Data di Pubblicazione:
2018
Citazione:
The genomic landscape of structural variations and complex events in multiple myeloma / F. Maura, K.J. Dawson, N. Angelopoulos, S. Minvielle, I. Martincorena, T.J. Mitchell, A. Fullam, F.S. PACCIARINI GONZALEZ, D. Glodzik, R. Szalat, M.K. Samur, M. Fulciniti, Y.T. Tai, F. Magrangeas, P. Moreau, K. Anderson, D.C. Wedge, M. Gerstung, P. Corradini, H. Avet-Loiseau, N. Munshi, P.J. Campbell, N. Bolli. - In: HAEMATOLOGICA. - ISSN 0390-6078. - 103:S3(2018), pp. BO002.S14-BO002.S14. (Intervento presentato al convegno Italian Society of Experimental Hematology tenutosi a Rimini nel 2018).
Abstract:
Introduction: Multiple Myeloma (MM) initiation and progression is
driven by recurrent cytogenetic events, i.e. multiple trisomies or translocations
within the immunoglobulin locus. Gene mutations have been
extensively studied, and they are generally involved in late phases of
disease development. On the contrary, very little is known about structural
variations (SV), which are increasingly emerging as critical driver
in several cancers.
Methods: We performed whole genome sequencing (WGS) on 67
CD138+ purified bone marrow MM samples from 30 patients (median
of 2 samples per patient; range 1-4), to which we added 22 previously
published cases (Chapman et al, Nature 2011) for a total of 89 tumour
samples. We defined SVs as inversions, translocations, internal tandem
duplications and deletions, which we analysed using publicly available
tools developed at the Wellcome Trust Sanger Institute. Events with > 3
independent SVs involved in distinct copy-number abnormalities
(CNAs) were defined as “complex”.
Results: We found a stunning 1887 unique SVs in the whole cohort,
with a heterogeneous distribution across the entire series (median 29 per
patients, range 0-156). IGH and MYC translocations were the most frequent
recurrent events and accounted for only 5.3% of the entire SV catalogue.
Integrating data on SV and CNAs we found that a SV was responsible
for ~90% of CNAs where a breakpoint could be mapped. Furthermore,
93% of patients carried multiple CNAs across different chromosomes
all sustained by the same complex SV. Our analysis thus offers a
pathogenic explanation of many recurrent CNAs in MM.Overall, 136
complex events were observed in 43/52 patients (83%). We found 34
instances of chromotripsis (Korbel J.O. et al., Cell 2013) in 18/52
patients. The vast majority (30/34) were clonal and conserved during
evolution, suggesting a potential early role in MM pathogenesis. In addition,
we observed 5 chromoplexy (Korbel J.O. et al., Cell 2013) events
acquired in 5 patients. More interestingly, in 13 patients we found an
entirely novel complex event characterized by multiple concatenated
translocations causing small CNAs on more than 2 different chromosomes,
that we named template insertion (TI). Interestingly, 77% of TIs
resulted in a translocation involving an important MM oncogene (8 MYC
and 2 CCND1), suggesting that this is a novel relevant driver mechanism
in MM. Reconstructing their order of acquisition, we show that SVs and
complex events are at the nodes of initiation and subclonal diversification
during MM life history, with high variability of timing from patient to
patient, confirming their driver role in MM pathogenesis.
Conclusions: In this study, we described for the first time the landscape
of MM SV and complex events, showing their critical role in MM pathogenesis.
Overall these data suggested a new pathogenetic model where
MM evolution is driven by few clonal sweeps promoted by heterogeneous
and private structural events.
Tipologia IRIS:
01 - Articolo su periodico
Elenco autori:
F. Maura, K.J. Dawson, N. Angelopoulos, S. Minvielle, I. Martincorena, T.J. Mitchell, A. Fullam, F.S. PACCIARINI GONZALEZ, D. Glodzik, R. Szalat, M.K. Samur, M. Fulciniti, Y.T. Tai, F. Magrangeas, P. Moreau, K. Anderson, D.C. Wedge, M. Gerstung, P. Corradini, H. Avet-Loiseau, N. Munshi, P.J. Campbell, N. Bolli
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