Repository logo
 
Publication

Genetic alterations of ALK in high-risk neuroblastoma patients. A SIOPEN study

2019-10-26Conference object Open access
Simple item page
dc.contributor.authorBellini, Angela
dc.contributor.authorBernard, Virginie
dc.contributor.authorAmbros, Inge
dc.contributor.authorF. Ambros, Peter
dc.contributor.authorde Preter, Katleen
dc.contributor.authorCombaret, Valérie
dc.contributor.authorBeiske, Klaus
dc.contributor.authorJeison, Marta
dc.contributor.authorMarques, Barbara
dc.contributor.authorMorini, Martina
dc.contributor.authorMazzocco, Katia
dc.contributor.authorDefferrari, Raffaella
dc.contributor.authorBetts, David
dc.contributor.authorMartinsson, Tommy
dc.contributor.authorMühlethaler-Mottet, Annick
dc.contributor.authorNoguera, Rosa
dc.contributor.authorFont de Mora, Jaime
dc.contributor.authorVicha, Ales
dc.contributor.authorLadenstein, Ruth
dc.contributor.authorValteau-Couanet, Dominique
dc.contributor.authorRossing, Caroline Maria
dc.contributor.authorBown, Nick
dc.contributor.authorTweddle, Deborah
dc.contributor.authorAvigad, Smadar
dc.contributor.authorLapouble, Eve
dc.contributor.authorChicard, Mathieu
dc.contributor.authorLeprovost, Nada
dc.contributor.authorClement, Nathalie
dc.contributor.authorBaulande, Sylvain
dc.contributor.authorPierron, Gaelle
dc.contributor.authorIrene, Jimenez
dc.contributor.authorJaydutt, Bhalshankar
dc.contributor.authorDelattre, Olivier
dc.contributor.authorMichon, Jean
dc.contributor.authorSchleiermacher, Gudrun
dc.date.accessioned2020-05-19T11:31:36Z
dc.date.available2020-05-19T11:31:36Z
dc.date.issued2019-10-26
dc.description.abstractBackground: In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through genomic amplification or activating point mutations. We studied ALK genetic alterations in high-risk NB patients to determine their frequency and prognostic impact. Methods: Diagnostic NB samples from 1039 patients enrolled in the SIOPEN-HR-NBL1 trial were studied to determine the ALK amplification status (copy number analysis; n=337), the ALK mutational profile (Sanger and/or NGS including deep sequencing, n=203) or both (n=499). The sensitivity of ALK mutated/ALK amplified or ALK wildtype NB cell lines ((CLB-GA (R1275Q), CLB-GE (F1174V; ALK-A), SKNBE-2C (ALK wt)) to simultaneous or consecutive combinations of ALK TKIs (crizotinib/lorlatinib) and/or chemotherapy (Etoposide and Doxorubicin) was then tested. Results: Genomic ALK amplifications were detected in 4.4% of cases (37/836); all but 2 showed MYCN amplification. ALK mutations were detected at a clonal level (>20% mutated allele fraction, MAF) in 9.8% of cases (69/702) (F1174 n=25, R1275 n=32, both F1174 and R1275 n=1, F1245 n=6, others n=5) and at a subclonal level (MAF 0.5-20%) in 3.7% of patients (22/586) (F1174 n=11, R1275 n=6, both F1174 and R1275 or F1174 and F1245 n=3, other n=2). A significantly poorer OS and EFS was observed in cases with clonal ALK mutations, versus all others (3-years OS 47% +/-6.4% versus 65% +/-2%, logrank, p< 0.0001) and in those with ALK amplifications, versus all others (3-years OS 31% +/-8.5% versus 66% +/- 1.9%; logrank, p<0.0001). A Cox proportional hazards procedure (450 patients with complete clinical/biological datasets) retained stage 4 disease (as opposed to non-stage 4) and ALK amplification as factors with a higher hazard of relapse/progression (hazard 2.3 and 2.2, respectively), whereas ALK mutation, MYCN amplification and age>18 months were not retained. The consecutive treatment of Doxorubicin followed by Lorlatinib had a synergistic effect in ALK mutated/amplified NB cell lines. Conclusion: Genetic alterations of ALK (clonal mutations, amplifications) in high-risk NB patients are associated with poorer survival. Further preclinical data are required to determine optimal treatment modalities for integration of TKI in upfront treatment strategies of HR NB patients with ALK alterations.pt_PT
dc.description.versionN/Apt_PT
dc.identifier.urihttp://hdl.handle.net/10400.18/6701
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/pt_PT
dc.subjectNeuroblastomapt_PT
dc.subjectALKpt_PT
dc.subjectSIOPENpt_PT
dc.subjectDoenças Genéticaspt_PT
dc.subjectNeuroblastomapt_PT
dc.titleGenetic alterations of ALK in high-risk neuroblastoma patients. A SIOPEN studypt_PT
dc.typeconference object
dspace.entity.typePublication
oaire.citation.conferencePlaceLyon, Francept_PT
oaire.citation.title51th Congress of the Société Internationale d’Oncologie Pédiatrique (SIOP), 23-26 October 2019pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typeconferenceObjectpt_PT

Files

Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
Abstract ALK SIOPEN SIOP2019_gs.pdf
Size:
267.22 KB
Format:
Adobe Portable Document Format
Download
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
1.71 KB
Format:
Item-specific license agreed upon to submission
Description:
Download

Collections

DGH - Posters/abstracts em congressos internacionais