Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment : a report from the prospective Lynch syndrome database

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Author(s): Title: Year: Version: Copyright: Rights: Rights url: Please cite the original version: CC BY 4.0 https://creativecommons.org/licenses/by/4.0/ Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment : a report from the prospective Lynch syndrome database © 2023 the Authors Published version Dominguez-Valentin, Mev; Haupt, Saskia; Seppälä, Toni T.; Sampson, Julian R.; Sunde, Lone; Bernstein, Inge; Jenkins, Mark A.; Engel, Christoph; Aretz, Stefan; Nielsen, Maartje; Capella, Gabriel; Balaguer, Francesc; Evans, Dafydd Gareth; Burn, John; Holinski-Feder, Elke; Bertario, Lucio; Bonanni, Bernardo; Lindblom, Annika; Levi, Zohar; Macrae, Finlay; Winship, Ingrid; Plazzer, John-Paul; Sijmons, Rolf; Laghi, Luigi; Della Valle, Adriana; Heinimann, Karl; Dębniak, Tadeusz; Fruscio, Robert; Lopez-Koestner, Francisco; Alvarez-Valenzuela, Karin; Katz, Lior H.; Laish, Ido; Vainer, Elez; Vaccaro, Carlos; Carraro, Dirce Maria; Monahan, Kevin; Half, Elizabeth; Stakelum, Aine; Winter, Des; Kennelly, Rory; Gluck, Nathan; Sheth, Harsh; Abu-Freha, Naim; Greenblatt, Marc; Rossi, Benedito Mauro; Bohorquez, Mabel; Cavestro, Giulia Martina; Lino-Silva, Leonardo S.; Horisberger, Karoline; Tibiletti, Maria Grazia; do Nascimento, Ivana; Thomas, Huw; Rossi, Norma Teresa; Apolinário da Silva, Leandro; Zaránd, Attila; RuizBañobre, Juan; Heuveline, Vincent; Mecklin, Jukka-Pekka; Pylvänäinen, Kirsi; Renkonen-Sinisalo, Laura; Lepistö, Anna; Peltomäki, Päivi; Therkildsen, Christina; Madsen, Mia Gebauer; Burgdorf, Stefan Kobbelgaard; Hopper, John L.; Win, Aung Ko; Haile, Robert W.; Lindor, Noralane; Gallinger, Steven; Le Marchand, Loïc; Newcomb, Polly A.; Figueiredo, Jane; Buchanan, Daniel D.; Thibodeau, Stephen N.; von Knebel Doeberitz, Magnus; Loeffler, Markus; Rahner, Nils; Schröck, Evelin; Steinke-Lange, Verena; Schmiegel, Wolff; Vangala, Deepak; Perne, Claudia; Hüneburg, Robert; Redler, Silke; Büttner, Reinhard; Weitz, Jürgen; Pineda, Marta; Duenas, Nuria; Vidal, Joan Brunet; Moreira, Leticia; Sánchez, Ariadna; Hovig, Eivind; Nakken, Sigve; Green, Kate; Lalloo, Fiona; Hill, James; Crosbie, Emma; Mints, Miriam; Goldberg, Yael; Tjandra, Douglas; ten Broeke, Sanne W.; Kariv, Revital; Rosner, Guy; Advani, Suresh H.; Thomas, Lidiya; Shah, Pankaj; Shah, Mithun; Neffa, Florencia; Esperon, Patricia; Pavicic, Walter; Torrezan, Giovana Tardin; Bassaneze, Thiago; Martin, Claudia Alejandra; Moslein, Gabriela; Moller, Pål Dominguez-Valentin, M., Haupt, S., Seppälä, T. T., Sampson, J. R., Sunde, L., Bernstein, I., Jenkins, M. A., Engel, C., Aretz, S., Nielsen, M., Capella, G., Balaguer, F., Evans, D. G., Burn, J., Holinski-Feder, E., Bertario, L., Bonanni, B., Lindblom, A., Levi, Z., . . . Moller, P. (2023). Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment : a report from the prospective Lynch syndrome database. EClinicalMedicine, 58, Article 101909. https://doi.org/10.1016/j.eclinm.2023.101909 2023 Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective Lynch syndrome database Mev Dominguez-Valentin, a , ∗ Saskia Haupt, b , c Toni T. Seppälä, d , e , f Julian R. Sampson, g Lone Sunde, h , i Inge Bernstein, j , k Mark A. Jenkins, l Christoph Engel, m Stefan Aretz, n Maartje Nielsen, o Gabriel Capella, p Francesc Balaguer, q Dafydd Gareth Evans, r John Burn, s Elke Holinski-Feder, t , u Lucio Bertario, v Bernardo Bonanni, w Annika Lindblom, x Zohar Levi, y Finlay Macrae, z , co Ingrid Winship, z , co , aa John-Paul Plazzer, z , co Rolf Sijmons, ab Luigi Laghi, ac Adriana Della Valle, ad Karl Heinimann, ae Tadeusz Dębniak, af Robert Fruscio, ag Francisco Lopez-Koestner, ah , cp Karin Alvarez-Valenzuela, ah , cp Lior H. Katz, ai Ido Laish, ai Elez Vainer, aj Carlos Vaccaro, ak Dirce Maria Carraro, al Kevin Monahan, am Elizabeth Half, an Aine Stakelum, ao Des Winter, ao Rory Kennelly, ao Nathan Gluck, ap Harsh Sheth, aq Naim Abu-Freha, ar Marc Greenblatt, as Benedito Mauro Rossi, at Mabel Bohorquez, au Giulia Martina Cavestro, av Leonardo S. Lino-Silva, aw Karoline Horisberger, ax , cq Maria Grazia Tibiletti, ay Ivana do Nascimento, az Huw Thomas, ba Norma Teresa Rossi, bb Leandro Apolinário da Silva, bc , cr Attila Zaránd, bd Juan Ruiz-Bañobre, be , cs Vincent