Germline Findings From Tumor-Only Comprehensive Genomic Profiling in the RATIONAL Study: A Missed Opportunity?
| Title: | Germline Findings From Tumor-Only Comprehensive Genomic Profiling in the RATIONAL Study: A Missed Opportunity? |
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| Authors: | Esposito Abate R; Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy.; Morabito A; Thoracic Department, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy.; Milella M; U.O.C. Oncology, Azienda Ospedaliera Universitaria Integrata, University and Hospital Trust of Verona, Verona, Italy.; Tabbò F; Medical Oncology Unit, ASLCN2 Alba e Bra, Michele e Pietro Ferrero Hospital, Verduno, Italy.; Guarneri V; Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.; Oncology 2, Istituto Oncologico Veneto (IOV) IRCCS, Padova, Italy.; Pelizzari G; Department of Oncology, Azienda Sanitaria Universitaria Friuli Centrale (ASUFC), Udine, Italy.; Rapposelli IG; Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) 'Dino Amadori', Meldola, Italy.; Berardi R; Department of Oncology, Università Politecnica delle Marche, AOU delle Marche, Ancona, Italy.; Buffoni L; Medical Oncology, Humanitas Gradenigo Hospital, Torino, Italy.; Bennicelli E; U.O. Medical Oncology 2, IRCCS Ospedale Policlinico San Martino, Genova, Italy.; Zanelli F; Medical Oncology, Comprehensive Cancer Centre IRCCS-AUSL Reggio Emilia, Reggio Emilia, Italy.; Tondini C; Oncology Unit, ASST Papa Giovanni XXIII, Bergamo, Italy.; Attademo L; Oncology Unit, Ospedale del Mare, Napoli, Italy.; Latiano TP; Medical Oncology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.; Corallo S; Department of Internal Medicine and Medical Therapy, University of Pavia, Pavia, Italy.; Comprehensive Cancer Center, IRCCS Policlinico San Matteo Foundation, Pavia, Italy.; Pruneri G; School of Medicine and Department of Diagnostic Innovation, Fondazione IRCCS, Istituto Nazionale Tumori, University of Milan, Milano, Italy.; Marmorino F; Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.; Caffo O; Department of Medical Oncology, Santa Chiara Hospital-APSS, Trento, Italy.; Antonuzzo L; Department of Experimental and Clinical Medicine, University of Florence, Firenze, Italy.; Oncology Unit, Careggi University Hospital, Firenze, Italy.; Tessitore S; Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy.; Novello S; Department of Oncology, University of Turin, S. Luigi Gonzaga Hospital, Torino, Italy.; Curigliano G; European Institute of Oncology, IRCCS, Milano, Italy.; Department of Oncology and Hemato-Oncology, University of Milano, Milano, Italy.; Pinto C; Medical Oncology, Comprehensive Cancer Centre IRCCS-AUSL Reggio Emilia, Reggio Emilia, Italy.; Normanno N; Scientific Directorate, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) 'Dino Amadori', Meldola, Italy.; De Luca A; Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy. |
| Source: | JCO precision oncology [JCO Precis Oncol] 2025 Sep; Vol. 9, pp. e2500399. Date of Electronic Publication: 2025 Sep 10. |
| Publication Type: | Journal Article; Multicenter Study; Observational Study |
| Language: | English |
| Journal Info: | Publisher: American Society of Clinical Oncology Country of Publication: United States NLM ID: 101705370 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2473-4284 (Electronic) Linking ISSN: 24734284 NLM ISO Abbreviation: JCO Precis Oncol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Alexandria, VA : American Society of Clinical Oncology, [2017]- |
| MeSH Terms: | Neoplasms*/genetics ; Germ-Line Mutation*; Genomics/methods ; Humans ; Male ; Female ; Middle Aged ; Adult ; Prospective Studies ; Aged ; Genetic Predisposition to Disease ; High-Throughput Nucleotide Sequencing ; Italy |
| 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. |
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| Entry Date(s): | Date Created: 20250910 Date Completed: 20250910 Latest Revision: 20250913 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC12419028 |
| DOI: | 10.1200/PO-25-00399 |
| PMID: | 40929615 |
| Database: | MEDLINE |
Journal Article; Multicenter Study; Observational Study