Distinct Patterns of Genomic Alterations in Adult T-Cell Leukemia-Lymphoma Endemic in the Western World
Authors: Pimentel Agustin , O'Hara Andrea , de Lima Rosangela , Xu Suying , Toomey Ngoc , Brites Carlos , Fan Yao-Shan , Ramos Juan Carlos 
Published: October 2019

Abstract
Introduction: Acute T-cell leukemia/lymphoma (ATLL) is a highly aggressive malignancy caused by HTLV-I, which is endemic in Japan, the Caribbean, and South America. ATLL carries a dismal prognosis and is generally incurable with conventional chemotherapy. ATLL is challenging to study at the molecular level, in part due to its complex genetic alterations likely resulting from years of HTLV-I driven T-cell proliferation and accumulation of genetic damage prior to malignant transformation. While no specific chromosome or genetic abnormalities have been proven to contribute to the pathogenesis of ATLL, older comparative genomic hybridization (CGH) studies performed in Japanese patients have demonstrated frequent genetic lesions (gains and losses) involving specific chromosomal regions, thus limited information exists about the chromosomal abnormalities occurring in the African ATLL variant commonly seen in the Western World.
Methods: In this study, we used a high-density oligo array 244K platform CGH platform (Agilent Technologies) with an average resolution of 8.9 Kb, to perform a comprehensive genomic analysis of 47 ATLL patient tumor specimens obtained from African-descendants in the United States, Caribbean and Brazil. Patients were sub-classified as acute-type (A) ATLL (n=31), lymphomatous (L) (n=8), chronic (n=7, six whom had unfavorable features), and one with smouldering type according to Shimoyama criteria. DNA samples were extracted from peripheral blood mononuclear cells or tumor samples from these patients and checked for quality.
Results: ATLL tumors exhibited complex genomic abnormalities and high copy number changes (CNCs). The average of copy number (CN) aberrations per sample was 238 in the L-group vs. 114 in acute/unfavorable chronic (A/UC) group. However, many chromosomal alterations were observed in this cohort, which had not been previously reported by other studies. The common CNCs were gains at 1q21-q44, 3, 3p, 7q22-q36, 8, 18, 19p13.1-p13.3, 21q21.1-q22.3, 22q12-q13 and losses at 5q13.2-q32, 6q11-q15, 9q13-q21. Gains in the 14 q32 (IGH) regions and losses in the 7p14.1 (TCRG), 7q34 (TCRB) and 14q11.2 (TCRA) regions involving small DNA segments were frequently observed. Genomic losses involving at least one or more known or candidate tumor suppressor genes were found in nearly all tumors, including some genes not previously implicated in ATLL. Some of the most significant gene or locus specific losses occurring in at least 20 % of the tumors in aggressive ATLL subtypes (A/UC and L) are summarized in Table 1. Losses of CDKN2A and CDKN2B tumor suppressor genes have been previously implicated in ATLL and other cancers. Several other genes found by this analysis have been implicated in apoptosis or cancer (i.e. CBLB, ANKRD11, IKZF1, and EPC1). IMMP2L deletion was associated with shorter survival time (2.3 weeks) compared with those cases without this gene deletion (29 weeks) in the A/UC group (p=0.005). ANKRD11 homo- or heterozygous deletions were seen in 37% of L-type and 19% of acute-type cases, and were associated with a shorter survival (13 vs. 43 weeks, p=<0.05) in the A group. CPN2/LRRC15 locus gains in 32% of A-type were linked to poorer survival (16 vs. 42 weeks, p=0.05).
Table 1. GENE FUNCTION LOSSES (n) GAINS (n) NRXN3 Membrane receptor, cell adhesion 23 A/UC 3 L NS IMMP2L Mitochondrial inner membrane peptidase 16 A/UC* 5 L 4 A/UC CDKN2A/ CDKN2B (P16INK4/p15INK4b) Cyclin-dependent kinase inhibitors, tumor suppressors 16 A/UC 2 L 1 A/UC 1 L CBLB E3 ubiquitin protein ligase 12 A/UC 1 L NS ANKRD11 Transcriptional inhibitor, co-activator of p53 6 A/UC* 3 L NS CPN2 Carboxypeptidase NS 10 A/UC* 2 L IKZF1 Zinc-finger DNA binding proteins , lymphocyte differentiation NS 6 A/UC 3 L INSIG1 Endoplasmic reticulum membrane protein, intracellular lipid metabolism NS 10 A/UC 1 L EPC1 Member of the polycomb group family, transcriptional activator and repressor 10 A/UC 2 L NS
* are genomic imbalances associated with a statistically significant reduction in survival. NS: non-significant.
Conclusion: In sum, using a high resolution CGH array we observed distinct patterns ofgenetic aberrations in ATLL endemic in the Western World. We have successfully narrowed the genomic regions containing potential candidate genes that could be relevant to the pathogenesis of this fatal disease. Functional studies are required to determine the role of some of these genes in the pathogenesis of ATLL.

Disclosures
O'Hara: BioDiscovery, Inc.: Employment.