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

This is a sel -a chi ed e sion o an o iginal a icle. This e sion may di e om he o iginal in pagina ion and ypog aphic de ails. Au ho (s): Ti le: Yea : Ve sion: Copy igh : Righ s: Righ s u l: Please ci e he o iginal e sion: CC BY 4.0 h ps://c ea i ecommons.o g/licenses/by/4.0/ Mo ali y by age, gene and gende in ca ie s o pa hogenic misma ch epai gene a ian s ecei ing su eillance o ea ly cance diagnosis and ea men : a epo om he p ospec i e Lynch synd ome da abase © 2023 he Au ho s Published e sion Dominguez-Valen in, Me ; Haup , Saskia; Seppälä, Toni T.; Sampson, Julian R.; Sunde, Lone; Be ns ein, Inge; Jenkins, Ma k A.; Engel, Ch is oph; A e z, S e an; Nielsen, Maa je; Capella, Gab iel; Balague , F ancesc; E ans, Da ydd Ga e h; Bu n, John; Holinski-Fede , Elke; Be a io, Lucio; Bonanni, Be na do; Lindblom, Annika; Le i, Zoha ; Mac ae, Finlay; Winship, Ing id; Plazze , John-Paul; Sijmons, Rol ; Laghi, Luigi; Della Valle, Ad iana; Heinimann, Ka l; Dębniak, Tadeusz; F uscio, Robe ; Lopez-Koes ne , F ancisco; Al a ez-Valenzuela, Ka in; Ka z, Lio H.; Laish, Ido; Vaine , Elez; Vacca o, Ca los; Ca a o, Di ce Ma ia; Monahan, Ke in; Hal , Elizabe h; S akelum, Aine; Win e , Des; Kennelly, Ro y; Gluck, Na han; She h, Ha sh; Abu-F eha, Naim; G eenbla , Ma c; Rossi, Benedi o Mau o; Boho quez, Mabel; Ca es o, Giulia Ma ina; Lino-Sil a, Leona do S.; Ho isbe ge , Ka oline; Tibile i, Ma ia G azia; do Nascimen o, I ana; Thomas, Huw; Rossi, No ma Te esa; Apoliná io da Sil a, Leand o; Za ánd, A ila; Ruiz- Bañob e, Juan; Heu eline, Vincen ; Mecklin, Jukka-Pekka; Pyl änäinen, Ki si; Renkonen-Sinisalo, Lau a; Lepis ö, Anna; Pel omäki, Päi i; The kildsen, Ch is ina; Madsen, Mia Gebaue ; Bu gdo , S e an Kobbelgaa d; Hoppe , John L.; Win, Aung Ko; Haile, Robe W.; Lindo , No alane; Gallinge , S e en; Le Ma chand, Loïc; Newcomb, Polly A.; Figuei edo, Jane; Buchanan, Daniel D.; Thibodeau, S ephen N.; on Knebel Doebe i z, Magnus; Loe le , Ma kus; Rahne , Nils; Sch öck, E elin; S einke-Lange, Ve ena; Schmiegel, Wol ; Vangala, Deepak; Pe ne, Claudia; Hünebu g, Robe ; Redle , Silke; Bü ne , Reinha d; Wei z, Jü gen; Pineda, Ma a; Duenas, Nu ia; Vidal, Joan B une ; Mo ei a, Le icia; Sánchez, A iadna; Ho ig, Ei ind; Nakken, Sig e; G een, Ka e; Lalloo, Fiona; Hill, James; C osbie, Emma; Min s, Mi iam; Goldbe g, Yael; Tjand a, Douglas; en B oeke, Sanne W.; Ka i , Re i al; Rosne , Guy; Ad ani, Su esh H.; Thomas, Lidiya; Shah, Pankaj; Shah, Mi hun; Ne a, Flo encia; Espe on, Pa icia; Pa icic, Wal e ; To ezan, Gio ana Ta din; Bassaneze, Thiago; Ma in, Claudia Alejand a; Moslein, Gab iela; Molle , Pål Dominguez-Valen in, M., Haup , S., Seppälä, T. T., Sampson, J. R., Sunde, L., Be ns ein, I., Jenkins, M. A., Engel, C., A e z, S., Nielsen, M., Capella, G., Balague , F., E ans, D. G., Bu n, J., Holinski-Fede , E., Be a io, L., Bonanni, B., Lindblom, A., Le i, Z., . . . Molle , P. (2023). Mo ali y by age, gene and gende in ca ie s o pa hogenic misma ch epai gene a ian s ecei ing su eillance o ea ly cance diagnosis and ea men : a epo om he p ospec i e Lynch synd ome da abase. EClinicalMedicine, 58, A icle 101909. h ps://doi.o g/10.1016/j.eclinm.2023.101909 2023 Mo ali