Heuveline, b , c Jukka-Pekka Mecklin, bf , ct Kirsi Pylvänäinen, bg Laura Renkonen-Sinisalo, e , f Anna Lepistö, e , f Päivi Peltomäki, bh Christina Therkildsen, bi Mia Gebauer Madsen, bj Stefan Kobbelgaard Burgdorf, bk John L. Hopper, bl Aung Ko Win, bl Robert W. Haile, bm Noralane Lindor, bn Steven Gallinger, bo Loïc Le Marchand, bp Polly A. Newcomb, bq Jane Figueiredo, bq Daniel D. Buchanan, br , bs , bt Stephen N. Thibodeau, bu Magnus von Knebel Doeberitz, bv , cu Markus Loeffler, m Nils Rahner, bw Evelin Schröck, bx , cv , cw , cx Verena Steinke-Lange, by , cy Wolff Schmiegel, bz Deepak Vangala, bz Claudia Perne, n Robert Hüneburg, ca Silke Redler, bw Reinhard Büttner, cb Jürgen Weitz, cc Marta Pineda, p Nuria Duenas, p Joan Brunet Vidal, p Leticia Moreira, q Ariadna Sánchez, q Eivind Hovig, a , cd Sigve Nakken, a , cd , ce Kate Green, r Fiona Lalloo, r James Hill, cf Emma Crosbie, cg , cz Miriam Mints, ch Yael Goldberg, ci Douglas Tjandra, z , co Sanne W. ten Broeke, ab Revital Kariv, ao Guy Rosner, ao Suresh H. Advani, cj Lidiya Thomas, cj Pankaj Shah, ck Mithun Shah, ck Florencia Neffa, ac Patricia Esperon, ac Walter Pavicic, cl Giovana Tardin Torrezan, ak Thiago Bassaneze, as Claudia Alejandra Martin, cm Gabriela Moslein, cn and Pål Moller a a Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, 0379, Oslo, Norway b Engineering Mathematics and Computing Lab (EMCL), Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Heidelberg, Germany c Data Mining and Uncertainty Quantification (DMQ), Heidelberg Institute for Theoretical Studies (HITS), Heidelberg, Germany d Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Center, Tampere University Hospital, Finland e Department of Gastrointestinal Surgery, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland f Applied Tumor Genomics, Research Program Unit, University of Helsinki, Helsinki, Finland g Division of Cancer and Genetics, Institute of Medical Genetics, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN, UK h Department of Clinical Genetics, Aalborg University Hospital, 9000, Aalborg, Denmark i Department of Biomedicine, Aarhus University, DK-8000, Aarhus, Denmark j Department of Surgical Gastroenterology, Aalborg University Hospital, Aalborg University, 9100, Aalborg, Denmark k Department of Clinical Medicine, Aalborg University Hospital, Aalborg University, 9100, Aalborg, Denmark l Melbourne School of Population and Global Health, Centre for Epidemiology and Biostatistics, The University of Melbourne, Parkville, 3010, Victoria, Australia m Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, 04107, Leipzig, Germany n Institute of Human Genetics, National Center for Hereditary Tumor Syndromes, Medical Faculty, University Hospital Bonn, University of Bonn, 53127, Bonn, Germany o Department of Clinical Genetics, Leids Universitair Medisch Centrum, 2300RC, Leiden, the Netherlands p Hereditary Cancer Program, Institut Català d’Oncologia-IDIBELL, L; Hospitalet de Llobregat, 08908, Barcelona, Spain q Gastroenterology Department, Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain r Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, M13 9WL, UK s Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, NE1 7RU, UK t Campus Innenstadt, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, 80336, Munich, Germany u Center of Medical Genetics, 80335, Munich, Germany Abbreviations: AIR, Annual incidence rate; CIs, Confidence intervals; CRC, Colorectal cancer; LS, Lynch syndrome; MMR, Mismatch repair; NCCN, National comprehensive cancer network; path_MMR, Pathogenic or likely pathogenic variant in one of the MMR genes (MLH1,MSH2,MSH6, or PMS2); PLSD, Prospective Lynch syndrome database *Corresponding author. Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo, Norway. E-mail address: mev.d[email protected] (M. Dominguez-Valentin). www.thelancet.com Vol ▪▪, 2023 1 Articles v Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology, Fondazione IRCCS Instituto Nazionale dei Tumori, IRCCS, 20141, Milan, Italy w Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, 20141, Milan, Italy x Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76, Stockholm, Sweden y Service High Risk GI Cancer Gastroenterology, Department Rabin Medical Center, Israel z Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melbourne, Australia aa Department of Medicine, University of Melbourne, Melbourne, Australia ab Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands ac Department of Medicine and Surgery, Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, University of Parma, Parma, Italy ad Hospital Fuerzas Armadas, Grupo Colaborativo Uruguayo, Investigación de Afecciones Oncológicas Hereditarias (GCU), Montevideo, Uruguay ae Medical Genetics, Institute for Medical Genetics and Pathology, University Hospital Basel, Switzerland af Department of Genetics and Pathology, International Hereditary Cancer Center, ul. Unii Lubelskiej 1, 71-252, Szczecin, Poland ag Department of Medicine and Surgery, University of Milan Bicocca, A.O. San Gerardo, Clinic of Obstetrics and Gynecology, Via Pergolesi 33, Monza (MB), Italy ah Clínica Universidad de los Andes, Chile ai Department of Gastroenterology, Hadassah, Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Israel aj Hadassah Medical Center, Israel ak Hereditary Cancer Program (PROCANHE) Hospital Italiano de Buenos Aires, Argentina al Clinical and Functional Genomics Group, A.C.Camargo Cancer Center, Sao Paulo, Brazil am Lynch Syndrome & Family Cancer Clinic, St Mark’s Hospital, Harrow, HA1 3UJ, London, UK an Gastrointestinal Cancer Prevention Unit, Gastroenterology Department, Rambam Health Care Campus, Haifa, Israel ao St Vincent’s University Hospital, Ireland ap Department of Gastroenterology, Tel-Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel-Aviv University, Israel aq Foundation for Research in Genetics and Endocrinology, Institute of Human Genetics, FRIGE House, Ahmedabad, 380015, India ar Soroka University Medical Center, Ben-Gurion University of the Negev, Beer Sheva, Southern Israel, Israel as University of Vermont, Larner College of Medicine, Burlington, VT, 05405, USA at Hospital Sirio Libanes, Sao Paulo, Brazil au University of Tolima, Tolima, Colombia av Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, 20132, Milan, Italy aw Surgical Pathology, Instituto Nacional de Cancerologia, Mexico City, Mexico ax Department of Visceral and Transplantation Surgery, University Hospital of Zurich, Switzerland ay Ospedale di Circolo ASST Settelaghi, Centro di Ricerca tumori eredo-familiari, Università dell’Insubria, Varese, Italy az Universidade Federal de Bahia, Bahia, Brazil ba St Mark’s Hospital, Department of Surgery and Cancer, Imperial College London, London, UK bb Fundación para el Progreso de la Medicina”y“Sanatorio Allende”, Córdoba, Argentina bc Hospital Universitário Oswaldo Cruz, Universidade de Pernambuco, Recife, Brazil bd 1st Department of Surgery, Semmelweis University, Hungary be Department of Medical Oncology, University Clinical Hospital of Santiago de Compostela (SERGAS); Trans-ational Medical Oncology Group (Oncomet), Health Research Institute of Santiago de Compostela (IDIS); Genomes and Disease, Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela (USC), 15706, Santiago de Compostela, Spain bf Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland bg Department of Education and Science, Central Finland Health Care District, Jyväskylä, Finland bh Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland bi The Danish HNPCC Register, Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark bj Department of Urology, Aarhus University Hospital, Denmark bk Department of Surgery and Transplantation, Rigshospitalet, Copenhagen University Hospital, Denmark bl Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia bm Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University, USA bn Department of Health Science Research, Mayo Clinic Arizona, USA bo Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Canada bp University of Hawaii Cancer Center, USA bq Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109-1024, USA br Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia bs University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia bt Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Victoria, Australia Articles 2 www.thelancet.com Vol ▪▪, 2023 bu Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA bv Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany bw Institute of Human Genetics, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Germany bx National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany by Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany