Abstract 1766: Distinct pattern of alterations in tp53 mutated and wild type acute myeloid leukemia (AML) patients
Authors: Ferrari Anna , Fonzi Eugenio , Fontana Maria Chiara , Rorà Andrea Ghelli Luserna Di , Manfrini Marco , Padella Antonella , Baldazzi Carmen , Papayannidis Cristina , Marconi Giovanni , Paolini Stefania , Guadagnuolo Viviana , Perricone Margherita , Robustelli Valentina , Imbrogno Enrica , Franchini Eugenia , Venturi Claudia , Zuffa Elisa , Abbenante Maria Chiara , Simonetti Giorgia , Testoni Nicoletta , Ottaviani Emanuela , Giovanni Martinelli 
Published: July 2017

Abstract
Background: Mutations in TP53 gene predict a poor prognosis in patients with AML. The reported TP53 mutation rate in AML is low (2.1%) by contrast AML with a complex karyotype (CK) is higher (69-78%) and have a poor outcome. Quite common is to found paired TP53 mutation together and a segmental 17p deletion.
Aims: To investigate the frequency, the types of mutations, the associated cytogenetic, the correlation with known molecular alterations and the prognostic role TP53 mutations in adult AML pts. Moreover we would identify genes/pathways that are mainly affected in the mutated TP53 group compared to the wt one.
Patients and Methods: 258 adult AML pts with miscellaneous cytogenetic abnormalities and normal karyotype were examined in our Institution for TP53 mutations using several methods, including Sanger sequencing, NGS and HiSeq2000 platform and were correlated with cytogenetic analysis. 124/258 samples were genotyped with SNP arrays (Affymetrix, 3 250K, 43 SNP 6.0, 78 CytoScan HD). Copy Number Alterations (CNAs) analyses were performed using Chromosome Analysis Suite (Affymetrix) and Nexus Copy Number (BioDiscovery) software.
Results: Mutation analysis detected TP53 mutations on 39 patients with 48 different types of mutations (32 deleterious point mutations; 4 deletions); nine pts have 2 mutations. We found 34/48 (70%) missense mutations, 5 mutations in the splice sites, 4 deletions ,2 intronic and and 3 others mutations. The mutation rate is of 15.1%. Mostly (28/39) of the TP53 mutated pts (71.8%) had CK while only 11/39 (28.2%) mutated pts have “no CK” (P&gt;0.0001). Alterations of TP53 were significantly associated with poor outcome (OS and EFS p&lt;0.0001). To take advantage of different methodological characteristics, on TP53 locus, we matched two software and cytogenetic analysis results. We identify 16 mutated pts that were also deleted and one pt that presented only a deletion. Therefore 50% of mutated pts present a concomitant deletion. OS of TP53 mutated and deleted pts is statistically inferior respect to muted pts (p&lt;0.0061). Comparing 32 TP53 mutated and 92 TP53 wt pts CNAs results that: a) chromosomes significantly alterated are 5q, 17p, 12p, 16q, 22q13.33 and 7q; b) over 900 genes are differentially involved (all in Loss); c) and that pathway categories mainly enriched are Signal Transduction, Metabolism, Immune System, Transmembrane transport of small molecules, Gene expression, Cell Cycle.
Conclusions: Our data demonstrated that TP53 mutations occur in 15.1% of AML with a higher frequency in the subgroup of CK-AML (p&lt;0.0001). They predicted to be deleterious and significantly correlated with worse prognosis especially if TP53 is both mutated and also deleted. For these reasons, TP53 mutation/deletion screening should be recommended. Different pattern of alterations in mutated and wt groups have to be deeper investigated. ELN, AIL, AIRC, progetto Regione-Università 2010-12 (L. Bolondi), FP7 NGS-PTL project.
Citation Format: Anna Ferrari, Eugenio Fonzi, Maria Chiara Fontana, Andrea Ghelli Luserna Di Rorà, Marco Manfrini, Antonella Padella, Carmen Baldazzi, Cristina Papayannidis, Giovanni Marconi, Stefania Paolini, Viviana Guadagnuolo, Margherita Perricone, Valentina Robustelli, Enrica Imbrogno, Eugenia Franchini, Claudia Venturi, Elisa Zuffa, Maria Chiara Abbenante, Giorgia Simonetti, Nicoletta Testoni, Emanuela Ottaviani, Martinelli Giovanni. Distinct pattern of alterations in tp53 mutated and wild type acute myeloid leukemia (AML) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1766. doi:10.1158/1538-7445.AM2017-1766