y by age, gene and gende in ca ie s o pa hogenic misma ch epai gene a ian s ecei ing su eillance o ea ly cance diagnosis and ea men : a epo om he p ospec i e Lynch synd ome da abase Me Dominguez-Valen in, a , ∗ Saskia Haup , b , c Toni T. Seppälä, d , e , Julian R. Sampson, g Lone Sunde, h , i Inge Be ns ein, j , k Ma k A. Jenkins, l Ch is oph Engel, m S e an A e z, n Maa je Nielsen, o Gab iel Capella, p F ancesc Balague , q Da ydd Ga e h E ans, John Bu n, s Elke Holinski-Fede , , u Lucio Be a io, Be na do Bonanni, w Annika Lindblom, x Zoha Le i, y Finlay Mac ae, z , co Ing id Winship, z , co , aa John-Paul Plazze , z , co Rol Sijmons, ab Luigi Laghi, ac Ad iana Della Valle, ad Ka l Heinimann, ae Tadeusz Dębniak, a Robe F uscio, ag F ancisco Lopez-Koes ne , ah , cp Ka in Al a ez-Valenzuela, ah , cp Lio H. Ka z, ai Ido Laish, ai Elez Vaine , aj Ca los Vacca o, ak Di ce Ma ia Ca a o, al Ke in Monahan, am Elizabe h Hal , an Aine S akelum, ao Des Win e , ao Ro y Kennelly, ao Na han Gluck, ap Ha sh She h, aq Naim Abu-F eha, a Ma c G eenbla , as Benedi o Mau o Rossi, a Mabel Boho quez, au Giulia Ma ina Ca es o, a Leona do S. Lino-Sil a, aw Ka oline Ho isbe ge , ax , cq Ma ia G azia Tibile i, ay I ana do Nascimen o, az Huw Thomas, ba No ma Te esa Rossi, bb Leand o Apoliná io da Sil a, bc , c A ila Za ánd, bd Juan Ruiz-Bañob e, be , cs Vincen Heu eline, b , c Jukka-Pekka Mecklin, b , c Ki si Pyl änäinen, bg Lau a Renkonen-Sinisalo, e , Anna Lepis ö, e , Päi i Pel omäki, bh Ch is ina The kildsen, bi Mia Gebaue Madsen, bj S e an Kobbelgaa d Bu gdo , bk John L. Hoppe , bl Aung Ko Win, bl Robe W. Haile, bm No alane Lindo , bn S e en Gallinge , bo Loïc Le Ma chand, bp Polly A. Newcomb, bq Jane Figuei edo, bq Daniel D. Buchanan, b , bs , b S ephen N. Thibodeau, bu Magnus on Knebel Doebe i z, b , cu Ma kus Loe fle , m Nils Rahne , bw E elin Sch öck, bx , c , cw , cx Ve ena S einke-Lange, by , cy Wol Schmiegel, bz Deepak Vangala, bz Claudia Pe ne, n Robe Hünebu g, ca Silke Redle , bw Reinha d Bü ne , cb Jü gen Wei z, cc Ma a Pineda, p Nu ia Duenas, p Joan B une Vidal, p Le icia Mo ei a, q A iadna Sánchez, q Ei ind Ho ig, a , cd Sig e Nakken, a , cd , ce Ka e G een, Fiona Lalloo, James Hill, c Emma C osbie, cg , cz Mi iam Min s, ch Yael Goldbe g, ci Douglas Tjand a, z , co Sanne W. en B oeke, ab Re i al Ka i , ao Guy Rosne , ao Su esh H. Ad ani, cj Lidiya Thomas, cj Pankaj Shah, ck Mi hun Shah, ck Flo encia Ne a, ac Pa icia Espe on, ac Wal e Pa icic, cl Gio ana Ta din To ezan, ak Thiago Bassaneze, as Claudia Alejand a Ma in, cm Gab iela Moslein, cn and Pål Molle a a Depa men o Tumo Biology, Ins i u e o Cance Resea ch, The No wegian Radium Hospi al, 0379, Oslo, No way b Enginee ing Ma hema ics and Compu ing Lab (EMCL), In e disciplina y Cen e o Scien ific Compu ing (IWR), Heidelbe g Uni e si y, Heidelbe g, Ge many c Da a Mining and Unce ain y Quan ifica ion (DMQ), Heidelbe g Ins i u e o Theo e ical S udies (HITS), Heidelbe g, Ge many d Facul y o Medicine and Heal h Technology, Tampe e Uni e si y and Tays Cance Cen e , Tampe e Uni e si y Hospi al, Finland e Depa men o Gas oin es inal Su ge y, Helsinki Uni e si y Cen al Hospi al, Uni e si y o Helsinki, Helsinki, Finland Applied Tumo