Salvatore Paiella, Erica Secchettin, Livia Archibugi, Raffaele De Luca, Cristiana Bonifacio, Luigi Laghi, Gabriella Lionetto, A. Milanetto, Giuliana Sereni, Chiara Coluccio, Gaetano Lauri, Arianna Dal Buono, Margherita Patruno, Giulia Gabriel, Romano Sassatelli, Cecilia Binda, Deborah Bonvissuto, Vera Uliana, Giuseppe Malleo, Giulia Martina Cavestro, Maria Terrin, Stefania Martino, Claudio Pasquali, Matteo De Pastena, Francesco De Cobelli, Valeria Poletti, Elisa Venturini, M. Puzzono, Alessandro Zerbi, Paolo Giorgio Arcidiacono, Roberto Salvia, Falconi Massimo, Gabriele Capurso, Carrara Silvia
BACKGROUND: Little is known about the genetic background of individuals with familial pancreatic cancer (PC). Integrating germline testing into surveillance may uncover previously unrecognized hereditary susceptibility and expand prevention strategies beyond BRCA testing alone. This study evaluated the genetic landscape of high-risk individuals due to familiality (HRI-FHs) enrolled in a national surveillance program. 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.