Germline pathogenic variants identification through comprehensive cancer genome profiling

Comprehensive cancer genome profiling (CGP) is recommended for the identification of actionable somatic mutations in a selected subgroup of cancer patients. Some variants detected by CGP can be constitutional. The aim of this study is to evaluate the rate of potential and confirmed constitutional pathogenic/likely pathogenic variants (overall defined as PVs) identified through CGP according to the recommendations of the European Society of Medical Oncology. This is a prospective interventional trial that enrolled patients with solid cancers in whom molecular assessment was clinically indicated based on national guidelines, referring them for CGP (ClinicalTrials.gov Identifier: NCT06020625). Patients with suspected constitutional variants were subsequently referred for germline testing. The present analysis focuses on the first two years of the program, from January 2022 to December 2023. Of 2688 samples (2674 patients) with a CGP report, more than half were represented by gynecologic cancers (endometrial and ovarian). 16% of the patients were addressed to genetic evaluation for 527 suspected constitutional PVs, with a compliance to genetic counselling of 80%. 331 patients underwent germline testing, of whom 73% harbored at least one PV, with 66% of tested variants confirmed to be germline. Interestingly, 16% of germline variants were secondary findings and 20% of the confirmed “on-tumor” germline PVs were in moderate-risk genes. Twenty additional constitutional PVs were identified in 19 patients based on the results of other somatic tests or through additional tests requested following genetic counselling (0.7% of the entire cohort). Constitutional PVs were detected in about 10% of an unselected solid tumor cohort through CGP. A relevant fraction of the constitutional PVs were secondary findings or constitutional variants in moderate penetrance genes, that would not have been detected based on current guidelines. The integration of CGP with systematic genetic counseling provides a comprehensive approach that optimizes both therapeutic decision-making and identification of hereditary cancer syndromes. Protocol ID: FPG500, ID number: 3837. The study was prospectively registered at ClinicalTrials.gov Identifier: NCT06020625.