89. Clinical implications of chromothripsis in hematological malignancies: A case series

Chromoanagenesis is a chromosomal event that results in the shattering and reassembly of one or more chromosomes. The most common form of chromoanagenesis is chromothripsis, a hallmark in most human cancers. chromothripsis is defined as random restructuring of shattered chromosomal segments resulting in complex structural rearrangements, duplications, deletions, gene fusions, amplification, and loss of tumor suppressor genes. This phenomenon has been described as a potential macroevolution schema for cancer cells. We present here a summary of the most clinically relevant genomic aberrations, with particular focus on copy number aberrations in a case series that highlight chromothripsis in two pediatric B cell-Acute lymphoblastic leukemia (B-ALL) and one adult diffuse large B cell lymphoma, not otherwise specified (DLBCL, NOS). Case 1: 2-year-old male with increased fevers, bruising, thrombocytopenia, and neutropenia. Bone marrow (BM) biopsy and FLOW showed hypercellular marrow an abnormal B lymphoblast population (61%). Case 2: 3-year-old male with bruising and thrombocytopenia. BM biopsy and Flow cytometry showed packed marrow with abnormal B-lymphoblasts (77%). Case 3: 26-year-old male with relapsed Hodgkin lymphoma presented with lytic lesions, and cytopenia. BM biopsy showed markedly hypercellular marrow (>95% cellular) with atypical lymphocytes consistent with germinal center B-cell type DLBCL, NOS, involving multiple sites including bone, bone marrow, lymph nodes, nasopharynx, kidney, and spleen. All cases had complex karyotypes with distinct abnormalities. Case 1: had two subclones: one with monosomy 7, the other with del(7q); multiple deletions (7p, 9p, 16p), and a dic (9;16) and multiple losses along the length of chromosome 18. Karyotype: 45,XY,dic(9;16)(p13;q11.2),abn(18)[3]/44,sl,-7[3]/45,sdl1,del(7)(q22)[3]/46,XY[11]​. Case 2: Highly complex and multiple losses along the length of chromosome 3, der(7)t(3;7), and der(5)del(5q). Karyotype: 46,XY,-3,+5,der(5)del(5)(q31.3q32)del(5)(q34q35.1),der(5)del(5)(q31.3q32)del(5)(q34q35.1),der(7)t(3;7)(p11.2;?q32)[15]/46,XY[5]. Both cases achieved remission with standard-risk chemotherapy. Case 3: exhibited a complex karyotype (43∼46,XY, -2,add(3)(p25),add(8)(p21),add(11)(q23),add(13)(q34),add(18)(q23)[cp14]/46,XY). SNP array and FISH confirmed BCL2 and KMT2A amplification, and cn-LOH of TP53 . The patient developed secondary AML, refused treatment and was deceased in late 2022. Research from pan-cancer sequencing along with other studies on chromothripsis described that crucial mechanistic insights into the initiation of chromothripsis is due to errors in chromosome segregation and the study highlights the association of chromothripsis with functional loss of TP53. Copy number alterations mediated by chromosomal segmental deletions and duplications may affect gene expression patterns through dosage imbalances, disruption, fusion, and change in cis/trans-regulatory sequences. The cases described here highlight the deregulation of various oncogenic targets affecting specific pathways that contribute to the molecular pathogenicity of the disease entity. This could be attributable to chromothripsis with complex CNVs of multiple chromosomes, suggesting chaotic events from defective cell cycle progression and double-strand breaks, leading to poor clinical outcomes. However, larger cohort studies are needed for risk stratification and personalized treatment strategies.