Abstract 2176: Whole-genome analysis of CNAs identifies four main evolution trajectories in multiple myeloma (MM) patients front-line treated with PI-based regimens
Authors: Terragna Carolina , Poletti Andrea , Solli Vincenza , Martello Marina , Santacroce Barbara , Termini Rosalinda , Borsi Enrica , Benni Chiara , Pantani Lucia , Zamagni Elena , Tacchetti Paola , Martinelli Giovanni , Cavo Michele 
Published: August 2018

Abstract
The inter- and intra-patients (pts) genetic heterogeneity of MM is the result of a competition between subclones harboring different genomic background, under the selective pressure of both microenvironment constrains and therapeutic treatment. Aim: to describe the clonal architecture changes driven by PI-based regimens in a cohort of homogeneously treated MM pts, by means of a genome-wide approach The study included 50 MM pts up-front treated with PI-based regimens. SNPs array data, derived from the BM CD138+ enriched cell fractions, as collected both at diagnosis (D) and at relapse (R), were analyzed with TAPS and Raw Copy R packages. In addition novel and personalized R-based scripts were designed, aimed at the detailed description of the whole genome CN changes. To be able to analyze the whole genome's changes between D and R, we first translated the signal derived from each of the 2,7x106 markers of the array (Cytoscan HD, Affymetrix) into gene-specific signals, therefore being able to describe CN changes of 20,172 genes. To highlight specific chromosomal regions affected by PI-based selective pressure, we than categorised the overall genomic CN changes, assuming that a limited number (9) of alternative genes' transitions might be observed between D and R. We therefore obtained dynamic profiles describing in details each genes' CNAs transitions, thus being able to highlight the following chromosomal regions particularly involved: chr 1p, 2p, 5, 15p, 19q (negative selection/extinction against CNs gains); chr 2q, 4 and 1p (positive selection/emersion of CNs losses and gains); chr13 and chr19p (mostly stable CN losses and gains). Each gene's CNAs transitions were also evaluated per pts, in order to describe the pts-specific evolutionary trajectories, thus highlighting an extremely high heterogeneity among pts, which might be roughly resumed in four main clonal evolution patterns: 32% of pts showed a stable, whereas 68% a branching evolution pattern. Among the branching patterns, three different behaviours were shown: 8% of pts showed a prevalent positive selection of CNAs, 24% showed a prevalent extinction of CNAs, whereas the remaining showed a blend of both behaviours. Of note, any correlation was observed between the presence of particular CNAs and the propensity to particular evolution patterns. Nevertheless, pts with stable evolution patterns had a slightly shorter median TTP, as compared to pts with branching patterns (22 vs 30 months, range 4-122 and 5-65, respectively). We concluded that the selective pressure of PI-based regimens mostly causes branching trajectories, even if any peculiar CNAs seem to guide at baseline this process. Overall, the clonal evolution patterns in MM remain still unpredictable, being probably driven by a combination of different factors, not yet fully depicted. Thanks to AIRC (MC), FB and FM (CT), AILBologna.
Citation Format: Carolina Terragna, Andrea Poletti, Vincenza Solli, Marina Martello, Barbara Santacroce, Rosalinda Termini, Enrica Borsi, Chiara Benni, Lucia Pantani, Elena Zamagni, Paola Tacchetti, Giovanni Martinelli, Michele Cavo. Whole-genome analysis of CNAs identifies four main evolution trajectories in multiple myeloma (MM) patients front-line treated with PI-based regimens [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 2176.