Germline Findings From Tumor-Only Comprehensive Genomic Profiling in the RATIONAL Study: A Missed Opportunity?
Year: 2025
Type: article
Abstract: PURPOSE: Tumor comprehensive genomic profiling (CGP) may detect potential germline pathogenic/likely pathogenic (P/LP) alterations as secondary findings. We analyzed the frequency of potentially germline variants and large rearrangements (LRs) in the RATIONAL study, an Italian multicenter, observational clinical trial that collects next-generation sequencing-based tumor profiling data, and evaluated how these findings were managed by the enrolling centers. PATIENTS AND METHODS: Patients prospectively enrolled in the pathway-B of the RATIONAL study and undergoing CGP with the FoundationOne CDx assays were included in the analysis. Potentially germline variants detected in 40 cancer susceptibility genes (CSGs) were classified in three classes with different actionability, most (MA), high (HA), and standard (SA), on the basis of penetrance, mutational spectrum, and intervention for prevention/early detection. RESULTS: On the basis of the European Society of Medical Oncology recommendations, we identified 225 potentially germline P/LP variants in 193/1,339 (14.4%) enrolled patients. In particular, 62/225 (27.5%) variants were detected in genes classified as MA-CSG class, 53/225 (23.6%) in genes belonging to the HA-CSG class, and 110/225 (48.9%) in the SA-CSG class. In addition, we detected 58 LRs in the 16/40 CSGs in 53/1,339 (3.95%) patients. Information about germline-focused analysis and follow-up was available for 99 patients with potentially germline variants. Surprisingly, 95/99 (96%) patients were not referred to oncogenetic consultation and follow-up, including 30/32 (93.75%) patients with variants in the MA-CSG class. CONCLUSION: Our data confirm the utility of CGP for the identification of potentially germline variants in CSGs, highlighting the importance of reporting LRs in addition to single-nucleotide variants and insertions/deletions. However, our findings also demonstrate a relative lack of knowledge of the implications of germline findings detected on tumor-only sequencing among oncologists and underline the need for specific training in this area.
Source: JCO Precision Oncology
DOI: 10.1200/po-25-00399
Authors: Riziero Esposito Abate, Alessandro Morabito, Michele Milella, Fabrizio Tabbò, Valentina Guarneri, Giacomo Pelizzari, Ilario G. Rapposelli, Rossana Berardi, Lucio Buffoni, Elisa Bennicelli, Francesca Zanelli, Carlo Tondini, Laura Attademo, Tiziana P. Latiano, Salvatore Corallo, Giancarlo Pruneri, Federica Marmorino, Orazio Caffo, Lorenzo Antonuzzo, Simona Tessitore, Silvia Novello, Giuseppe Curigliano, Carmine Pinto, Nicola Normanno, Antonella De Luca
Institutions: Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, Azienda Sanitaria Locale CN2, Ospedale Michele e Pietro Ferrero - Verduno, University of Padua, Istituto Oncologico Veneto, Azienda sanitaria universitaria Friuli Centrale, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Marche Polytechnic University, Ospedale Humanitas Gradenigo, Ospedale Policlinico San Martino, Azienda Sanitaria Unità Locale di Reggio Emilia, Ospedale Papa Giovanni XXIII, Casa Sollievo della Sofferenza, University of Pavia, Policlinico San Matteo Fondazione, University of Milan, Fondazione IRCCS Istituto Nazionale dei Tumori, University of Pisa, Ospedale Santa Chiara, Azienda Ospedaliero-Universitaria Careggi, University of Florence, University of Turin, European Institute of Oncology
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
OpenAlex ID: W4414108657