is in modified logarithmic form.) Two other segments on chromosome 11q are amplified, one of which contains MLL. In addition to chromosome 11q changes, the majority of cells appear to have a large interstitial deletion of 5q, monosomy 18, and a small interstitial deletion of 22q11.1.
INTERESTING FEATURES
Array comparative genomic hybridization (aCGH) shows multiple adjacent segments alternating between copy number gains and losses on chromosome 11q. Three segments of copy number gains are compatible with duplications at 40% mosaicism in the cell population tested. Four segments of copy number losses are compatible with deletions at 80% mosaicism. Independent genomic rearrangements would unlikely account for these findings. Recently, chromothripsis has been described, which involves catastrophic shattering of a localized genomic region followed by disordered rejoining of some segments and loss of other segments (Ref 1). The localization of multiple copy number changes to chromosome 11q has some semblance of chromothripsis. However chromothripsis has not been characterized in the context of mosaic cell populations. One possible scenario which fits our aCGH findings is the presence of two abnormal and genetically distinct populations (each 40% of cellularity) containing 4 segmental deletions alternating with 3 normal segments and 4 segmental deletions alternating with 3 segmental duplications. The first population would have a genomic structure compatible with chromothripsis. The second population would have a genomic structure compatible with chromoanasynthesis, which has similar molecular findings as chromothripsis, but is characterized by an inherent DNA replicative and repair process, and allows for duplications, triplications, amplifications, as well as greater than 2 copy number states (Ref 2). Massive parallel sequencing may confirm our theory of two abnormal cell populations and provide valuable insight to understand the mechanism of the complex structural rearrangements in this case.
Ref:1. Stephens, PJ et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell. 2011 Jan 7;144(1):27-40. 2. Liu, P et al. Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements. Cell. 2011 Sep 16;146(6):889-903.PROPOSED DIAGNOSIS
MDS with complex cytogenetic rearrangements possibly containing features of both chromothripsis and chromoanasynthesis.
CONSENSUS DIAGNOSIS
Myelodysplastic syndrome with complex cytogenetic abnormalities, in a patient with a remote history of Agent Orange exposure