With the advancement of genomic research, today there are several high-potential tools available for genetic screening. Among these, the identification of variants through sequencing of selected genes, the presence of which can indicate a high risk of developing a particular disease over a lifetime, for example hereditary breast and ovarian cancer (HBOC, hereditary breast and ovarian cancer).
Early identification of predisposed individuals enables the organization of targeted surveillance and prevention programs. The added value lies in the ability to intercept so-called “silent risk carriers”: individuals who, in the absence of a clear clinical or family history, would escape current screening criteria, which are highly selective.
These are the findings of the STEPS Project (sequencing test for early prevention screening), developed at the Functional Genomics Laboratory, led by molecular biologist and geneticist Davide Cacchiarelli, at TIGEM (Telethon Institute of Genomics and Medicine) in Pozzuoli (Naples), presented at the Milan Longevity Summit (May 20-23, 2026) during the talk “Population genomic screening: intercepting tumors and cardiovascular risk before symptoms,” delivered by Rosa De Santis, a researcher at the Functional Genomics Laboratory of TIGEM in Pozzuoli.
A Critical Question
How many women in the general population are silent carriers of a genetic variant that predisposes to breast or ovarian cancer, without their knowledge? The most surprising data come from the U.S. WISDOM study, which enrolled more than 46,000 women with no prior diagnosis of breast cancer: among the participants found to carry a pathogenic variant in one of nine genes analyzed, nearly one in three, 30%, were unaware of any family history of breast cancer. These are exactly the “silent carriers” that current screening criteria, largely based on family history, would fail to intercept.
Thus, about 3% of the women tested were found to carry a pathogenic variant, and most of these variants were in moderately penetrant genes, such as CHEK2, ATM, or PALB2, more common than the high-penetrance genes like BRCA1 and BRCA2.
“Data that underscore the importance of risk stratification—explains De Santis—as an essential element of targeted prevention: identifying high-risk individuals means defining an actionable profile on which early intervention can be implemented, both by correcting lifestyle factors and by dedicated surveillance strategies. It’s important to distinguish two scenarios: in most sporadic cancers the dominant risk factor is age, since the disease results from the accumulation of variants over a lifetime; in hereditary forms, predisposition is present from birth and cancer tends to occur at a younger age. It is precisely in this second group that early identification of carriers becomes decisive, allowing the initiation of targeted surveillance programs many years before the disease would manifest.
Alongside targeted sequencing, several predictive models—often AI-based—estimate an individual risk for a specific disease. Among these is the Polygenic Risk Score, which, by combining thousands of DNA variants, estimates an individual predisposition to complex diseases such as cardiovascular disease, diabetes, or cancers; the NMR Metabolomics, which uses metabolite analysis to estimate risk across multiple diseases; the Routine Health Record, which, based on a person’s medical history and prior events, maps the health trajectory of an individual; and the Retinal Fundus Photographs, which forecast early signs of disease at the phenotypic level via imaging of the ocular fundus.
There is also an ongoing, UK Biobank-based study that evaluates risk estimates for numerous diseases from a single blood draw, analyzing more than a thousand plasma proteins with an average follow-up of about 13 years.
«These tools, when applied to population cohorts, are valuable, but it’s important to clarify a fundamental distinction—continues the researcher—namely that predictive models provide probabilities. They indicate that a person’s risk of developing a disease is higher than average, but they do not identify a specific cause. Targeted genetic screening, like STEPS, works at a different level by pinpointing a specific pathogenic variant, which on its own confers a high risk and for which there is already patient-specific clinical action (more intensive surveillance, risk-reduction interventions, cascade testing for relatives). A truly comprehensive preventive approach for longevity requires both levels: probabilistic models to guide lifestyle choices, and genetic screening to intercept those at high risk who require concrete intervention.
Access Criteria
Although extremely useful, genetic screenings are not for everyone: their use requires specific selection criteria. Staying within the context of breast cancer, in Italy one refers to the AIOM guidelines (Italian Association of Medical Oncology) and SIGU (Italian Society of Human Genetics), which are based on the patient’s personal history (ovarian cancer, bilateral breast cancer, male breast cancer), on age of onset (breast cancer before 40, or triple-negative before 60), or on particular associations (bilateral breast cancer before 50, or a strong family history with more than three relatives affected).
