Abstract A012: The Spanish Familial Pancreatic Cancer Registry (PANGENFAM): Genetic testing and follow-up of high risk individuals
Authors: Melian Emma , de Paredes Ana García García , Rodríguez Mercedes , López Jorge Villalón , Muñoz María , Blaquez Javier , Ruz Ignacio , Sanjuanbenito Alfonso , Lobo Eduardo , Lopéz Victoria , Ponce Carmen Guillen , Foruny Olcina José Ramón , Durán Sergio López , Carrato Alfredo , Earl Julie 
Published: January 2024

Abstract
Introduction: The Spanish familial pancreatic cancer registry (PANGENFAM) was established in 2009, with the main objective to study the genetic and phenotypic characteristics of familial pancreatic cancer families and offer screening of high-risk individuals for early detection. Methods: Targeted panel and exome sequencing of 52 FPC and 33 sporadic PDAC cases was performed to identify genes and novel variants related to PDAC risk. Healthy high-risk relatives of FPC cases enter into a screening that consists of an annual MRI, echo-endoscopy and routine blood tests, which is followed by a biopsy if a suspicious lesion is identified. Results: The registry and associated biobank is maintained thanks to a stable collaboration between the departments of Medical Oncology, Gastroenterology, Radiology General Surgery and Pathology. The registry currently includes over 150 families and 350 individuals, including PDAC cases and high risk individuals. Targeted sequencing analysis of DNA repair genes involved in familial cancer identified pathogenic variants in 7.5% of FPC cases in the MLH1 and CDKN2A genes, likely pathogenic variants were found in 5.7% of cases in the genes MUTYH, TERT and ATM. Likely pathogenic variants were found in 9.4% of sporadic cases in the genes POLQ, CHEK2 and FANCM and no pathogenic variants were identified. By exome sequencing, missense variants with a damaging effect were found in 11 FPC cases, including stop gain, stop loss or frameshift variants in 5 FPC cases (45.45%), affecting WWOX, C2orf83, CYP3A5 and TANGO2. KRAS somatic mutations in codon 12 and 13 were more frequently detected in sporadic PDAC cases (70%) compared to familial cases (16%) via the liquid biopsy. Interestingly, the median overall survival for sporadic and familial PDAC cases in our cohort was 10.2 vs. 21.7 months (p⇒0.01), respectively, even when adjusted for stage at diagnosis and first line adjuvant therapy. From all the families included in the registry, 185 were offered the high-risk screening program for early detection. Currently 129 individuals are actively participating in the screening program, of which, 72% of these individuals have a non-normal looking pancreas via MRI or EUS. The most commonly detected lesions were cysts and IPMN found in 32% and 12% individuals, respectively. Screening has successfully detected and treated solid lesions in 4 high-risk individuals, including 3 early PDAC and 1 neuroendocrine tumor. An additional 11 individuals with lesions with worrisome features are under close follow-up. Conclusions: Panel sequencing has identified pathogenic variants in known familial cancer genes that are also associated with FPC risk. Exome sequencing in panel negative FPC cases has identified novel risk associated genes. The molecular and clinical profile of FPC and sporadic cases are distinct which should be taken into account in the clinic.
Citation Format: Emma Melian, Ana García García de Paredes, Mercedes Rodríguez, Jorge Villalón López, María Muñoz, Javier Blaquez, Ignacio Ruz, Alfonso Sanjuanbenito, Eduardo Lobo, Victoria Lopéz, Carmen Guillen Ponce, José Ramón Foruny Olcina, Sergio López Durán, Alfredo Carrato, Julie Earl. The Spanish Familial Pancreatic Cancer Registry (PANGENFAM): Genetic testing and follow-up of high risk individuals [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A012.