Nov 05: Using next-generation sequencing to profile tumor cells from patients with solid tumors, researchers at Fondazione Policlinico Universitario A. Gemelli IRCCS identified genetic alterations associated with cancer predisposition in 10% of the subjects examined. These alterations are also present in the patient’s healthy cells; they contribute to tumor development and may be present in relatives.
These findings are the result of work conducted within the FPG500 program—an initiative strongly backed by Professor Giovanni Scambia, former Scientific Director of the Fondazione Policlinico Universitario Agostino Gemelli IRCCS, which started in 2022. The research was carried out by Simona Duranti, Arianna Panfili, and Camilla Nero, and coordinated by Professor Maurizio Genuardi—Professor of Medical Genetics at the Università Cattolica del Sacro Cuore - Dipartimento di Scienze della Vita e Salute Pubblica – and Director of Unità Operativa Complessa di Genetica Medica, Fondazione Policlinico Universitario A. Gemelli IRCCS. This type of genomic analysis led to the identification of several patients with a hereditary cancer-predisposition syndrome; one-third of these cases would likely have gone undetected with standard diagnostic pathways. The study has just been published in the journal Genome Medicine.
The research involved genomic profiling of specific tumor types, using next-generation sequencing to analyze over 500 genes. In addition to detecting genetic variants acquired during a patient’s lifetime—which promote tumor development and help guide the selection of the most effective therapeutic approach—the study also identified alterations of suspected constitutional nature. These variants are present from birth in all of the patient's healthy cells and occur in genes that play a key role in cancer development. Constitutional genetic alterations were present in one out of every 10 patients. It can therefore be concluded that a genetic predisposition to cancer was identified in one in ten patients.
Specifically, during the first two years of the program (January 2022 – December 2023), approximately 2,700 samples were analyzed from patients with solid tumors—predominantly gynecological cancers (endometrial and ovarian). Through the integrated, multidisciplinary efforts of various specialists—including molecular biologists, bioinformaticians, oncologists, geneticists, and molecular care managers—.16% of the patients who underwent tumor profiling were referred to specialist genetics evaluation. Among those invited, 80% attended the genetic consultation.
Background
Comprehensive genomic tumor profiling is recommended to identify mutations that are amenable to therapeutic intervention ("actionable mutations") in a subset of cancer patients. In Italy, the National Health Service provides reimbursement for tests targeting a limited number of genes— those associated with specific therapies and cancer types, such as lung, ovarian, or colon cancer. However, these consist of panels focused on individual cancer types. "Testing for over 500 genes is not part of standard clinical practice," Dr. Duranti and Dr. Panfili explain. "At Policlinico Gemelli, this is offered as part of the FPG500 program, which serves both diagnostic and research purposes," they add.
Some variants detected with this test may be constitutional in nature. The purpose of the study was to evaluate the frequency of constitutional (germline) DNA variants with pathogenic significance—that is, those predisposing to cancer—in accordance with the recommendations of the European Society for Medical Oncology (ESMO).The study enrolled 2,674 patients with solid tumors for whom molecular testing had been requested.
Through germline genetic testing, constitutional variants—present from birth and predisposing to cancer—were detected in approximately 10% of the patients. A significant proportion of these constitutional variants (16%) would not have been identified using current clinical guidelines, as they occurred in genes not typically associated with the specific type of cancer present. Furthermore, 20% of these variants involve genes associated with moderate risk—genes that current guidelines for genetic testing do not mandate for systematic investigation. This implies that standard diagnostic pathways would likely have missed roughly one-third of the individuals with a hereditary cancer-predisposing syndrome.
“Identifying these genetic alterations makes a tangible contribution to precision medicine and precision prevention, impacting multiple aspects of cancer patient management,” Professor Genuardi explains. Such information can guide therapeutic decisions and support the planning of surveillance strategies for other organs at risk, as well as strategies for reducing cancer risk—such as prophylactic surgery or targeted medical therapy (for example, the use of aspirin in Lynch syndrome). Equally important, it enables cascade testing for family members, to determine whether they have inherited the predisposing gene variant present in the family. Those identified at high risk can then access personalized prevention, surveillance, or risk-reduction pathways before a potential tumor develops, the research team concludes.
Next steps for the study
The researchers conclude: “In the coming months, we plan to investigate additional hereditary alterations in genes beyond those analyzed so far among the patients already profiled” the researchers explain. “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.”
