Abstract 656: Distinct pattern of alterations in TP53 mutated/deleted and wild-type high risk acute myeloid leukemia (AML) patients: Identification of new "targetable" genes/pathways
Authors: Ferrari Anna , Fonzi Eugenio , Rorà Andrea Ghelli Luserna Di , Fontana Maria Chiara , Manfrini Marco , Baldazzi Carmen , Papayannidis Cristina , Solli Vincenza , Padella Antonella , Marconi Giovanni , Paolini Stefania , Robustelli Valentina , Imbrogno Enrica , Franchini Eugenia , Margherita Perricone , Abbenante Maria Chiara , Simonetti Giorgia , Testoni Nicoletta , Ottaviani Emanuela , Cavo Michele , Martinelli Giovanni 
Published: August 2018

Abstract
Background: The reported TP53 mutation rate in AML is relatively low (7.5-9%, TCGA) and predict a poor prognosis. In 2017 European LeukemiaNet recommended for AML to add TP53 mutations (muts) in the risk stratification. Specific chromosomal aneuploidies are closely correlated with each other and with presence of TP53 muts. Aims: Considering that TP53 mut AML pts have HRisk and no target therapy, we would identify genes/pathways that are mainly CNA-affected (Copy Number Alteration) in the mut TP53 group compared to the wt one. Patients and Methods: 358 adult AML pts were screened for TP53 muts. 219/358 samples were genotyped with SNP arrays. CNA analyses were performed using two software to confirm or integrate karyotype data. Fisher's exact test and pathway enrichment analyses were performed. Results: We detected TP53 muts in 52/358 (14.5%) pts. Mostly (34/52) of the TP53 mut pts (65.4%) had complex karyotype. TP53 alterations were significantly associated with poor outcome (OS and EFS p&lt;0.0001). On TP53 locus, we matched CNA and cytogenetic analyses results. We identify 23 mutated pts that were also deleted (alt) and 7 pts that presented only a TP53 deletion. Therefore 44.2% of mut pts present a concomitant deletion. OS of TP53 alt pts is not statistically inferior respect to mut pts (p=0.77). Comparing 52 TP53 alt and 167 TP53 wt pts CNAs results that: a) chrs significantly altered are 5q and 17p but there are also highly significant »Spot» losses (7q, 20p, 21q, 22q, 19q); b) TP53 CNAs are present in the 44% of TP53 alt vs 0.63% of wt pts; c) over 9013 genes are differentially involved (mainly in Loss, 93.1%); d) that pathway categories mainly enriched are Immune System, Metabolism, Signal Transduction; e) TP53 deletion seems less deleterious (in terms of OS) than TP53 mutation or TP53 alt; f) some TP53 protein-protein interacting genes like SKP1, CDK5, PPP2CA, CSNK1G3 and STAT5B are highly altered and drug target. Conclusions: TP53 muts with or without deletion were predicted to be deleterious and significantly correlated with worse prognosis. For these reasons, TP53 mutation/deletion screening should be recommended. Different alterations groups have been identified in terms of genes, pathway enrichment and protein-protein interaction between ALT and Wt; needed a deeper investigation to better focus on few targetable nodes of this complex network. Three groups comparison (Wt,TP53 Mut,TP53 MutDel pts) analyses would give us the opportunity to select a more appropriate target therapy in these pts. Different pattern of alterations in alt and wt groups have to be deeper investigated to discover targetable nodes of this complex network. ELN, AIL, AIRC, PRIN, Regione-Università 2010-12 (L. Bolondi), FP7 NGS-PTL; HARMONY.
Citation Format: Anna Ferrari, Eugenio Fonzi, Andrea Ghelli Luserna Di Rorà, Maria Chiara Fontana, Marco Manfrini, Carmen Baldazzi, Cristina Papayannidis, Vincenza Solli, Antonella Padella, Giovanni Marconi, Stefania Paolini, Valentina Robustelli, Enrica Imbrogno, Eugenia Franchini, Perricone Margherita, Maria Chiara Abbenante, Giorgia Simonetti, Nicoletta Testoni, Emanuela Ottaviani, Michele Cavo, Giovanni Martinelli. Distinct pattern of alterations in TP53 mutated/deleted and wild-type high risk acute myeloid leukemia (AML) patients: Identification of new "targetable" genes/pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 656.