Role ofPOLEandPOLD1in familial cancer
Por:
Mur, P, Garcia-Mulero, S, del Valle, J, Magraner-Pardo, L, Vidal, A, Pineda, M, Cinnirella, G, Martin-Ramos, E, Pons, T, Lopez-Doriga, A, Belhadj, S, Feliubadalo, L, Munoz-Torres, PM, Navarro, M, Grau, E, Darder, E, Llort, G, Sanz, J, Cajal, TRY, Balmana, J, Brunet, J, Moreno, V, Piulats, JM, Matias-Guiu, X, Sanz-Pamplona, R, Aligue, R, Capella, G, Lazaro, C, Valle, L
Publicada:
1 dic 2020
Ahead of Print:
1 ago 2020
Resumen:
Purpose Germline pathogenic variants in the exonuclease domain (ED) of polymerasesPOLEandPOLD1predispose to adenomatous polyps, colorectal cancer (CRC), endometrial tumors, and other malignancies, and exhibit increased mutation rate and highly specific associated mutational signatures. The tumor spectrum and prevalence ofPOLEandPOLD1variants in hereditary cancer are evaluated in this study. Methods POLEandPOLD1were sequenced in 2813 unrelated probands referred for genetic counseling (2309 hereditary cancer patients subjected to a multigene panel, and 504 patients selected based on phenotypic characteristics). Cosegregation and case-control studies, yeast-based functional assays, and tumor mutational analyses were performed for variant interpretation. Results Twelve ED missense variants, 6 loss-of-function, and 23 outside-ED predicted-deleterious missense variants, all with population allele frequencies <1%, were identified. One ED variant (POLEp.Met294Arg) was classified as likely pathogenic, four as likely benign, and seven as variants of unknown significance. The most commonly associated tumor types were colorectal, endometrial and ovarian cancers. Loss-of-function and outside-ED variants are likely not pathogenic for this syndrome. Conclusions Polymerase proofreading-associated syndrome constitutes 0.1-0.4% of familial cancer cases, reaching 0.3-0.7% when only CRC and polyposis are considered. ED variant interpretation is challenging and should include multiple pieces of evidence.
Filiaciones:
Mur, P:
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Barcelona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol ONCOBELL, Barcelona, Spain
Garcia-Mulero, S:
IDIBELL, Catalan Inst Oncol, Oncol Data Analyt Program ODAP, Barcelona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol ONCOBELL, Barcelona, Spain
del Valle, J:
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol ONCOBELL, Barcelona, Spain
IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Barcelona, Spain
Magraner-Pardo, L:
Spanish Natl Canc Res Ctr CNIO, Prostate Canc Clin Res Unit, Madrid, Spain
Vidal, A:
IDIBELL, Dept Pathol, Bellvitge Univ Hosp, Barcelona, Spain
Pineda, M:
IDIBELL, Program Mol Mech & Expt Therapy Oncol ONCOBELL, Barcelona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Barcelona, Spain
Cinnirella, G:
IDIBELL, Program Mol Mech & Expt Therapy Oncol ONCOBELL, Barcelona, Spain
IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Barcelona, Spain
Martin-Ramos, E:
Univ Barcelona, Sch Med, Dept Biomed Sci, IDIBAPS, Barcelona, Spain
Pons, T:
Spanish Natl Res Council, Natl Ctr Biotechnol CNB CSIC, Dept Immunol & Oncol, Madrid, Spain
Lopez-Doriga, A:
Ctr Invest Biomed Red Epidemiol & Salud Publ CIBE, Madrid, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol ONCOBELL, Barcelona, Spain
IDIBELL, Catalan Inst Oncol, Oncol Data Analyt Program ODAP, Barcelona, Spain
Belhadj, S:
IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Barcelona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol ONCOBELL, Barcelona, Spain
Feliubadalo, L:
IDIBELL, Program Mol Mech & Expt Therapy Oncol ONCOBELL, Barcelona, Spain
IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Barcelona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
Munoz-Torres, PM:
IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Barcelona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol ONCOBELL, Barcelona, Spain
Navarro, M:
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Barcelona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol ONCOBELL, Barcelona, Spain
Grau, E:
IDIBELL, Program Mol Mech & Expt Therapy Oncol ONCOBELL, Barcelona, Spain
IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Barcelona, Spain
Darder, E:
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol ONCOBELL, Barcelona, Spain
IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Barcelona, Spain
Llort, G:
Consorci Sanitari Terrassa, Barcelona, Spain
Hosp Univ Parc Tauli, Dept Med Oncol, Parc Tauli, Barcelona, Spain
Sanz, J:
Althaia Xarxa Assistencial Univ Manresa, Med Oncol Dept, Genet Counseling Unit, Manresa, Spain
Cajal, TRY:
Hosp Santa Creu I St Pau, Dept Med Oncol, Barcelona, Spain
Balmana, J:
Vall dHebron Univ Hosp, Vall dHebron Inst Oncol VHIO, Dept Med Oncol, Barcelona, Spain
Brunet, J:
IDIBELL, Program Mol Mech & Expt Therapy Oncol ONCOBELL, Barcelona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Barcelona, Spain
IDIBGi, Hereditary Canc Program, Catalan Inst Oncol, Girona, Spain
Moreno, V:
IDIBELL, Catalan Inst Oncol, Oncol Data Analyt Program ODAP, Barcelona, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol ONCOBELL, Barcelona, Spain
Univ Barcelona, Fac Med, Dept Clin Sci, Barcelona, Spain
Ctr Invest Biomed Red Epidemiol & Salud Publ CIBE, Madrid, Spain
Piulats, JM:
IDIBELL, Program Mol Mech & Expt Therapy Oncol ONCOBELL, Barcelona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
Bellvitge Univ Hosp, Dept Med Oncol, IDIBELL, Barcelona, Spain
Matias-Guiu, X:
IDIBELL, Program Mol Mech & Expt Therapy Oncol ONCOBELL, Barcelona, Spain
IDIBELL, Dept Pathol, Bellvitge Univ Hosp, Barcelona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
Sanz-Pamplona, R:
IDIBELL, Program Mol Mech & Expt Therapy Oncol ONCOBELL, Barcelona, Spain
Ctr Invest Biomed Red Epidemiol & Salud Publ CIBE, Madrid, Spain
IDIBELL, Catalan Inst Oncol, Oncol Data Analyt Program ODAP, Barcelona, Spain
Aligue, R:
Univ Barcelona, Sch Med, Dept Biomed Sci, IDIBAPS, Barcelona, Spain
Capella, G:
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol ONCOBELL, Barcelona, Spain
IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Barcelona, Spain
Lazaro, C:
IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Barcelona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
IDIBELL, Program Mol Mech & Expt Therapy Oncol ONCOBELL, Barcelona, Spain
Valle, L:
IDIBELL, Program Mol Mech & Expt Therapy Oncol ONCOBELL, Barcelona, Spain
Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain
IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Barcelona, Spain
Hybrid Gold, Green Published
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