bz Department of Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany ca Department of Internal Medicine, University Hospital Bonn, Bonn, Germany cb Institute of Pathology, Faculty of Medicine and University Hospital Cologne, Cologne, Germany cc Technische Universität Dresden, Dresden, Germany cd Centre for Bioinformatics, Department of Informatics, University of Oslo, Oslo, Norway ce Centre for Cancer Cell Reprogramming (CanCell), Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway cf Department of Surgery, Central Manchester University Hospitals NHS Foundation Trust and University of Manchester, London, UK cg Gynaecological Oncology Research Group, Manchester University NHS Foundation Trust, Manchester, UK ch Division of Obstetrics and Gyneacology, Department of Women’s and Children’s Health, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden ci Head Adult Genetic Service, Raphael Recanati Genetic Institute, Rabin Medical Center–Beilinson Hospital, Petach Tikva, Israel cj Sushrut Hospital and Research Centre, Mumbai, India ck Zydus Cancer Centre, Ahmedabad, India cl Instituto de Medicina Traslacional e Ingenieria Biomedica (IMTIB), CONICET IU, Hospital Italiano de Buenos Aires, Buenos Aires, 94, Argentina cm Hospital Privado Universiatrio de Córdoba, Cordoba, Argentina cn Surgical Center for Hereditary Tumors, Ev. Bethesda Khs Duisburg, University Witten-Herdecke, Herdecke, Germany co Department of Medicine, Melbourne University, Melbourne, Australia cp Programa Cáncer Heredo Familiar, Santiago, Chile cq Depart-ment of Surgery, Universitätsmedizin Mainz, Germany cr SEQUIPE, Recife, Brazil cs Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029, Madrid, Spain ct Department of Surgery, Central Finland Health Care District, Jyväskylä, Finland cu Cooperation Unit Applied Tumour Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany cv German Cancer Consortium (DKTK) Dresden and German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany cw Institute for Clinical Genetics, Faculty of Medicine and University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany cx Hereditary Cancer Syndrome Center Dresden, Faculty of Medicine and University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany cy MGZ - Medical Genetics Center, Munich, Germany cz Division of Cancer Sciences, University of Manchester, Manchester, UK Summary Background The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time. Methods The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender. Findings Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers. Interpretation In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. eClinicalMedicine 2023;▪: 101909 Published Online XXX https://doi.org/10. 1016/j.eclinm.2023. 101909 Articles www.thelancet.com Vol ▪▪, 2023 3 Funding We acknowledge funding from the Norwegian Cancer Society, contract 194751-2017. Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Keywords: Mortality; Survival; Lynch syndrome; Cancer risk; MLH1;MSH2;MSH6;PMS2; Prospective study Introduction Lynch syndrome (LS) is caused by pathogenic variants in any of the four mismatch repair genes, MLH1, MSH2,MSH6 or PMS2 or by deletion of the 3′end of EPCAM (TACSTD1) which results in hypermethylation of the MSH2 promoter (path_MMR). 1 Colonoscopy with polypectomy has been advocated to prevent colorectal cancer (CRC) in path_MMR carriers 2 ; but several reports have found high CRC incidence in path_MMR carriers despite surveillance colonoscopy, as well as high gynaecological cancer incidence. 3–8 The efficacy of surveillance for non-colorectal cancers in LS is not well evidenced. 9 Survival following cancer diagnosis has been reported, 4 guidelines for clinical interventions have been issued 10 and the extent to which management practices align with research findings and with the guidelines based upon them has been discussed. 11 The main goal for intervention in a person with an inherited cancer risk is to prevent premature death, 12 but success in achieving this has been difficult to measure in LS, and the reports mentioned above have focused largely on cancer incidence as a surrogate endpoint for survival. Recently, the USA National Comprehensive Cancer Network (NCCN) guidelines described the geneand organ-specific cumulative cancer risks in path_MMR carriers based on various data sources, including the Prospective Lynch Syndrome Database (PLSD). 