PURPOSETumor 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 METHODSPatients 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.RESULTSOn 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.CONCLUSIONOur 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.
Germline Findings From Tumor-Only Comprehensive Genomic Profiling in the RATIONAL Study: A Missed Opportunity?
Guarneri, Valentina;
2025
Abstract
PURPOSETumor 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 METHODSPatients 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.RESULTSOn 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.CONCLUSIONOur 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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