title: Risk stratification of T-cell Acute Lymphoblastic Leukemia patients based on gene expression, mutations and copy number variation.
abstract: Gene expression, copy number variations (CNV), mutations and survival were studied to delineate TCRγδ+T-cell acute lymphoblastic leukemia (T-ALL) as a distinct subgroup from TCRαβ+T-ALL. Gene Ontology analysis showed that differential regulation of genes involved in pathways for leukemogenesis, apoptosis, cytokine-cytokine receptor interaction and antigen processing/presentation may offer a survival benefit to TCRγδ+T-ALL patients. Genes involved in disease biology and having equal expression in both the subgroups, were further analysed for mutations and CNV using droplet digital PCR. TCRγδ+T-ALL patients exhibited differential level of mutations for NOTCH1 and IKZF3; however BRAF mutations were detected at equal levels in both the subgroups. Although TCRγδ+T-ALL patients with these mutations demonstrated improved disease-free survival (DFS) as compared TCRαβ+T-ALL patients, it was not statistically significant. Patients with homozygous deletion of CDKN2A/CDKN2B showed poor DFS in each subgroup. TCRγδ+T-ALL patients with wild type/heterozygous deletion of CDKN2A/CDKN2B possess significantly better DFS over TCRαβ+T-ALL patients (p=0.017 and 0.045, respectively). Thus, the present study has for the first time demonstrated TCRγδ clonality and CDKN2A/CDKN2B CNV together as potential prognostic markers in management of T-ALL. Further understanding the functional significance of differentially regulated genes in T-ALL patients would aid in designing risk based treatment strategies in subset specific manner.
authors.affiliation: Chiplunkar Lab, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India.
authors.forename: Gauri
authors.initials: G
authors.lastname: Mirji
authors.affiliation: Chiplunkar Lab, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India.
authors.forename: Jaydeep
authors.initials: J
authors.lastname: Bhat
authors.affiliation: Chiplunkar Lab, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Kode
authors.affiliation: Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India.
authors.forename: Shripad
authors.initials: S
authors.lastname: Banavali
authors.affiliation: Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India.
authors.forename: Manju
authors.initials: M
authors.lastname: Sengar
authors.affiliation: Bio-Rad Laboratories India Pvt. Ltd., Mumbai, India.
authors.forename: Prashant
authors.initials: P
authors.lastname: Khadke
authors.affiliation: Bio-Rad Laboratories India Pvt. Ltd., Mumbai, India.
authors.forename: Osama
authors.initials: O
authors.lastname: Sait
authors.affiliation: Chiplunkar Lab, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India. Electronic address: schiplunkar@actrec.gov.in.
authors.forename: Shubhada
authors.initials: S
authors.lastname: Chiplunkar
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D056915:DNA Copy Number Variations; D005260:Female; D015870:Gene Expression; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000145:classification / Q000175:diagnosis* / Q000235:genetics*; D011379:Prognosis; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis; D018570:Risk Assessment; D055815:Young Adult
chemical_list: C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016692:Receptors, Antigen, T-Cell, gamma-delta
keywords: Copy number variation; Droplet digital PCR; Gene expression profiling; Mutations; T-ALL; TCRγδ+T-ALL