Discovering Hereditary Risk Through Surveillance: A Prospective Genetic Analysis of Individuals With Familial Pancreatic Cancer.
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Paiella Salvatore, Secchettin Erica, Archibugi Livia, De Luca Raffaele, Bonifacio Cristiana, Laghi Luigi, Lionetto Gabriella, Milanetto Anna Caterina, Sereni Giuliana, Coluccio Chiara, Lauri Gaetano, Dal Buono Arianna, Patruno Margherita, Gabriel Giulia, Sassatelli Romano, Binda Cecilia, Bonvissuto Deborah, Uliana Vera, Malleo Giuseppe, Cavestro Giulia Martina, Terrin Maria, Martino Stefania, Pasquali Claudio, De Pastena Matteo, De Cobelli Francesco, Poletti Valeria, Venturini Elisa, Puzzono Marta, Zerbi Alessandro, Arcidiacono Paolo Giorgio, Salvia Roberto, Falconi Massimo, Capurso Gabriele, Carrara Silvia
Аннотация
METHODS: Five hundred HRI-FHs from seven centers underwent surveillance and germline testing with a 41-gene NGS panel. Pathogenic/likely pathogenic variants (PGVs) and variants of unknown significance (VUS) were identified and correlated with clinical and imaging findings.
RESULTS: Overall, forty-four (8.8%) out of 500 HRI-FHs carried at least one PGV, including 3.4% in high-penetrance genes (ATM, BRCA1/2, PALB2, BRIP1). Notably, 8 out of 17 (47%) of ATM, BRCA1/2, PALB2 carriers would not have met the national testing criteria based solely on their family history. An additional 5.4% (27/500) carried PGVs in genes linked to other hereditary conditions (CFTR, MUTYH, CTRC, SPINK1, APC), and 39.6% harbored at least one VUS. PGV status, age, and female gender were independent predictors of radiological abnormalities. Two PCs were diagnosed, both in mutation-negative individuals.
DISCUSSION: Integrating germline testing into surveillance redefines the management of familial PC. It uncovers hereditary susceptibility beyond classical criteria and supports cascade testing. PC also arises in mutation-negative HRI. #NCT05724992.