Impact of TP53 gene variants on prognosis and survival of childhood acute lymphoblastic leukemia

Abstract

The tumor suppressor protein 53 (TP53) gene is one of the most studied genes in cancer. Although TP53 variants are rare events in acute leukemia, recent observations showed that relapse samples might harbor TP53 variants. Here, we aimed to determine TP53 variants (hotspot region, exon 4–11) in childhood acute lymphoblastic leukemia (B and T-ALL) patients (n = 94) including diagnostic-relapse pairs (n = 15) by amplicon sequencing and evaluate the clinical impact of these variants. In total, nine different (E298*, R283C, R273H, L252F, C229F, I195T, E286G, c.955_956insC, and c.920-1G > C) variants were identified in 17 (18%) childhood ALL patients. c.(920-1G> C) splice site variant and c.(955_956insC) insertion were reported for the first time. In diagnose-relapse pair samples, we identified acquired and/or loss of TP53 variants in the samples at the time of relapse. TP53 variants were found to be more common in T-ALL (37%) than in B-ALL patients (9%). Pathogenic TP53 variants were associated with a shorter overall survival time (p = 0.001).TP53 variants were found to be associated with inferior outcomes in our cohort and can be an independent risk factor for poor prognosis in childhood acute leukemia patients. Identification of low-frequent variants with next-generation sequencing approaches enables better knowledge of the clonal dynamics of ALL.

Keywords:

• TP53
• Next Generation Amplicon Sequencing
• B-ALL
• T-ALL
• prognosis

Acknowledgements

Concept: M.S., O.H.N., Y.E., U.O., S.F. Data collection or processing: S.K., Z.K., T.T.C., S.A.G., Y.Y., S.F., O.H.N. Analysis or interpretation: M.S., O.H.N., Y.E., U.O., S.F. Literature review: M.S., O.H.N., Y.E., U.O., S.F. Writing: S.F., M.S., O.H.N., Y.E. .

Authorship contributions

Concept: M.S., O.H.N., Y.E., U.O., S.F. Data collection or processing: S.K., Z.K., T.T.C., S.A.G., Y.Y., S.F., O.H.N. Analysis or interpretation: M.S., O.H.N., Y.E., U.O., S.F. Literature review: M.S., O.H.N., Y.E., U.O., S.F. Writing: S.F., M.S., O.H.N., Y.E.

Ethics committee approval

The study was approved by the local ethics committee and conducted in accordance with the Declaration of Helsinki.

Patient consent

The patient consent form was signed and obtained from all the participants of the study.

Disclosure statement

No conflict of interest was declared by the authors.

Additional information

Funding

This study was funded by Scientific Research Project Coordination Unit of Istanbul University (Project No:34101 and TDP-2016-20520).