N33: Validation And Updating Of Path_MLH1 In Cases With Class 4 And 5 Genetic Variants; A Prospective Lynch Syndrome Database (PLSD) Report

T. Seppälä1, J. P. Plazzer2, M. Dominguez-Valentin3, S. Nakken4, C. Engel5, S. Aretz5, M. A. Jenkins6, L. Sunde7, I. Bernstein7, F. Balaguer8, A. Lindblom9, D. G. Evans10, L. Bertario11, J. Burn12, E. Holinski-Feder13, F. Lopez-Koestner14, A. Della Valle15, K. Heinimann16, C. A. Vaccaro17, W. H. de Vos tot Nederveen Cappel18, R. H. Sijmons19, N. Gluck20, L. Katz20, G. M. Cavestro11, E. Hovig4, F. Macrae21, G. Möslein22, J. Sampson23, G. Capella8, J. P. Mecklin1, P. Møller24

1 – Finland. 2 – InSiGHT database, Australia. 3 – PLSD curator Norway. 4 – Norway. 5 – German HNPCC consortium. 6 – Colon Cancer Family Registry, Australia, USA, Canada. 7 – Denmark. 8 – Spain. 9 – Sweden. 10 – Manchester, United Kingdom. 11 – Italy. 12 – Newcastle, United Kingdom. 13 – Münich, Germany. 14 – Chile. 15 – Uruguay. 16 – Switzerland. 17 – Argentina. 18 – Leiden, Holland. 19 – Groningen, Holland. 20 – Israel. 21 – Melbourne, Australia. 22 – Germany. 23 – Cardiff, United Kingdom. 24 – PLSD PI; OUS Norway, Witten-Herdecke, Germany.


Aim: Determine average risks for and survival after cancer in path_MLH1 carriers.

Method: Previously reported results were validated in an independent series of path_MLH1 carriers followed-up by colonoscopy. Combined results merging former and present series included only carriers with pathogenic class 4 or 5 variants listed in the InSiGHT database.

Results: The validation series including 10,037 observation years confirmed previously published cumulative risk for any cancer: at fifty years, 37% in the validation series compared to 40% in the previous series, and at 75 years, 78% compared to 76%. The combined series of path_MLH1 variant carriers included 24,297 observation years. Cumulative risk for cancer in specific organs or group of organs at 75 years were (males/females): Any cancer 70%/80%; colon_rectum 56%/47%; endometrium  -/37%; ovaries -/11%; stomach_duodenum_bileduct_pancreas 21%/11%; ureter_kidney  4.7%/3.6%; urinary bladder 6.4%/4.9%; prostate 12%/-; breast -/12%; brain 0.7%/1.6%. Ten-year crude survival after cancer in different organs were: colon 86%; endometrium 90%; ovaries 82%; ureter_kidney 61%; urinary bladder 54%; prostate 90%, breast 80%; brain 0%.

Conclusion: PLSD reports average risks for and survival after cancer in path_MLH1 carriers of variants classified as clinically actionable in the InSiGHT database. See www.PLSD.eu for risk determination in any single patient by age and gender.