13 However, when advocating colonoscopy for the prevention of CRC, NCCN did not acknowledge that the CRC incidences reported by PLSD were determined in individuals undergoing colonoscopy surveillance. It was also stated that the incidences of some other cancers had not been reported in the literature and the average ages at diagnosis of cancers were described without indicating how they were obtained. There is a lack of evidence that surveillance prevents extracolonic cancers, but current guidelines do include surveillance recommendations for some of the many extracolonic cancers associated with LS. 10,13–16 There is limited information on CRC and extracolonic cancer mortality in path_MMR carriers who receive colonoscopy surveillance. Providing new data on mortality was the focus of this study. The updated version of PLSD upon which the current study is based includes 71,713 prospective followup years, allowing us for the first time to present mortality outcomes by gene and gender, for each organ in which LS-associated cancers occur. We also present data that will help to fill the knowledge gaps in the recent NCCN guidelines when they are next updated, including the median age at cancer diagnosis in each organ by gene and gender. Methods The PLSD design The PLSD is a prospective observational study without a control group that was designed in 2012 and that provides an aggregated compilation of combined genetic and clinical information from all contributors up to October 2022. The eligibility criteria include path_MMR carriers with or without a previous cancer who are aged 25 years or older on the day of their first prospectively planned and completed surveillance colonoscopy. 4–8,10,11,17–19 Cancers are Research in context Evidence before this study We searched PubMed up to October, 2022 for articles in English published using the search terms “Lynch syndrome and cancer risk”,“Lynch syndrome and survival”,“Lynch syndrome and mortality”,“extra colonic Lynch syndrome tumor”,“Lynch syndrome and colorectal cancer incidence” and “surveillance and Lynch syndrome”in the title or abstract. However, reduction of colorectal cancer incidence by colonoscopy surveillance has not been documented and there are limited data regarding risks for other cancer types and the effectiveness of wider cancer surveillance in individuals with Lynch syndrome. Previously, outcomes from interventions including colonoscopy have been reported as cancer incidences, not survival. Added value of this study In carriers of MMR variants undergoing colonoscopy surveillance, colorectal cancer was frequent but associated with low mortality whilesomeothercancers,notablybileduct,pancreasandbrain, were associated with high mortality and more deaths followed non-colorectal than colorectal cancers. Implications of all the available evidence Prevention and treatment of non-colorectal cancers should be prioritised to further reduce mortality in path_MMR carriers. Articles 4 www.thelancet.com Vol ▪▪, 2023 grouped by the three first positions in the ICD9 classification system. This fails to identify sebaceous gland cancers. Osteosarcomas are recognised as part of LS, 20 but were found too infrequently to be included in the presentation of cancer incidences. In this study, cancers in the following organs are denoted as LS cancers: colon, rectum, endometrium, ovary, small intestine, bile duct, pancreas, stomach, prostate, urinary bladder, ureter, brain and osteosarcoma. Adenocarcinomas share some phenotypic characteristics, and there is a small possibility that a subsequent cancer might have been a recurrence from a previous cancer in the same or another organ. However, local recurrences are usually clinically distinguished from metachronous primaries. The path_MMR carriers in the current study were followed up with colonoscopy and gynaecological surveillance according to local implementation of international recommendations. The gynaecological follow-up carried out by PLSD contributing centres has been reported previously and is not evidencebased. 