title: Molecular profiling of gene copy number abnormalities in key regulatory genes in high-risk B-lineage acute lymphoblastic leukemia: frequency and their association with clinicopathological findings in Indian patients.
abstract: Genes related to key cellular pathways are frequently altered in B cell ALL and are associated with poor survival especially in high-risk (HR) subgroups. We examined gene copy number abnormalities (CNA) in 101 Indian HR B cell ALL patients and their correlation with clinicopathological features by multiplex ligation-dependent probe amplification. Overall, CNA were detected in 59 (59%) cases, with 26, 10 and 23% of cases harboring 1, 2 or +3 CNA. CNA were more prevalent in BCR-ABL1 (60%), pediatric (64%) and high WCC (WBC count) (63%) patients. Frequent genes deletions included CDNK2A/B (26%), IKZF1 (25%), PAX5 (14%), JAK2 (7%), BTG1 (6%), RB1 (5%), EBF1 (4%), ETV6 (4%), while PAR1 region genes were predominantly duplicated (20%). EBF1 deletions selectively associated with adults, IKZF1 deletions occurred frequently in high WCC and BCR-ABL1 cases, while PAR1 region gains significantly associated with MLL-AF4 cases. IKZF1 haploinsufficiency group was predominant, especially in adults (65%), high WCC (60%) patients and BCR-ABL1-negative (78%) patients. Most cases harbored multiple concurrent CNA, with IKZF1 concomitantly occurring with CDNK2A/B, PAX5 and BTG1, while JAK2 occurred with CDNK2A/B and PAX5. Mutually exclusive CNA included ETV6 and IKZF1/RB1, and EBF1 and JAK2. Our results corroborate with global reports, aggregating molecular markers in Indian HR B-ALL cases. Integration of CNA data from rapid methods like MLPA, onto background of existing gold-standard methods detecting significant chromosomal abnormalities, provides a comprehensive genetic profile in B-ALL.
authors.affiliation: Research and Development Division, Molecular Pathology, Clinical Research Services, SRL Limited, Plot No.1, Prime Square Building, S.V. Road, Goregaon (W), Mumbai, 400062, India.
authors.forename: Prerana
authors.initials: P
authors.lastname: Bhandari
authors.affiliation: Research and Development Division, Molecular Pathology, Clinical Research Services, SRL Limited, Plot No.1, Prime Square Building, S.V. Road, Goregaon (W), Mumbai, 400062, India.
authors.forename: Firoz
authors.initials: F
authors.lastname: Ahmad
authors.affiliation: Research and Development Division, Molecular Pathology, Clinical Research Services, SRL Limited, Plot No.1, Prime Square Building, S.V. Road, Goregaon (W), Mumbai, 400062, India. brdas@srl.in.
authors.forename: Bibhu Ranjan
authors.initials: BR
authors.lastname: Das
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D002648:Child; D002675:Child, Preschool; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D020869:Gene Expression Profiling; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics; D007194:India; D007223:Infant; D008297:Male; D008875:Middle Aged; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D055815:Young Adult
chemical_list: C497239:IKZF1 protein, human; D051740:Ikaros Transcription Factor
keywords: Copy number abnormalities (CNA); High-risk B-ALL; IKZF1; MLPA