“This selective screening system has its limits: it focuses only on high-risk populations, missing silent carriers with significant cost-time barriers. To overcome these challenges, the proposal of our study—explains De Santis—is to broaden recruitment criteria, intercepting potential individuals who would slip through current guidelines. In our STEPS pilot study we identified 27 carriers of pathogenic variants who, applying the current AIOM criteria, would not have been considered, including a subset entirely without known family history, all while keeping costs highly sustainable.
The study employs next-generation sequencing (NGS) of DNA to search for genetic variants. The pilot phase validated the panel on about 700 samples collected at 5 Italian centers, with the aim of reaching around 10,000 individuals with oncologic disease and high familial risk. The cohorts, both retrospective and prospective, are stratified by tumor subtype, age of onset, and family history, enabling the typing of HBOC-related variants even in patients already affected who could thus benefit from targeted therapies.
«The identification and validation of this panel have proven effective, sustainable, and reproducible in a real-world population context, successfully intercepting exactly those silent carriers. Today we can say that population genomic screening is technically feasible and analytically validated; what remains to be demonstrated—through dedicated studies—is its impact on the most important outcomes, such as mortality reduction in unselected populations.
Preventive Opportunities
Not only hereditary cancer risk. Once the HBOC panel’s effectiveness is demonstrated, the idea is to expand it to opportunistically identify, during the same sequencing performed for the primary indication, other clinically actionable pathogenic variants with autosomal dominant transmission, thereby realizing a “comprehensive prevention” extended to other hereditary conditions: oncologic (Lynch syndrome, Li-Fraumeni syndrome), cardiac, metabolic, and rare diseases. This is the objective of STEPS+, the project’s evolution, which broadens the analysis flow to genes associated with so-called secondary findings in a broader screening cohort.
Starting from the same HBOC panel that has been validated, STEPS+ applies the ACMG SF v3.2 overlay, i.e., the opportunistic analysis of 81 gene-phenotype pairs clinically relevant, defined in 2023 by the American College of Medical Genetics and Genomics and Genomics, maintaining the same scalable and cost-effective approach. The ACMG list of secondary findings was created precisely to report opportunistically to people who are already undergoing a diagnostic test, not as a population screening tool.
Applying it to a screening cohort, as STEPS+ does, means pushing beyond the original intent for which it was conceived. A direction that the ACMG does not yet officially endorse, but which several research groups are evaluating. After the test, interpretation of variants by specialized geneticists ensures a structured workflow for delivering results, accompanied by mandatory genetic counseling.
«These secondary findings, for example, include individuals with Lynch syndrome, a hereditary genetic condition that increases the risk of several cancers, particularly colorectal and endometrial cancer; familial hypercholesterolemia; hereditary cardiomyopathies; Li-Fraumeni syndrome, a rare inherited condition that elevates the risk of multiple cancers over a lifetime; and many others. Extending the analysis to secondary findings allows interception of cardiovascular and metabolic risk, initiating targeted prevention. Therefore, a one-shot genetic test can thus guide effective surveillance and prevention strategies, with potential impacts lasting for decades.
Looking Ahead
Expanding screening to the general population also carries certain risks that are important to consider. Analyzing many genes inevitably leads to encountering variants of uncertain significance: alterations whose real clinical weight is not yet known. There is also the risk of initiating unnecessary follow-ups or, in extreme cases, preventive interventions for variants that might never translate into disease.
That is why the delivery of a genetic result can never be left on its own: it must go through a counseling process to help the person understand what that data truly means, and, crucially, what it does not mean. For these reasons, expanding genetic screening to the entire population remains a debated topic. In the United States, the USPSTF preventive task force recommends genetic testing only for women with personal or family risk history and discourages it as routine practice for the general population, as the overall benefit is still considered uncertain.
The idea of broadening criteria should thus be understood as a path of research to pursue and validate, not as a settled recommendation. More than technology or costs, implementation remains the real challenge today: we need shared workflows that include informed consent, decisions about result disclosure, and reimbursement policies. A crucial bottleneck, in particular, lies in clinical genetics resources: in Italy the number of trained geneticists in healthcare settings is limited, and every positive result requires pre- and post-test counseling.
«These are the first challenges to overcome—concludes De Santis—to offer more health, for longer, to individuals at greater risk, with positive implications for the entire health ecosystem.
References
Fiscalini A, Blum K, Fergus K et al. WISDOM randomized trial comparing risk-based versus annual breast cancer screening: study cohort characteristics and design. NPJ Breast Cancer, 2026.
Abbonati a Karla Miller
