Nadim Hamzaoui1, Flora Alarcon2, Nicolas Leulliot3, Rosine Guimbaud4, Bruno Buecher5, Chrystelle Colas6, Carole Corsini7, Gregory Nuel8, Benoît Terris9, Pierre Laurent-Puig10, Stanislas Chaussade11, Marion Dhooge11, Clément Madru3, Eric Clauser12,13. 1. Service de Génétique et Biologie Moléculaires, Hôpital Cochin, APHP Centre Université de Paris and Inserm UMR_S1016, Institut Cochin, Université de Paris, Paris, France. nadim.hamzaoui@aphp.fr. 2. Mathématiques appliquées Paris 5 (MAP5) CNRS: UMR8145, Université de Paris, Paris, France. 3. Laboratoire de Cristallographie et RMN Biologiques, UMR CNRS 8015, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Pharmacie de Paris, Paris, France. 4. Unité d'oncogénétique, Institut Claudius Regaud, IUCT-Oncopole, Toulouse, France. 5. Department of Medical Oncology, Institut Curie, Paris Sciences Lettres Research University, Paris, France. 6. Department of Genetics, Institut Curie, Paris Sciences Lettres Research University, Paris, France. 7. Medical Genetics Department, Centre Hospitalier Regional Universitaire de Montpellier, Montpellier, Languedoc-Roussillon, France. 8. Institute of Mathematics, National Center for French Research, Laboratory of Probability, University Pierre et Marie Curie, Sorbonne University, Paris, France. 9. Department of Pathology, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France. 10. Department of Biochemistry, Unit of Pharmacogenetics and Molecular Oncology, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France. 11. Department of gastroenterology, Cochin hospital, assistance publique-Hôpitaux de Paris, Paris Descartes university, Paris, France. 12. Service de Génétique et Biologie Moléculaires, Hôpital Cochin, APHP Centre Université de Paris and Inserm UMR_S1016, Institut Cochin, Université de Paris, Paris, France. 13. INSERM U970, Paris Descartes University, Paris, France.
Abstract
PURPOSE: Polymerase proofreading-associated polyposis is a dominantly inherited colorectal cancer syndrome caused by exonuclease domain missense variants in the DNA polymerases POLE and POLD1. Manifestations may also include malignancies at extracolonic sites. Cancer risks in this syndrome are not yet accurately quantified. METHODS: We sequenced POLE and POLD1 exonuclease domains in 354 individuals with early/familial colorectal cancer (CRC) or adenomatous polyposis. We assessed the pathogenicity of POLE variants with yeast fluctuation assays and structural modeling. We estimated the penetrance function for each cancer site in variant carriers with a previously published nonparametric method based on survival analysis approach, able to manage unknown genotypes. RESULTS: Pathogenic POLE exonuclease domain variants P286L, M294R, P324L, N363K, D368N, L424V, K425R, and P436S were found in ten families. The estimated cumulative risk of CRC at 30, 50, and 70 years was 11.1% (95% confidence interval [CI]: 4.2-17.5), 48.5% (33.2-60.3), and 74% (51.6-86.1). Cumulative risk of glioblastoma was 18.7% (3.2-25.8) at 70 years. Variants interfering with DNA binding (P286L and N363K) had a significantly higher mutagenic effect than variants disrupting ion metal coordination at the exonuclease site. CONCLUSION: The risk estimates derived from this study provide a rational basis on which to provide genetic counseling to POLE variant carriers.
PURPOSE: Polymerase proofreading-associated polyposis is a dominantly inherited colorectal cancer syndrome caused by exonuclease domain missense variants in the DNA polymerases POLE and POLD1. Manifestations may also include malignancies at extracolonic sites. Cancer risks in this syndrome are not yet accurately quantified. METHODS: We sequenced POLE and POLD1 exonuclease domains in 354 individuals with early/familial colorectal cancer (CRC) or adenomatous polyposis. We assessed the pathogenicity of POLE variants with yeast fluctuation assays and structural modeling. We estimated the penetrance function for each cancer site in variant carriers with a previously published nonparametric method based on survival analysis approach, able to manage unknown genotypes. RESULTS: Pathogenic POLE exonuclease domain variants P286L, M294R, P324L, N363K, D368N, L424V, K425R, and P436S were found in ten families. The estimated cumulative risk of CRC at 30, 50, and 70 years was 11.1% (95% confidence interval [CI]: 4.2-17.5), 48.5% (33.2-60.3), and 74% (51.6-86.1). Cumulative risk of glioblastoma was 18.7% (3.2-25.8) at 70 years. Variants interfering with DNA binding (P286L and N363K) had a significantly higher mutagenic effect than variants disrupting ion metal coordination at the exonuclease site. CONCLUSION: The risk estimates derived from this study provide a rational basis on which to provide genetic counseling to POLE variant carriers.
Authors: Pierre Saintigny; Sylvie Chevret; Benoit Rousseau; Ivan Bieche; Eric Pasmant; Nadim Hamzaoui; Nicolas Leulliot; Lucas Michon; Aurelien de Reynies; Valerie Attignon; Michael B Foote; Julien Masliah-Planchon; Magali Svrcek; Romain Cohen; Victor Simmet; Paule Augereau; David Malka; Antoine Hollebecque; Damien Pouessel; Carlos Gomez-Roca; Rosine Guimbaud; Amandine Bruyas; Marielle Guillet; Jean-Jacques Grob; Muriel Duluc; Sophie Cousin; Christelle de la Fouchardiere; Aude Flechon; Frederic Rolland; Sandrine Hiret; Esma Saada-Bouzid; Olivier Bouche; Thierry Andre; Diane Pannier; Farid El Hajbi; Stephane Oudard; Christophe Tournigand; Jean-Charles Soria; Stephane Champiat; Drew G Gerber; Dennis Stephens; Michelle F Lamendola-Essel; Steven B Maron; Bill H Diplas; Guillem Argiles; Asha R Krishnan; Severine Tabone-Eglinger; Anthony Ferrari; Neil H Segal; Andrea Cercek; Natalie Hoog-Labouret; Frederic Legrand; Clotilde Simon; Assia Lamrani-Ghaouti; Luis A Diaz; Aurelien Marabelle Journal: Cancer Discov Date: 2022-06-02 Impact factor: 38.272
Authors: Maxime Amoyel; Arthur Belle; Marion Dhooge; Einas Abou Ali; Rachel Hallit; Frederic Prat; Anthony Dohan; Benoit Terris; Stanislas Chaussade; Romain Coriat; Maximilien Barret Journal: Endosc Int Open Date: 2022-01-14