ECP 2022 Abstract Book

Virchows Archiv (2022) 481 (Suppl 1):S1–S364 13 several phase III trials. However, its high failure rate and limited accessibility establish a need for a clinically validated laboratory developed test. Methods: The algorithm behind the Geneva HRD test was developed on 457 high grade serous ovarian samples and 112 triple negative breast cancer samples from the TCGA. As part of the ENGOT HRD European Initiative the algorithm, applied on OncoScan(TM) CNV Assay data, was compared to Myriad with respect to the PFS on 85+384 samples from the PAOLA-1/ ENGOT-ov25 phase 3 trial. Results: The analysis of the TCGA cohort revealed that a nor- malization of the number of large-scale state transitions by the number of whole genome doubling events allows a better separa- tion and classification of HR-deficient samples than the tripar- tite score used by Myriad or the genomic LOH score used by Foundation Medicine. On the PAOLA-1 samples, the Geneva test yielded a similar hazard ratio as the Myriad test with respect to the addition of Olaparib or placebo to the Bevacizumab main- tenance treatment (HR=0.32 vs 0.31). Compared to Myriad, the test yielded a lower technical failure rate (2% vs 11%) and a posi- tive and negative predictive value of 90% and 85%. Conclusion: The proposed test is a viable alternative to the Myriad myChoice HRD test and can be easily deployed in a clinical labora- tory. The performance is similar to the commercial test in terms of hazard ratio but the lower failure rate of the Geneva HRD test allows a 10% increase (375 vs 340) in the number of patients that will receive a conclusive laboratory result. Funding: AstraZeneca/Merck OFP-12-005 Clinical utility of tumour-only targeted panel sequencing in childhood tumours Y. Mok*, C.H. Kuick, J.Y. Goh, N. Chia, M.S. Nwe, K.T. Chang *National University Health System, Singapore Background & objectives: Broad based genomic profiling is increasingly part of the standard workup for paediatric cancers. In this study, we evaluate the clinical utility of tumour-only sequenc- ing in a cohort of 94 paediatric tumours using a targeted next gen- eration sequencing panel. Methods: 94 cases of paediatric solid tumours spanning multiple subtypes were recruited, including relapsed and refractory childhood cancers. Nucleic acid extracted from formalin-fixed paraffin embedded tissue was tested with Illumina Ampliseq Childhood Cancer Panel, which includes single nucleotide variants, copy number variants and gene fusions involving >130 genes. All clinically significant variants were reviewed at a multi-disciplinary tumour board. Results: 94 cases of paediatric solid tumours from 87 individuals were sequenced, including bone and soft tissue tumours (n=30), central nervous system (CNS) tumours (n=17), lymphomas (n=9), sympathetic nervous system tumours (n=8), renal tumours (n=8), liver tumours (n= 5) and other tumour types. Clinically relevant variants were identified in 57 cases (60.6%). Variants were of diagnostic significance in 54 cases (57.5%), thera- peutic significance in 34 cases (36.2%), and prognostic significance in 11 cases (11.7%). A potential germline alteration was detected in 9 cases (9.3%). Based on the sequencing findings, 3 cases had a change in diagnosis: pancreatic Ewing sarcoma, myeloid sarcoma with KMT2A-MLLT3 gene fusion and metastatic colitis-associated colorectal adenocarcinoma (poorly-differentiated). Conclusion: Paediatric tumour types that benefitted most from tumour-only sequencing were soft tissue tumours (67% of cases with clinically relevant variants) and CNS tumours (65% of cases with clinically relevant variants). Whilst changes in histological diagnoses were rare, molecular findings were extremely useful in assisting diagnosis of rare or poorly-differentiated entities, as well as tumours occurring in uncharacteristic locations. Funding: VIVA-KKH Brain and Solid Tumour Programme OFP-12-006 The activation of Jagged1 signalling by chemotherapeutic agents counteracts the Oxaliplatin/5Fluorouracil- mediated anti-cancer effects: a novel mechanism of drug resistance in colon cancer M. Pelullo*, S. Zema, M. Decarolis, A. Villari, A. Montalti, I. Screpanti, D. Bellavia *Center for Life Nano-&Neuro-Science (CL2NS@Sapienza), Isti- tuto Italiano di Tecnologia, Rome, Italy Background & objectives: Colorectal cancer (CRC) is a lead- ing cause of mortality worldwide, characterized by metastasis and resistance to therapy. Recently, we demonstrated that Kras mutation drives the activation of Jag1-ICD oncogene, via-ERK1/2. Herein, we explore the new intrinsic drug-resistance mechanisms, Jag1-ICD-mediated. Methods: Human CRC cell lines were treated with different chemotherapeutic compounds (e.g. OXP, 5FU and GSIs), alone or in combination, and subjected to in-vitro assays, to evaluate proliferation, metastasis and chemoresistance. CRC resistant cells were obtained by chronical treatment with low doses of OXP/5FU. The resistant cells were analysed by colony-formation assays and by qRT-PCR to assess growth and gene-reprogramming ability. Results: Herein, we evaluate the effects of OXP, 5FU and GSIs alone or in combination, on Jagged1 processing in CRC cell lines. We demonstrate that the anticancer drugs, OXP and 5FU, lead directly to a massive Jag1-ICD activation that results in the selec- tion of a drug-resistant subpopulation. The chemoresistance mecha- nism is induced by a forced Jag1-ICD accumulation that protects cells from apoptosis, under the activation of Jag1-ICD-dependent pro-survival targets. In addition, GSIs induce the proliferation of Jag1-ICD positive CRC cells, functioning as tumour-promoting agents. Finally, the Jagged1 abrogation in OXP- or 5FU-resistant subpopulations is enough to restore the sensitivity to chemother- apy, confirming that drug resistance is Jag1-ICD-dependent. Conclusion: Overall, our data show that Jagged1 processing is directly activated by the most potent chemotherapeutic agents (OXP/5FU) or by GSIs compounds. Moreover, we unveil a new role for Jag1-ICD oncogene which controls both apoptosis and proliferation, in CRC cells upon chemotherapeutic treatments. Therefore, we demonstrate the existence of a new mechanism of intrinsic drug-resistance, where Jag1-ICD functions as pivotal nuclear effector. Finally, we suggest Jagged1 as molecular predictive biomarker for the chemotherapy-outcome in CRC patients bearing Krasmut and over-expressing Jagged1. OFP-12-007 Ultra-fast gene fusion assessment as a reflex testing in daily clinical practice for advanced non-small cell lung cancer patients V. Hofman, S. Heeke, C. Bontoux*, L. Chalabreysse, M. Barritault, P. Bringuier, T. Fenouil, N. Benzerdjeb, H. Begueret, J. Merlio, C. Caumont, N. Piton, J. Sabourin, S. Evrard, C. Syrykh, E. Long- Mira, S. Lassalle, M. Ilié, P. Hofman *Laboratoire de pathologie Clinique et experimentale, CHU de Nice, Université Côte d’Azur, Nice, France Background & objectives: There is an urgent need to improve the broad molecular profiling of advanced non-squamous non-small S50