4,17 Statistical analysis Annual incidence rates in 5-year cohorts by gene and gender for cancer in each organ and in groups of organs were calculated in MySQL80©. Overall survival was estimated using the Nelson-Aalen algorithm in R. 21 Categorization of carriers as dead or alive was made at last observation and was made for all carriers. Crude mortality at 75 years of age following cancer in specific organs was calculated as cumulative incidence at 65 years for cancer in each organ multiplied by (1–10-year survival) following cancer diagnosis in that organ. The reported mortality is an empirical observation which includes no assumptions, and includes death from any cause, including synchronous and metachronous cancers associated with LS. Possible overdiagnosis of colon cancer due to colonoscopy 21 was adjusted for when calculating survival: incidence and survival are to be measured simultaneously when combined like this. PLSD incidences should not be compared with survival measured in other ways. We are not aware of any studies to measure mortality by other means and to our knowledge there is no previous report on mortality as an outcome of screening for early cancer diagnosis in LS. Confounders to our method for estimating survival include time-trends in treatments that may reduce mortality, which this report did not consider. The point estimates for path_PMS2 carriershavewideconfidence intervals because of the low number of carriers and follow-up years collated by the PLSD. Cancers detected prospectively were scored as the first tumor in each organ in carriers who had not had cancer in that organ before or at inclusion (ignoring prospectively diagnosed cancers in other organs and excluding previous cancers and prevalent cancers identified at inclusion). No synchronous or subsequent cancer in the same organ was scored as an event. Cumulative risk for cancer was set to zero at age 25 years, and annual incidence rates (AIRs) for five-year cohorts from 25 to 75 years of age were calculated as the starting point for further calculations in R© (version 4.2.0). In the current report, the cumulative incidences (risks) and their 95% confidence intervals (CIs) were calculated using Nelson-Aalen estimates with an underlying Poisson distribution. For calculating the median age of cancer diagnosis, the risk has to be conditioned on those patients who developed any cancer during their lifetime. For this, the conditional risk was computed by dividing the risk estimate in each five-year age cohort by the lifetime risk (approximated by the risk at 75 years of age), mapping the risk on the interval [0%; 100%]. The corresponding conditional 95% CIs were computed accordingly, conditioned on the life-time risk and truncated to the interval [0%; 100%]. We then performed a piecewise linear interpolation of the conditional risk and conditional 95% CIs for the five-year age cohorts to determine the median age of cancer onset. The latter corresponds to the age at which the interpolated conditional risk hits the 50% conditional risk limit. The same intersection calculations were performed for the corresponding 95% confidence intervals. Ethics statement The study adhered to the principles set out in the Declaration of Helsinki. It was approved by the Norwegian Data Protection Authority (reference 2001/29882) and the Ethics Committee (reference S-02030). Genetic testing was performed with informed consent according to local and national requirements and all reporting centres exported only de-identified data to PLSD. Patients had been followed up prospectively according to international and local clinical guidelines, as previously described. 3–7,17–19,22 Role of the funding source The funding body had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. MD-V and PM had access to dataset and all authors contributed data to the PLSD and reviewed and approved the manuscript. All authors have read and agreed to the final version of the manuscript. Version. All authors had full access to all the data in the study and accept responsibility for the decision to submit for publication. Results Characteristics of the PLSD patients, follow-up years, gene, gender, and country In addition to the 6350 carriers included in our previous report, 4 data from 2150 new path_MMR carriers were provided by 18 new contributing centres and by Articles www.thelancet.com Vol ▪▪, 2023 5 previously contributing centres that provided information on newly recruited carriers. In total, 25 countries in five continents (Supplementary Table S1) were represented in the