COPY NUMBER ALTERATIONS ASSOCIATED WITH HYPERDIPLOIDY IN CHILDHOOD WITH B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA

Abstract

Introduction: : The presence of genetic alterations is widely used to stratify B-cell precursor Acute Lymphoblastic Leukemia (BCP-ALL) treatment. The most common cytogenetic abnormality in BCP-ALL is hyperdiploidy (good prognosis) which can be classified as low or near-hyperdiploidy (47-49 chromosomes) and high hyperdiploidy (HeH, more than 50 chromosomes). However, the presence of secondary abnormalities, such as copy number alterations (CNA), associated with a hyperdiploid karyotype may alter the prognosis. Objective: : The aim of this study was to analyze the frequency of hyperdiploidy associated with CNA in a cohort of BCP-ALL patients. Material and methods: : Forty-nine bone marrow samples of BCP-ALL patients were tested with conventional karyotype, and the DNA undergone to the MLPA SALSA Probemix P036 to detect aneuploidies and to MLPA SALSA Probemix P335 to identify specific gene deletions and amplifications. Results: Most patients were aged less than 6 years-old (31/49). The molecular cytogenetic showed that 35/49 (71,4%) cases had low hyperdiploidy and the minority had high hyperdiploidy (28,6%). The presence of somatic trissomies of chromosome 21 was frequent. However, amplifications were observed in CDKN2A/B (5/49), EBF1 (11/49), IKZF1 (3/49), PAX5 (11/49), JAK2 (1/49), ETV6 (7/49), BTG1 (4/49), RB1 (1/49), CRLF2 (10/49) and PAR1 region (31/49). Deletions were observed in CDKN2A/B (7/49), EBF1 (1/49), IKZF1 (4/49), PAX5 (7/49), JAK2 (1/49), ETV6 (2/49) and RB1 (2/49). Discussion: : According to the literature, the most frequent deletions present in hyperdiploidy occurs in IKZF1 , CDKN2A/B , PAX5 and ETV6 genes. Besides, these genes play a key role in B-cell development or cell cycle regulation. However, amplifications are not frequently reported. Deletions in genes present in the PAR1 region (CRLF2 , IL3RA , CSF2RA and P2RY8 ) are often associated with the genetic fusion P2RY8::CRLF2 . Although, the most frequent amplifications observed in our study were present in PAR1 region, PAX5 and EBF1 . Also, the investigation of CNAs is relevant since further studies revealed that patients with hyperdiploid karyotypes and deletions in IKZF1 gene were associated with a higher MRD and resistance to prednisone and L-asparaginase. Conclusion: : In this study, we showed the importance of molecular methods to characterize the genetic alterations in pediatric patients with BCP-ALL to aid in prognosis and in treatment choice. Supported by: FAPERJ, Ministério da Saúde - INCA.