Comprehensive Tumor Profiling Uncovers Overlooked Hereditary Cancer Risk Genes

Patients with solid tumors often undergo molecular profiling to identify alterations that can guide therapy. This testing may also reveal constitutional cancer-predisposing DNA variants, which are present from birth in healthy cells and may have implications for relatives.

However, standard diagnostic pathways can miss hereditary cancer-predisposition syndromes when these variants occur outside genes typically associated with a patient’s cancer type. By examining a broader range of genes, comprehensive tumor genomic profiling may uncover these otherwise missed hereditary risks, according to new findings.

Researchers at Fondazione Policlinico Universitario A. Gemelli IRCCS (Rome, Italy) used next-generation sequencing (NGS) within the FPG500 program to analyze more than 500 genes in solid tumor samples. The approach detects acquired genetic variants that promote tumor development and may guide treatment selection, while also identifying alterations suspected to be constitutional. These suspected constitutional variants require germline genetic testing to determine whether they are also present in healthy cells throughout the body.

Following European Society for Medical Oncology (ESMO) recommendations, the study evaluated the frequency of germline pathogenic variants associated with cancer predisposition. Between January 2022 and December 2023, the program analyzed approximately 2,700 samples from 2,674 patients, predominantly those with gynecological cancers such as endometrial and ovarian cancer.

The multidisciplinary team included molecular biologists, bioinformaticians, oncologists, geneticists, and molecular care managers. The study reported that 0.16% of profiled patients were referred for specialist genetics evaluation, with 80% of those invited attending consultation.

Germline genetic testing identified cancer-predisposing constitutional variants in approximately 10% of patients. Of these variants, 16% would have been missed under current clinical guidelines because they occurred in genes not typically associated with the patient’s cancer type. A further 20% involved moderate-risk genes that guidelines do not require to be investigated systematically. Together, these findings suggest that standard diagnostic pathways would likely have missed about one-third of patients with hereditary cancer-predisposition syndromes.

The findings were published in Genome Medicine on October 27, 2026, in a study involving Fondazione Policlinico Universitario A. Gemelli IRCCS and Università Cattolica del Sacro Cuore. The researchers stated that identifying these alterations can support therapeutic decisions, surveillance strategies for other organs at risk, and risk-reduction approaches such as prophylactic surgery or targeted medical therapy. The work also enables cascade testing in relatives to determine whether they inherited the familial predisposing variant.

“In the coming months, we plan to investigate additional hereditary alterations in genes beyond those analyzed so far among the patients already profiled. We also want to measure the concrete impact of these findings: how many patients subsequently enrolled in surveillance and risk-reduction programs; how many at-risk family members underwent genetic testing; how many of them were found to be carriers; and how many, in turn, began a prevention program. The goal is to further strengthen precision medicine, which is one of the core missions of our IRCCS,” said the researchers.

Related Links
Fondazione Policlinico Universitario A. Gemelli IRCCS
Università Cattolica del Sacro Cuore