current PLSD dataset that comprised 8500 path_MMR carriers (4588 females and 3912 males) with a mean age of 42.5 and 43.6 years for path_MLH1/ MSH2 carriers compared to 48.3 and 49.9 years for path_MSH6/PMS2 carriers at inclusion. They were followed up with surveillance colonoscopy and provided 71,713 prospective observation years, with a mean follow-up time of 8.4 years. When stratified by gene, there were 3171 (37.3%) path_MSH2 carriers, 3131 (36.8%) path_MLH1, 1649 path_MSH6 (19.4%) and 549 (6.5%) path_PMS2 carriers in the study. Supplementary Table S1 describes the numbers of patients, follow-up years and age at inclusion, stratified by gene, gender, and country. During prospective observation, 1853 first cancers in any organ were diagnosed (Supplementary Table S2)of which 1436 (77.5%) were LS-associated cancers (stomach, small intestine, biliary tract, pancreas, colon, rectum, endometrium, ovaries, osteosarcoma, prostate, brain, urinary bladder and ureter). Cancers of the colon (n = 481, 26% of all cancers), endometrium (n = 237, 12.8%), skin (n = 155, 8.4%), and rectum (n = 137, 7.4%) were most frequent, but skin cancers were not reported consistently. In Supplementary Tables S3–S6, we also present the incidence for breast cancers. Although this cancer is mentioned in the NCCN guidelines, 13 we do not consider breast cancer to be a part of LS and hence do not discuss the findings. 23 Survival and mortality Ten-year crude survival after cancer of the colon that occurred before 65 years of age was 87% and 72% after rectal, 92% after endometrial, 85% after ovarian, 73% after upper urinary tract, 71% after urinary bladder, 76% after prostate, 42% after bile duct, 63% after stomach, 70% after small bowel, 17% after pancreas and 34% after brain cancers. Fiveand 10-year survival are detailed in Supplementary Table S7. Figs. 1 and 2illustrate that there were no significant differences by gene in the 10-year survival after colon or endometrial cancer. For colon cancer this was 86% [80%– 92%] in path_MLH1, 89% [82%–96%] in path_MSH2 and 85% [67%–100%] in path_MSH6 carriers and for +++++++++++ +++++++++++ ++++ ++ +++ ++ 0.00 0.25 0.50 0.75 1.00 0510 Time Survival probability Strata ++++ 241 141 76 165 82 39 22 12 6 300 0510 Time Strata Number at risk path_MLH1 path_MSH2 path_MSH6 path_PMS2 path_MLH1 path_MSH2 path_MSH6 path_PMS2 Fig. 1: Crude survival (%) in path_MLH1, path_MSH2, path_MSH6 and path_PMS2 carriers subjected to colonoscopy surveillance after colon cancer diagnosed before age of 65 years. The dark line showed the survival probability, and the bars showed the 95% confidence interval for each path_MMR carrier: path_MLH1 (orange), path_MSH2 (green), path_MSH6 (blue) and path_PMS2 (purple). Categorization of carriers as dead or alive was made at last observation and was made for all carriers. Articles 6 www.thelancet.com Vol ▪▪, 2023 endometrial cancer: 93% [88%–99%],91% [85%–98%] and 89% [75%–100%], respectively. Supplementary Figs. S1– S10 show the 10-year survival by gene for rectal and extracolonic cancers, including ovarian, ureter and kidney, urinary bladder, prostate, stomach, small bowel, biliary tract, pancreas, and brain cancers. Mortality by organ, gene and gender at 75 years of age is presented in Table 1. As shown, for male path_MLH1 and path_MSH6 carriers, mortality was similar after CRC compared to mortality after non-CRC cancers. Path_MSH2 carriers of both genders and female path_MSH6 carriers had more deaths after nonCRC. Importantly, the combined incidences of deaths after colon and rectal cancer for all path_MMR carriers comprised less than half of the total deaths following any LS cancer. Counting numbers (not incidences) of deaths in the total series, deaths following CRC accounted for less than half of all deaths following an LS cancer (n = 76, 36%) (Table 2). Gyneacological cancer (n = 31, 14.8%), ureter and kidney (n = 16, 7.7%), stomach cancer (n = 16, 7.7%) and pancreas (n = 14, 6.7%) were the other cancers associated with a high number of deaths (Table 2). Median age of cancer diagnosis and cumulative incidences of cancers by age, gene, gender, and organ The median ages of cancer diagnosis and the cumulative incidences of cancers in path_ MLH1,path_MSH2, path_MSH6 and path_PMS2 carriers in different organs by age, gene and gender are given in Table 3 and Supplementary