Abstract 3582: Chromothripsis in AML patients: A new mechanism of cancer initiation and progression
Authors: Fontana Maria Chiara , Guadagnuolo Viviana , Papayannidis Cristina , Marconi Giovanni , Simonetti Giorgia , Padella Antonella , Manfrini Marco , Santacroce Barbara , Perricone Margherita , Lo Monaco Silvia , Ottaviani Emanuela , Soverini Simona , Cavo Michele , Martinelli Giovanni 
Published: July 2016

Abstract
Introduction: Genomic rearrangements can drive the development of cancer through different mechanisms: chromothripsis, a catastrophic mechanism of genomic instability, could be relevant for hematological disease.
Aim: To discover the mechanisms underlying the pathogenesis of Acute Myeloid Leukemia (AML), we studied chromothripsis in our cohort of patients (pts).
Methods: We perform SNP Array 6.0 or Cytoscan HD Array (Affymetrix) in a cohort of 104 AML pts at diagnosis. SNP Array data were analyzed by Nexus Copy Number™ v7.5 (BioDiscovery).
Results: Seven/104 pts (6.7%) showed chromothripsis events involving different chromosomes (8, 17, 11, 5 and 16). These pts had median age of 68.5 years (range 56-76), complex karyotype and high risk disease according to ELN definition. Among the pts showing chromothripsis, we compared chromosomic abnormalities of pts with de novo (5/7) and secondary (2/7) AML. De novo AML showed a prevalence of trisomy of chromosome 8 in a non-statistical way (4/5 vs 0/2), due to the low number of cases. However, we identified significant differences in the pattern of genes altered in the two groups. De novo AML had copy number gain of PEX1, ANK1, NCOA2, ESRP1, TPD52, ESRP1, ZFPM2 and MITF (p &lt;0.047). In the secondary AML group we detected amplification of APC and deletions of FOXO1 and APP (p &lt;0.047)with enrichment of WNT signaling pathway proteins (p &lt;0.001). The pathways recurrently targeted by chromosomal alteration in de novo AML pts were protein acetylation, transcription factor and histone acetiltrasferase (p &lt;0.001). Moreover, by comparing pts with and without chromothripsis, we identified several genes differentially altered between the 2 groups (p&lt;0.001), including deletion of CYFIP2, TBCA, CRHBP, FNDC9, IQGAP2, TUB3 and GAS8 and amplification of ZFPM2 in pts with chromothripsis, with 5q being the main altered chromosomic region. The most significantly affected pathways in the chromothripsis group were cytoskeleton, microtubules formation, histone acetyltransferase and immune and antigen presentation response pathways (p&lt;0.001).
Conclusion: Our data suggest that different pathways and genomic alterations are involved in chromothripsis events in de novo and secondary AML, which could be explained by the repeated rounds of stress underwent by leukemic cells in secondary AML cases. Cytoskeleton and microtubules formation pathways appear to be the main cellular processes implicated in chromothripsis genesis, while alterations of histone acetyltransferase, immune response and antigen presentation pathways could sustain leukemic cells after chromothripsis.
Acknowledgement: ELN, AIL, AIRC, PRIN, progetto Regione-Università 2010-12(L. Bolondi), FP7 NGS-PTL project.
Citation Format: Maria Chiara Fontana, Viviana Guadagnuolo, Cristina Papayannidis, Giovanni Marconi, Giorgia Simonetti, Antonella Padella, Marco Manfrini, Barbara Santacroce, Margherita Perricone, Silvia Lo Monaco, Emanuela Ottaviani, Simona Soverini, Michele Cavo, Giovanni Martinelli. Chromothripsis in AML patients: A new mechanism of cancer initiation and progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3582.