Genomics, Resea ch P og am Uni , Uni e si y o Helsinki, Helsinki, Finland g Di ision o Cance and Gene ics, Ins i u e o Medical Gene ics, Ca di Uni e si y School o Medicine, Hea h Pa k, Ca di , CF14 4XN, UK h Depa men o Clinical Gene ics, Aalbo g Uni e si y Hospi al, 9000, Aalbo g, Denma k i Depa men o Biomedicine, Aa hus Uni e si y, DK-8000, Aa hus, Denma k j Depa men o Su gical Gas oen e ology, Aalbo g Uni e si y Hospi al, Aalbo g Uni e si y, 9100, Aalbo g, Denma k k Depa men o Clinical Medicine, Aalbo g Uni e si y Hospi al, Aalbo g Uni e si y, 9100, Aalbo g, Denma k l Melbou ne School o Popula ion and Global Heal h, Cen e o Epidemiology and Bios a is ics, The Uni e si y o Melbou ne, Pa k ille, 3010, Vic o ia, Aus alia m Ins i u e o Medical In o ma ics, S a is ics and Epidemiology, Uni e si y o Leipzig, 04107, Leipzig, Ge many n Ins i u e o Human Gene ics, Na ional Cen e o He edi a y Tumo Synd omes, Medical Facul y, Uni e si y Hospi al Bonn, Uni e si y o Bonn, 53127, Bonn, Ge many o Depa men o Clinical Gene ics, Leids Uni e si ai Medisch Cen um, 2300RC, Leiden, he Ne he lands p He edi a y Cance P og am, Ins i u Ca alà d’Oncologia-IDIBELL, L; Hospi ale de Llob ega , 08908, Ba celona, Spain q Gas oen e ology Depa men , Hospi al Clínic de Ba celona, Cen o de In es igación Biomédica en Red de En e medades Hepá icas y Diges i as (CIBERehd), Ins i u d’In es igacions Biomediques Augus Pi i Sunye (IDIBAPS), Uni e si a de Ba celona, Ba celona, Spain Manches e Cen e o Genomic Medicine, Manches e Uni e si y NHS Founda ion T us , Manches e , M13 9WL, UK s Facul y o Medical Sciences, Newcas le Uni e si y, Newcas le Upon Tyne, NE1 7RU, UK Campus Innens ad , Medizinische Klinik und Poliklinik IV, Klinikum de Uni e si ä München, 80336, Munich, Ge many u Cen e o Medical Gene ics, 80335, Munich, Ge many Abb e ia ions: AIR, Annual incidence a e; CIs, Confidence in e als; CRC, Colo ec al cance ; LS, Lynch synd ome; MMR, Misma ch epai ; NCCN, Na ional comp ehensi e cance ne wo k; pa h_MMR, Pa hogenic o likely pa hogenic a ian in one o he MMR genes (MLH1,MSH2,MSH6, o PMS2); PLSD, P ospec i e Lynch synd ome da abase *Co esponding au ho . Depa men o Tumo Biology, Ins i u e o Cance Resea ch, The No wegian Radium Hospi al, Oslo, No way. E-mail add ess: me .d[email p o ec ed] (M. Dominguez-Valen in). www. helance .com Vol ▪▪, 2023 1 A icles Di ision o Cance P e en ion and Gene ics, IEO, Eu opean Ins i u e o Oncology, Fondazione IRCCS Ins i u o Nazionale dei Tumo i, IRCCS, 20141, Milan, I aly w Di ision o Cance P e en ion and Gene ics, IEO, Eu opean Ins i u e o Oncology IRCCS, 20141, Milan, I aly x Depa men o Molecula Medicine and Su ge y, Ka olinska Ins i u e , 171 76, S ockholm, Sweden y Se ice High Risk GI Cance Gas oen e ology, Depa men Rabin Medical Cen e , Is ael z Colo ec al Medicine and Gene ics, The Royal Melbou ne Hospi al, Melbou ne, Aus alia aa Depa men o Medicine, Uni e si y o Melbou ne, Melbou ne, Aus alia ab Depa men o Gene ics, Uni e si y o G oningen, Uni e si y Medical Cen e G oningen, G oningen, he Ne he lands ac Depa men o Medicine and Su ge y, Labo a o y o Molecula Gas oen e ology, IRCCS Humani as Resea ch Hospi al, Uni e si y o Pa ma, Pa ma, I aly ad Hospi al Fue zas A madas, G upo Colabo