Targeting resistant OC “a movie that start at the end” Sandro Pignata On behalf of MITO

Ovarian Cancer Considered poorly tagetable. Mutations with low frequency Genetic instability Most of our knowledge from primary biopsies (including TGCA) Platinum sensitive mostly HRD positive Platinum resistant: alternative targets?

Longitudinal heterogeneity Beltrame Annals of Oncology 2015

Longitudinal heterogeneity Beltrame Annals of Oncology 2015

Very few frequent mutation except p53 and BRCA CCNE1 amplification was common in primary resistant and refractory disease. Gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. Nel progetto del cancer genome atlas è stata documentata l’ambia eterogeneità dei tumori sierosi di alto grado, tuttavia poco sisa dell’evoluzione genomica dei tumori sierosi di alto grado sotto pressione selettiva della chemioterapia. questo studio pubbilicato nel maggio di quest anno su NATURE FINALIZZATO A IDENTIFICARE I DRIVERS LEGATI ALLA RESISTENZA AL TRATTEMNTO CON PLATINO. E’ stato il primo studio a sequenziare l’intero genoma di un'ampia coorte HGSC al fine di esaminare le varianti strutturali ad alta risoluzione. E’ stato, inoltre effettuato un’ analisi del trascrittoma,della metilazione, edi espressione dei microRNA (miRNA) a supporto i dati WGS e comparato tumori primitivi resistenti refrattari e sensibili. Questi sono stati comparati con campioni ottenuti da autopsie. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. Patch AM, et al Nature 2015

Schwarz RF et al Plos one 2015

Retrospective and perspective collection of samples Inclusion criteria: Ovarian cancer patients with chemoresistant disease (Palliation surgery, pleural biopsies…..) and available sample and clinical history. Other samples required: Tumor at diagnosis (possibly including a sample of normal tissue) Tumor at first platinum sensitive relapse if available In the perspective phase: Blood at diagnosis, Blood at relapse Feasibility: Evaluation of the number of available samples (CRF to the groups interseted) Pathological revision of available samples for evaluation of tumor proportion and its quality (avoid necrotic samples). Definition of procedures for DNA and RNA and central extraction.

Proposed plan Identification of the cases (ENGOT consortium) tumor tissue (Consortium of labs) RNAseq: evaluation of gene and miRNA expression CNV: copy number variation WES Two phases: Discovery set (Cohort with resistante sample and basal sample Targeted sequencing on more patients to validate Funding action: European consortium for a possible H2020 application