Development of the NOGGO GIS v1 Assay, a Comprehensive Hybrid-Capture-Based NGS Assay for Therapeutic Stratification of Homologous Repair Deficiency Driven Tumors and Clinical Validation

Eva Maria Willing*, Claudia Vollbrecht, Christine Vössing, Peggy Weist, Simon Schallenberg, Johanna M. Herbst, Stefanie Schatz, Balázs Jóri, Guillaume Bataillon, Philipp Harter, Vanda Salutari, Antonio Gonzáles Martin, Ignace Vergote, Nicoletta Colombo, Julia Roeper, Tobias Berg, Regina Berger, Bettina Kah, Trine Jakobi Noettrup, Markus FalkKathrin Arndt, Andreas Polten, Isabelle Ray-Coquard, Franziska Selzam, Judith Pirngruber, Stefanie Schmidt, Michael Hummel, Markus Tiemann, David Horst, Jalid Sehouli, Eric Pujade-Lauraine, Katharina Tiemann, Elena Ioana Braicu, Lukas C. Heukamp

*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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Abstract

The worldwide approval of the combination maintenance therapy of olaparib and bevacizumab in advanced high-grade serous ovarian cancer requires complex molecular diagnostic assays that are sufficiently robust for the routine detection of driver mutations in homologous recombination repair (HRR) genes and genomic instability (GI), employing formalin-fixed (FFPE) paraffin-embedded tumor samples without matched normal tissue. We therefore established a DNA-based hybrid capture NGS assay and an associated bioinformatic pipeline that fulfils our institution’s specific needs. The assay´s target regions cover the full exonic territory of relevant cancer-related genes and HRR genes and more than 20,000 evenly distributed single nucleotide polymorphism (SNP) loci to allow for the detection of genome-wide allele specific copy number alterations (CNA). To determine GI status, we implemented an %CNA score that is robust across a broad range of tumor cell content (25–85%) often found in routine FFPE samples. The assay was established using high-grade serous ovarian cancer samples for which BRCA1 and BRCA2 mutation status as well as Myriad MyChoice homologous repair deficiency (HRD) status was known. The NOGGO (Northeastern German Society for Gynecologic Oncology) GIS (GI-Score) v1 assay was clinically validated on more than 400 samples of the ENGOT PAOLA-1 clinical trial as part of the European Network for Gynaecological Oncological Trial groups (ENGOT) HRD European Initiative. The “NOGGO GIS v1 assay” performed using highly robust hazard ratios for progression-free survival (PFS) and overall survival (OS), as well a significantly lower dropout rate than the Myriad MyChoice clinical trial assay supporting the clinical utility of the assay. We also provide proof of a modular and scalable routine diagnostic method, that can be flexibly adapted and adjusted to meet future clinical needs, emerging biomarkers, and further tumor entities.

OriginalsprogEngelsk
Artikelnummer3445
TidsskriftCancers
Vol/bind15
Udgave nummer13
Antal sider13
ISSN2072-6694
DOI
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
We thank Agilent Technologies for supporting this project with reagents. Elena Ioana Braicu is a Feodor Lynen fellow of the Humboldt Foundation and a participant of the Charité Clinical Scientist Program funded by the Charité Universitätsmedizin Berlin and the Berlin Institute of Health. We would like to acknowledge the invaluable technical support from Ingrid Gerdes, Simone Gnoth, Sabine Weber.

Publisher Copyright:
© 2023 by the authors.

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