1420PD - May patient genetic characteristics explain heterogeneity of treatment efficacy in Ewing Sarcoma? A GWAS study

Date 27 September 2014
Event ESMO 2014
Session Sarcoma
Topics Pathology/Molecular Biology
Sarcoma
Translational Research
Basic Scientific Principles
Basic Principles in the Management and Treatment (of cancer)
Presenter BRICE Fresneau
Citation Annals of Oncology (2014) 25 (suppl_4): iv494-iv510. 10.1093/annonc/mdu354
Authors B. Fresneau1, D.G. Cox2, N. Gaspar3, G. Pierron4, J. Michon5, V. Laurence6, P. Marec-Bérard7, N. Corradini8, C. Lervat9, C. Schmitt10, L. Saumet11, E. Lapouble4, P. Broet12, M. Le Deley13, O. Delattre4, G. Le Teuff14
  • 1Pediatric Oncology, Biostatistics, GUSTAVE ROUSSY, 94805 - VILLEJUIF/FR
  • 2U1052, Centre Léon Bérard, LYON/FR
  • 3Pediatric Oncology, GUSTAVE ROUSSY, 94805 - VILLEJUIF/FR
  • 4Unite De Genetique Somatique, INSTITUT CURIE, PARIS/FR
  • 5Pediatric Oncology, INSTITUT CURIE, PARIS/FR
  • 6Medical Oncology, INSTITUT CURIE, PARIS/FR
  • 7Pedriatric Oncology, Centre Léon-Bérard, Lyon/FR
  • 8Pediatric Oncology, CHU, Nantes/FR
  • 9Pediatric Oncology, Centre Oscar-Lambret, Lille/FR
  • 10Pediatric Oncology, CHU, NANCY/FR
  • 11Pediatric Oncology, CHU, MONTPELLIER/FR
  • 12Inserm U669, Assistance Publique-Hôpitaux de Paris, Hôpital Paul Brousse, VILLEJUIF/FR
  • 13Biostatistics, Gustave Roussy, Villejuif/FR
  • 14Department Of Statistics And Epidemiology, Institut Gustave Roussy, 94805 - Villejuif/FR

 

Abstract

Aim

In the collaborative Euro-EWING99 study (EE99), Ewing sarcoma patients (EW pts) received vincristine ifosfamide doxorubicin etoposide induction (VIDE); maintenance treatment was stratified by initial staging and histological response. We conducted a genome-wide association study (GWAS) to identify Single Nucleotide Polymorphisms (SNPs) which may influence efficacy outcomes.

Methods

289/807 French pts registered in EE99 before 2010 were genotyped for 598821 SNPs. Association of each SNP with poor histological response to VIDE (>10% viable cells) was assessed by logistic regression adjusted for age, gender and the 2 first eigenvectors to correct for population stratification. Three genetic models were tested: additive, dominant and recessive. Multivariate Cox models were used to test for association with progression-free and overall survival (PFS, OS). To account for multiple comparisons, we set the p-value threshold for significant associations at 5.10−7.

Results

After quality control, 277 pts (median age 14.7y [0.5; 48.4]; 96/277 metastatic; median follow-up 6.9y) and 561924 SNPs are included in the analysis. 146/194 pts operated after VIDE induction were good responders. We detected no genome-wide significant association with histological response. The lowest p-value was obtained for SNP rs2247119 (OR=4.5 [95%CI 2.4; 8.3] p=2.10−6, additive model) located in the PHF11 gene (transcription factor). An association between PHF11 down-regulation through hypermethylation in EW samples and poor prognosis has been described (Alholle 2013). Two SNPs were associated with PFS: rs4653137 (chr 1, KIAA0319L gene, HR=3.9 [2.3; 6.6] p=3.10−7) and rs9489215 (chr 6, DCBLD1 gene, HR=2.3 [1.6; 3.2] p=1.10−6). DBCLD1 has been found associated with poor prognosis in small cell lung cancer (Han 2014). These 2 SNPs were not significantly associated with OS (p=1.10−5 and 2.10−5), unlike SNP rs3781854 (chr 11, ELP4 gene, HR=2.5 [1.8; 3.6] p=6.10−7).

Conclusions

The GWAS study showed weak signals of association with treatment efficacy in EW. Further studies are needed to validate these associations, and explore the mechanisms and clinical utility of these variants.

Disclosure

All authors have declared no conflicts of interest.