a i o U uguayo, In es igación de A ecciones Oncológicas He edi a ias (GCU), Mon e ideo, U uguay ae Medical Gene ics, Ins i u e o Medical Gene ics and Pa hology, Uni e si y Hospi al Basel, Swi ze land a Depa men o Gene ics and Pa hology, In e na ional He edi a y Cance Cen e , ul. Unii Lubelskiej 1, 71-252, Szczecin, Poland ag Depa men o Medicine and Su ge y, Uni e si y o Milan Bicocca, A.O. San Ge a do, Clinic o Obs e ics and Gynecology, Via Pe golesi 33, Monza (MB), I aly ah Clínica Uni e sidad de los Andes, Chile ai Depa men o Gas oen e ology, Hadassah, Medical Cen e , Facul y o Medicine, Heb ew Uni e si y o Je usalem, Is ael aj Hadassah Medical Cen e , Is ael ak He edi a y Cance P og am (PROCANHE) Hospi al I aliano de Buenos Ai es, A gen ina al Clinical and Func ional Genomics G oup, A.C.Cama go Cance Cen e , Sao Paulo, B azil am Lynch Synd ome & Family Cance Clinic, S Ma k’s Hospi al, Ha ow, HA1 3UJ, London, UK an Gas oin es inal Cance P e en ion Uni , Gas oen e ology Depa men , Rambam Heal h Ca e Campus, Hai a, Is ael ao S Vincen ’s Uni e si y Hospi al, I eland ap Depa men o Gas oen e ology, Tel-A i Sou asky Medical Cen e and Sackle Facul y o Medicine, Tel-A i Uni e si y, Is ael aq Founda ion o Resea ch in Gene ics and Endoc inology, Ins i u e o Human Gene ics, FRIGE House, Ahmedabad, 380015, India a So oka Uni e si y Medical Cen e , Ben-Gu ion Uni e si y o he Nege , Bee She a, Sou he n Is ael, Is ael as Uni e si y o Ve mon , La ne College o Medicine, Bu ling on, VT, 05405, USA a Hospi al Si io Libanes, Sao Paulo, B azil au Uni e si y o Tolima, Tolima, Colombia a Gas oen e ology and Gas oin es inal Endoscopy Uni , Di ision o Expe imen al Oncology, IRCCS San Ra aele Scien ific Ins i u e, Vi a-Salu e San Ra aele Uni e si y, 20132, Milan, I aly aw Su gical Pa hology, Ins i u o Nacional de Cance ologia, Mexico Ci y, Mexico ax Depa men o Visce al and T ansplan a ion Su ge y, Uni e si y Hospi al o Zu ich, Swi ze land ay Ospedale di Ci colo ASST Se elaghi, Cen o di Rice ca umo i e edo- amilia i, Uni e si à dell’Insub ia, Va ese, I aly az Uni e sidade Fede al de Bahia, Bahia, B azil ba S Ma k’s Hospi al, Depa men o Su ge y and Cance , Impe ial College London, London, UK bb Fundación pa a el P og eso de la Medicina”y“Sana o io Allende”, Có doba, A gen ina bc Hospi al Uni e si á io Oswaldo C uz, Uni e sidade de Pe nambuco, Reci e, B azil bd 1s Depa men o Su ge y, Semmelweis Uni e si y, Hunga y be Depa men o Medical Oncology, Uni e si y Clinical Hospi al o San iago de Compos ela (SERGAS); T ans-a ional Medical Oncology G oup (Oncome ), Heal h Resea ch Ins i u e o San iago de Compos ela (IDIS); Genomes and Disease, Cen e o Resea ch in Molecula Medicine and Ch onic Diseases (CiMUS), Uni e si y o San iago de Compos ela (USC), 15706, San iago de Compos ela, Spain b Facul y o Spo and Heal h Sciences, Uni e si y o Jy äskylä, Jy äskylä, Finland bg Depa men o Educa ion and Science, Cen al Finland Heal h Ca e Dis ic , Jy äskylä, Finland bh Depa men o Medical and Clinical Gene ics, Uni e si y o Helsinki, Helsinki, Finland bi The Danish HNPCC Regis e , Clinical Resea ch Cen e, Copenhagen Uni e si y Hospi al, H ido e, Denma k bj Depa men o U ology, Aa hus Uni e si y Hospi al, Denma k bk