A comprehensive analysis of candidate genes in familial pancreatic cancer families reveals a high frequency of potentially pathogenic germline variants
Por:
Earl, J, Galindo-Pumarino, C, Encinas, J, Barreto, E, Castillo, ME, Pachon, V, Ferreiro, R, Rodriguez-Garrote, M, Gonzalez-Martinez, S, Cajal, TRY, Diaz, LR, Chirivella-Gonzalez, I, Rodriguez, M, de Castro, EM, Garcia-Seisdedos, D, Munoz, G, Rosa, JMR, Marquez, M, Malats, N, Carrato, A
Publicada:
1 mar 2020
Resumen:
Background: The 5-year survival rate of patients with pancreatic ductal adenocarcinoma (PDAC) is around 5% due to the fact that the majority of patients presentwith advanced disease that is treatment resistant. Familial pancreatic cancer (FPC) is a rare disorder that is defined as a family with at least two affected first degree relatives, with an estimated incidence of 4%-10%. The genetic basis is unknown in the majority of families although around 10%-13% of families carry germlinemutations in known genes associated with hereditary cancer and pancreatitis syndromes. Methods: Panel sequencing was performed of 35 genes associated with hereditary cancer in 43 PDAC cases from families with an apparent hereditary pancreatic cancer syndrome. Findings: Pathogenic variants were identified in 19% (5/26) of PDAC cases from pure FPC families in the genes MLH1, CDKN2A, POLQ and FANCM. Low frequency potentially pathogenic VUS were also identified in 35% (9/26) of PDAC cases from FPC families in the genes FANCC, MLH1, PMS2, CFTR, APC and MUTYH. Furthermore, an important proportion of PDAC cases harboured more than one pathogenic, likely pathogenic or potentially pathogenic VUS, highlighting themultigene phenotype of FPC. Interpretation: The genetic basis of familial or hereditary pancreatic cancer can be explained in 21% of families by previously described hereditary cancer genes. Low frequency variants in other DNA repair genes are also present in 35% of families which may contribute to the risk of pancreatic cancer development. Funding: This study was funded by the Instituto de Salud Carlos III (Plan Estatal de I + D + i 2013-2016): ISCIII (PI09/02221, PI12/01635, PI15/02101 and PI18/1034) and co-financed by the European Development Regional Fund "A way to achieve Europe" (ERDF), the Biomedical Research Network in Cancer: CIBERONC (CB16/12/00446), Red Tematica de investigacion cooperativa en cancer: RTICC (RD12/0036/0073) and La Asociacion Espanola contra el Cancer: AECC (Grupos Coordinados Estables 2016). (c) 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Filiaciones:
Earl, J:
Ramon y Cajal Hlth Res Inst IRYCIS, Med Oncol Res Lab, Mol Epidemiol & Predict Tumor Markers Grp, Carretera Colmenar Km 9100, Madrid 28034, Spain
Biomed Res Network Canc CIBERONC, C Monforte de Lemos 3-5,Pabellon 11, Madrid 28029, Spain
Galindo-Pumarino, C:
Ramon y Cajal Hlth Res Inst IRYCIS, Med Oncol Res Lab, Mol Epidemiol & Predict Tumor Markers Grp, Carretera Colmenar Km 9100, Madrid 28034, Spain
Biomed Res Network Canc CIBERONC, C Monforte de Lemos 3-5,Pabellon 11, Madrid 28029, Spain
Encinas, J:
Ramon y Cajal Hlth Res Inst IRYCIS, Med Oncol Res Lab, Mol Epidemiol & Predict Tumor Markers Grp, Carretera Colmenar Km 9100, Madrid 28034, Spain
Barreto, E:
Ramon y Cajal Hlth Res Inst IRYCIS, Med Oncol Res Lab, Mol Epidemiol & Predict Tumor Markers Grp, Carretera Colmenar Km 9100, Madrid 28034, Spain
Castillo, ME:
Ramon y Cajal Hlth Res Inst IRYCIS, Med Oncol Res Lab, Mol Epidemiol & Predict Tumor Markers Grp, Carretera Colmenar Km 9100, Madrid 28034, Spain
Pachon, V:
Ramon y Cajal Hlth Res Inst IRYCIS, Med Oncol Res Lab, Mol Epidemiol & Predict Tumor Markers Grp, Carretera Colmenar Km 9100, Madrid 28034, Spain
Biomed Res Network Canc CIBERONC, C Monforte de Lemos 3-5,Pabellon 11, Madrid 28029, Spain
Ferreiro, R:
Ramon y Cajal Hlth Res Inst IRYCIS, Med Oncol Res Lab, Mol Epidemiol & Predict Tumor Markers Grp, Carretera Colmenar Km 9100, Madrid 28034, Spain
Rodriguez-Garrote, M:
Ramon y Cajal Hlth Res Inst IRYCIS, Med Oncol Res Lab, Mol Epidemiol & Predict Tumor Markers Grp, Carretera Colmenar Km 9100, Madrid 28034, Spain
Biomed Res Network Canc CIBERONC, C Monforte de Lemos 3-5,Pabellon 11, Madrid 28029, Spain
Gonzalez-Martinez, S:
Ramon y Cajal Hlth Res Inst IRYCIS, Med Oncol Res Lab, Mol Epidemiol & Predict Tumor Markers Grp, Carretera Colmenar Km 9100, Madrid 28034, Spain
Cajal, TRY:
Santa Creu & St Pau Hosp, Med Oncol Dept, Mas Casanovas 90, Barcelona 08041, Spain
Diaz, LR:
12 Octubre Hosp, Familial & Hereditary Canc Unit, Med Oncol Dept, Av Cordoba S-N, Madrid 28041, Spain
Chirivella-Gonzalez, I:
Valencia Univ Hosp Clin, Genet Counselling Unit, Av Blasco Ibanez 17, Valencia 46010, Spain
Rodriguez, M:
Hosp Teresa Herrera, A Coruna Biomed Res Inst, Xubias de Arriba 84, La Coruna 15006, Spain
de Castro, EM:
Marques de Valdecilla Univ Hosp, Med Oncol Dept, Av Valdecilla 25, Santander 39008, Spain
Garcia-Seisdedos, D:
Inst Ramon y Cajal Invest Sanitaria IRYCIS, Translat Genom Core Facil, Madrid, Spain
Munoz, G:
Inst Ramon y Cajal Invest Sanitaria IRYCIS, Translat Genom Core Facil, Madrid, Spain
Rosa, JMR:
Inst Ramon y Cajal Invest Sanitaria IRYCIS, Pathol Dept, Madrid, Spain
Marquez, M:
Biomed Res Network Canc CIBERONC, C Monforte de Lemos 3-5,Pabellon 11, Madrid 28029, Spain
Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, Madrid, Spain
Malats, N:
Biomed Res Network Canc CIBERONC, C Monforte de Lemos 3-5,Pabellon 11, Madrid 28029, Spain
Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, Madrid, Spain
Carrato, A:
Ramon y Cajal Hlth Res Inst IRYCIS, Med Oncol Res Lab, Mol Epidemiol & Predict Tumor Markers Grp, Carretera Colmenar Km 9100, Madrid 28034, Spain
Biomed Res Network Canc CIBERONC, C Monforte de Lemos 3-5,Pabellon 11, Madrid 28029, Spain
Gold, Green Published
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