Tables S3–S6, respectively. We used the same format as the 2021 NCCN report 13 and present LSassociated cancers only, based on previous PLSD reports but excluding osteosarcoma (the 11 cases found were insufficient for statistical calculations). Incidences of groups of cancers such as urinary tract cancers, endometrial or ovarian cancers and upper gastrointestinal tract cancers are also given. Median ages at cancer diagnoses by gene, organ, and gender have not been reported before in LS. We found a younger median age at diagnosis for cancers in path_MSH2 carriers than in path_MLH1 carriers, with the exception of CRC, urinary bladder, bile duct/gall bladder and brain cancers. An older median age at diagnosis was observed for cancers in path_MSH6 and path_PMS2 carriers. +++++++++++ +++++++++++ ++ + ++ ++++ + ++ ++ 0.00 0.25 0.50 0.75 1.00 0510 Time Survival probability Strata +++ 93 58 38 82 54 27 36 15 6 541 0510 Time Strata Number at risk path_MLH1 path_MSH2 +path_MSH6 path_MLH1 path_MSH2 path_MSH6 path_PMS2 path_PMS2 Fig. 2: Crude survival (%) in path_MLH1, path_MSH2,path_MSH6 and path_PMS2 carriers subjected to colonoscopy surveillance after colon cancer diagnosed before age of 65 years. The dark line showed the survival probability, and the bars showed the 95% confidence interval for each path_MMR carrier: path_MLH1 (orange), path_MSH2 (green), path_MSH6 (blue) and path_PMS2 (purple). Categorization of carriers as dead or alive was made at last observation and was made for all carriers. Articles www.thelancet.com Vol ▪▪, 2023 7 Cancer type Pathogenic variants 10-year survival Males Females Cumulative incidence 65 years Mortality 75 years Cumulative incidence 65 years Mortality 75 years Colon path_MLH1 87% 48.4% [42.4–54.8] 6% 36.3% [31.0–42.3] 5% path_MSH2 41.5% [34.8–48.8] 5% 29.8% [24.6–35.8] 4% path_MSH6 12.7% [6.8–23.1] 2% 10.1% [5.8–17.1] 1% path_PMS2 9.5% [2.5–32.9] 1% 2.8% [0.4–18.2] 0% Rectum path_MLH1 72% 6.0% [3.8–9.3] 2% 4.6% [2.9–7.3] 1% path_MSH2 12.6% [9.2–17.3] 4% 7.6% [5.1–11.1] 2% path_MSH6 5.1% [2.3–11.1] 1% 3.9% [1.8–8.6] 1% path_PMS2 0% [NA] 0% 2.2% [0.3–14.6] 1% Endometrium path_MLH1 92% na 31.7% [26.5–37.7] 3% path_MSH2 37.6% [31.3–44.8] 3% path_MSH6 32.1% [24.2–41.7] 3% path_PMS2 12.7% [5.5–27.9] 1% Ovary path_MLH1 85% na 8.0% [5.3–12.0] 1% path_MSH2 10.6% [7.2–15.6] 2% path_MSH6 2.9% [0.9–8.7] 0% path_PMS2 2.5% [0.4–16.3] 0% Stomach path_MLH1 63% 2.8% [1.5–5.2] 1% 2.0% [1.0–4.2] 1% path_MSH2 4.3% [2.5–7.6] 2% 2.6% [1.4–5.0] 1% path_MSH6 0.7% [0.1–4.9] 0% 0.7% [0.1–4.7] 0% path_PMS2 2.7% [0.4–17.5] 1% 0% [NA] 0% Small intestine path_MLH1 70% 4.4% [2.6–7.2] 1% 2.5% [1.3–4.6] 1% path_MSH2 4.5% [2.6–7.6] 1% 3.2% [1.8–5.6] 1% path_MSH6 0.7% [0.1–4.8] 0% 0.6% [0.1–4.0] 0% path_PMS2 3.3% [0.5–21.3] 1% 2.1% [0.3–14.0] 1% Bile duct path_MLH1 42% 2.9% [1.5–5.6] 2% 1.5% [0.7–3.3] 1% path_MSH2 1.0% [0.3–3.2] 1% 0.8% [0.3–2.4] 0% path_MSH6 0% [NA] 0% 0% [NA] 0% path_PMS2 0% [NA] 0% 0% [NA] 0% Pancreas path_MLH1 17% 1.1% [0.4–2.9] 1% 1.9% [0.9–4.0] 2% path_MSH2 1.4% [0.5–3.7] 1% 1.2% [0.5–3.3] 1% path_MSH6 0% [NA] 0% 0.7% [0.1–4.8] 1% path_PMS2 0% [NA] 0% 0% [NA] 0% Ureter/kidney path_MLH1 73% 2.5% [1.3–5.1] 1% 1.7% [0.8–3.8] 0% path_MSH2 11.5% [8.2–16.0] 3% 9.7% [6.9–13.5] 3% path_MSH6 1.4% [0.3–5.4] 0% 3.2% [1.3–7.4] 1% path_PMS2 0% [NA] 0% 0% [NA] 0% Urinary bladder path_MLH1 71% 3.3% [1.8–6.1] 1% 1.3% [0.6–3.2] 0% path_MSH2 5.9% [3.7–9.4] 2% 4.7% [2.8–7.7] 1% path_MSH6 3.0% [1.1–7.9] 1% 1.8% [0.6–5.6] 1% path_PMS2 0% [NA] 0% 0% [NA] 0% Prostate path_MLH1 76% 5.3% [3.2–8.7] 1% na path_MSH2 10.6% [7.5–15.0] 3% path_MSH6 3.0% [1.1–7.7] 1% path_PMS2 3.3% [0.5–21.5] 1% Brain path_MLH1 34% 0% [NA] 0% 0.9% [0.3–2.4] 1% path_MSH2 3.3% [1.7–6.3] 2% 1.4% [0.5–3.8] 1% path_MSH6 0.8% [0.1–5.3] 1% 1.2% [0.3–4.6] 1% path_PMS2 0% [NA] 0% 7.3% [1.1–41.6] 5% a Mortality was calculated as cumulative incidence at 65 years of age multiplied by (1–10 years survival) from Supplementary Table S4. a Caused by only one case at young age, which is not significantly different from zero, na: not applicable. Table 1: Mortality by cancer, gene and gender at 75 years in path_MMR carriers: mortality at 75 years was calculated as cumulative incidence at 65 years with [95% confidence intervals] multiplied by (1 –ten years survival) following cancer in that organ. Articles 8 www.thelancet.com Vol ▪▪, 2023