Germline pathogenic variants among Mexican patients with adenocarcinoma of the pancreas.
Authors: Rodriguez Olivares Jose Luis , Chavarri Guerra Yanin , Arteaga Jazmin , De la Mora Molina Hector , Rodríguez-Faure Andrés , Hernández Ana María , Castillo Danielle , Weitzel Jeffrey N. 
Published: January 2022

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Background: The reported frequency of germline pathogenic variants (PVs) in patients with pancreatic cancer is 8-10%. Depending on the setting, pancreatic cancer-associated germline PVs in the BRCA and CDKN2A genes are the most commonly detected. The mismatch repair genes (MMR; Lynch syndrome) , TP53, STK11, ATM and PALB2 are also associated with an increased risk of pancreatic cancer . The identification of PVs in patients with pancreatic cancer is important as there may be a benefit of targeted therapies, such as PARP inhibitors for cases with defective double strand break repair or response to immunotherapy with defective MMR and high tumor mutational burden. Additionally, identification of predisposing PVs can enable screening and prevention for other family members through cascade testing. According to international guidelines, all patients diagnosed with exocrine pancreatic cancer are candidates for genetic testing. However, there is an underrepresentation of ethnic/ racial minorities, including Hispanic patients, in genetic studies. Methods: Between April 2017 and May 2020, patients with diagnosis of pancreatic adenocarcinoma who were treated at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán and enrolled in the international Clinical Cancer Genomics Community Research Network registry were included in this analysis. Genetic testing was performed by full sequencing of the following genes: BRCA1, BRCA2, TP53, NF1, ATM, CHEK2, PALB2, CDKN2A, BRIP1, RAD50, RAD51C, RAD51D, MLH1, MSH2, MSH6, PMS2 and EPCAM, as well as multiplex ligation-dependent probe amplification for selected genes and BRCA1 ex9-12del (Mexican founder mutation) screening with a three-primer polymerase chain reaction. Pedigrees, clinical and demographic data were obtained from the clinical records. Results: Forty-two patients with a diagnosis of pancreatic adenocarcinoma were included, with a median age at diagnosis of 57 years (range, 43-79), and 23/42 (55%) were women. The proportion of cases with operable, unresectable and metastatic disease at diagnosis was similar (33.3% for each group). The frequency of PVs was 11.9% ( ATM n =2, TP53 n =1, PALB2 n =1 and CHEK2 n =1). With a median follow-up 20 months 29/42 patients had died at the time of analysis (69%), the median overall survival was 16 months (range 3-84 months). No PVs were detected in the 4/42 patients who met the definition of familial pancreatic cancer (9.5%). Conclusions: Our results confirm the presence of PVs in cancer susceptibility genes in Mexican patients with pancreatic cancer, which is similar to that reported in other populations. However, it is notable that no BRCA PVs were identified in this small sample, as they are the most common PV found in other populations. Given to the heterogeneity of the PVs identified, our study supports the use of multi- gene panel testing in Hispanic patients with pancreatic cancer.