Discovering Hereditary Risk Through Surveillance: A Prospective Genetic Analysis of Individuals With Familial Pancreatic Cancer.
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.
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.
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.
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.
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.
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.
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.
Authors
Paiella Paiella, Secchettin Secchettin, Archibugi Archibugi, De Luca De Luca, Bonifacio Bonifacio, Laghi Laghi, Lionetto Lionetto, Milanetto Milanetto, Sereni Sereni, Coluccio Coluccio, Lauri Lauri, Dal Buono Dal Buono, Patruno Patruno, Gabriel Gabriel, Sassatelli Sassatelli, Binda Binda, Bonvissuto Bonvissuto, Uliana Uliana, Malleo Malleo, Cavestro Cavestro, Terrin Terrin, Martino Martino, Pasquali Pasquali, De Pastena De Pastena, De Cobelli De Cobelli, Poletti Poletti, Venturini Venturini, Puzzono Puzzono, Zerbi Zerbi, Arcidiacono Arcidiacono, Salvia Salvia, Falconi Falconi, Capurso Capurso, Carrara Carrara
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