Investigating the genetic predisposition of rare hereditary cancer syndromes

Investigating the genetic predisposition of rare hereditary cancer syndromes via the Hellenic Precision
Medicine Network

P. Apostolou (1), V. Dellatola (1), E. Mendrinou (1), I. Stefanaki (2), E. Fountzilas (3), D. Yannoukakos (1), I. Konstantopoulou (1), F. Fostira (1)

1 Human Molecular Genetics Laboratory, INRaSTES, National Center for Scientific Research “Demokritos”,
Athens, Greece
2 1st Department of Dermatology and Venereology, Medical School, National and Kapodistrian University
of Athens, “A. Sygros” Hospital for Skin and Venereal Diseases, Athens, Greece
3 Department of Medical Oncology, St. Lukes’s Hospital, Thessaloniki, Greece.

Background: Greece lacks organized genetic centers, certified counselors and geneticists. Genetic testing
for hereditary cancer is generally not reimbursed by national healthcare insurance policies, except in
selected cases. As a result, patients and their families bear the financial burden. To address this gap, a
state-funded program, Hellenic Network of Precision Medicine (HNPM), has been established to both
investigate cancer biomarkers and hereditary cancer susceptibility. HNPM leverages the expertise of
research and academic laboratories to seamlessly integrate diagnostic and research needs.

Materials and Methods: Through the dedicated HNPM portal, from September 2024 to January 2025, 192
patients (mean age at diagnosis 49.5 years; range 19-80 years) with malignant/pre-malignant diagnoses
fulfilling international testing criteria were referred to the Human Molecular Genetics Laboratory, which
serves as a reference laboratory in hereditary cancer in the last 30 years. Analysis was performed via
massively parallel sequencing and MLPA.

Results: Overall, 20.8% (40/192) of patients carried germline pathogenic variants (PVs) distributed in six
cancer susceptibility genes known to be associated with rare or ultra-rare cancer syndromes. The reported
rate of variants of unknown significance (VUS) was 1%. A large fraction, i.e. 60%, of the families already
proceeded to cascade testing for the familial PV.

Conclusion: This initial approach emphasizes the importance of an organized infrastructure, which
includes laboratories with extensive expertise in the field. By offering pro bono genetic testing for
hereditary cancer predisposition, a number of rare hereditary cancer cases are promptly identified whilst
paving the way for personalized treatments and cancer prevention.