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- Title
OAB-006: A novel algorithm to identify, characterize and define the prognostic impact of complex catastrophic events in Multiple Myeloma.
- Authors
Solli, Vincenza; Poletti, Andrea; Borsi, Enrica; Martello, Marina; Pantani, Lucia; Armuzzi, Silvia; Vigliotta, Ilaria; Zamagni, Elena; Tacchetti, Paola; Rocchi, Serena; Mancuso, Katia; Mazzocchetti, Gaia; Taurisano, Barbara; Pistis, Ignazia; Cavo, Michele; Terragna, Carolina
- Abstract
Multiple Myeloma (MM) is a genetically complex disease, characterized by the recurrence of several chromosomal aberrations, which impair the disease prognosis. The use of genome-wide technologies has recently highlighted the existence of Complex Chromosomal Events (CCEs), caused by distinct phenomenons: Chromothripsis (CT), caused by single-step genomic events, and Stepwise Events (SE), consequence of multiple, small and sequential genomic events, occurring throughout subsequent cell cycles. The prognostic impact of CT in MM has not yet been fully elucidated. Aims of our study were: (1) to detect CCEs in MM, with a focus on CT, by using an original and reliable bio-informatic algorithm, (2) to characterize the genetic and genomic context of CT and (3) to correlate the presence of CTwith pts prognosis. A total of 488 newly diagnosed MM patients (pts) have been included in the study. Genomic data have been obtained by SNPs arrays on bone marrow (BM) aspirates CD138+ enriched cell fractions; data were analysed by Affymetrix's programs and R-scripts. An original algorithm able to discriminate among the 2 different CCEs (CT and SE),was set up and tested, by implementing the most commonly reported guidelines for CCEs identification with knowledges on MM-specific highly heterogeneous genomic context. CCEs were detected in 174 pts (36% with at least one CCE): in particular, 46/174 pts (26%) carried CT. CT can affect any chromosome, yet showing significant associations with the following genomic regions: chr1p (p=8.37E-15), chr2q (p=4.27E-8), chr11q (p=6.99E-5) and chr22q (p=5.15E-7). Pts carrying CT were more likely to carry also IgH translocations associated to bad prognosis (p=0.002, HR 3.4) and TP53 deletions (p=1.16E-5, HR=6.26). The presence of any CT event conferred hazard ratio of 1.52 (p=0.019) and 1.68 (p=0.019) to pts' progression-free (PFS) and overall survival (OS), respectively, independently from the presence of both TP53 deletion and translocation t(4;14), as evaluated in a multivariated model. An association between CT events and XBP1 gene deletion was observed; since XBP1 expression has been correlated to an effective proteasome inhibitor (PI) therapy response, CT events particularly impacted survival expectancies of PI-treated pts, whose PFS and OS were significanlty worse than those of other pts (p=0.0098 and =0.023, respecitvely). Finally, the same CT events acquired at diagnosis were observed in those 4/55 pts, whose BM aspirates were analysed also at relapse, thus suggesting that, once occurred, CT might have a driver role for disease progression. Our results showed that CT impact MM pts prognosis, independently from the genomic region affected and the pts' genomic backgroung. AIRC_IG2014, RF-2016.
- Publication
Clinical Lymphoma, Myeloma & Leukemia, 2021, Vol 21, pS4
- ISSN
2152-2650
- Publication type
Article
- DOI
10.1016/S2152-2650(21)02080-2