Chromosome Complexity Is Associated with Age and Metastasis in Synovial Sarcomas: Validation of Expression and Genomic Prognostic Signatures
Pauline Lagarde, Joanna Przybyl, Celine Brulard, Antoine Italiano, Daniel Orbach, Binh Bui, Philippe Terrier, Raf Sciot, Maria Debiec-Rychter, Jean-Michel Coindre, Fred Chibon. Bergonie Institute, Bordeaux, France; INSERM U916, Bordeaux, France; Curie Institute, Paris, France; IGR, Villejuif, France; Catholic University and University Hospitals, Leuven, Belgium
Background: Synovial sarcoma (SS) is a high grade soft tissue sarcoma which accounts for 2-5% of all soft tissue sarcomas. It is one of the rare sarcomas that occur in adolescents as well as in adults. Nevertheless, metastasis occurs with a much lower frequency in the former. SS oncogenesis is explained by a specific translocation t(X;18), but the genetic basis of SS metastasis is poorly understood. We recently published expression (CINSARC) and genomic (GI) prognostic signatures related to mitosis control and chromosome integrity in other sarcomas and asked whether these signatures could predict SS outcome.
Design: We selected fully annotated primary untreated SS with frozen tissue and molecular confirmation. We established expression and genomic profiles for 92 and 79 SS cases, respectively.
Results: As demonstrated by metastasis-free survival and multivariate analyses, CINSARC and GI have strong and independent prognostic values (p < 1 x 10-4). To identify a SS specific signature, we compared expression profiles of SS with or without metastasis in a training set and a 52-genes prognostic signature was identified and validated in a validation set. These genes are involved in the same pathways than CINSARC and 14 are common with CINSARC.
Moreover, comparing genomic profiles of adult versus pediatric SS we observed that in both situations metastasis was associated with genome complexity and that the adult genome was much more frequently rearranged. In line with this, the pediatric good-prognosis patients, according to GI, do not metastasize.
Conclusions: Results clearly indicate that SS metastasis development is associated with chromosome complexity and mitosis control and that CINSARC and GI are powerful prognostic factors. Data also mean that the higher metastasis frequency in adult SS likely is associated to the higher frequency of rearranged genome in adults.
Finally, among these signatures, GI is the best overall and clearly the most clinically relevant considering that CGH is applicable to FFPE samples and already used in pathology laboratories. We now aim to set up a clinical trial to validate GI as eligibility criteria for chemotherapy, specifically in pediatric SS.
Category: Special Category - Pan-genomic/Pan-proteomic approaches to Cancer
Tuesday, March 20, 2012 1:45 PM
Platform Session: Section H1, Tuesday Afternoon