Depa men o Su ge y and T ansplan a ion, Rigshospi ale , Copenhagen Uni e si y Hospi al, Denma k bl Cen e o Epidemiology and Bios a is ics, Melbou ne School o Popula ion and Global Heal h, The Uni e si y o Melbou ne, Pa k ille, Vic o ia, Aus alia bm Depa men o Medicine, Di ision o Oncology, S an o d Cance Ins i u e, S an o d Uni e si y, USA bn Depa men o Heal h Science Resea ch, Mayo Clinic A izona, USA bo Lunen eld Tanenbaum Resea ch Ins i u e, Moun Sinai Hospi al, Uni e si y o To on o, Canada bp Uni e si y o Hawaii Cance Cen e , USA bq Public Heal h Sciences Di ision, F ed Hu chinson Cance Resea ch Cen e , Sea le, WA, 98109-1024, USA b Colo ec al Oncogenomics G oup, Depa men o Clinical Pa hology, The Uni e si y o Melbou ne, Pa k ille, Vic o ia, Aus alia bs Uni e si y o Melbou ne Cen e o Cance Resea ch, Vic o ian Comp ehensi e Cance Cen e, Pa k ille, Vic o ia, Aus alia b Genomic Medicine and Family Cance Clinic, Royal Melbou ne Hospi al, Pa k ille, Vic o ia, Aus alia A icles 2 www. helance .com Vol ▪▪, 2023 bu Depa men o Labo a o y Medicine and Pa hology, Mayo Clinic, Roches e , MN, 55905, USA b Depa men o Applied Tumou Biology, Ins i u e o Pa hology, Uni e si y Hospi al Heidelbe g, Heidelbe g, Ge many bw Ins i u e o Human Gene ics, Medical Facul y and Uni e si y Hospi al Düsseldo , Hein ich-Heine-Uni e si y Düsseldo , Ge many bx Na ional Cen e o Tumo Diseases (NCT), Pa ne Si e D esden, D esden, Ge many by Medizinische Klinik und Poliklinik IV, Campus Innens ad , Klinikum de Uni e si ä München, Munich, Ge many bz Depa men o Medicine, Knappscha sk ankenhaus, Ruh -Uni e si y Bochum, Bochum, Ge many ca Depa men o In e nal Medicine, Uni e si y Hospi al Bonn, Bonn, Ge many cb Ins i u e o Pa hology, Facul y o Medicine and Uni e si y Hospi al Cologne, Cologne, Ge many cc Technische Uni e si ä D esden, D esden, Ge many cd Cen e o Bioin o ma ics, Depa men o In o ma ics, Uni e si y o Oslo, Oslo, No way ce Cen e o Cance Cell Rep og amming (CanCell), Ins i u e o Clinical Medicine, Facul y o Medicine, Uni e si y o Oslo, Oslo, No way c Depa men o Su ge y, Cen al Manches e Uni e si y Hospi als NHS Founda ion T us and Uni e si y o Manches e , London, UK cg Gynaecological Oncology Resea ch G oup, Manches e Uni e si y NHS Founda ion T us , Manches e , UK ch Di ision o Obs e ics and Gyneacology, Depa men o Women’s and Child en’s Heal h, Ka olinska Ins i u e , Ka olinska Uni e si y Hospi al, Solna, S ockholm, Sweden ci Head Adul Gene ic Se ice, Raphael Recana i Gene ic Ins i u e, Rabin Medical Cen e –Beilinson Hospi al, Pe ach Tik a, Is ael cj Sush u Hospi al and Resea ch Cen e, Mumbai, India ck Zydus Cance Cen e, Ahmedabad, India cl Ins i u o de Medicina T aslacional e Ingenie ia Biomedica (IMTIB), CONICET IU, Hospi al I aliano de Buenos Ai es, Buenos Ai es, 94, A gen ina cm Hospi al P i ado Uni e sia io de Có doba, Co doba, A gen ina cn Su gical Cen e o He edi a y Tumo s, E . Be hesda Khs Duisbu g, Uni e si y Wi en-He decke, He decke, Ge many co Depa men o Medicine, Melbou ne Uni e si y, Melbou ne, Aus alia cp P og ama Cánce He edo Familia , San iago, Chile cq Depa -men o Su ge y, Uni e si ä smedizin Mainz, Ge many c SEQUIPE, Reci e, B azil cs Cen o de In es igación Biomédica en Red Cánce (CIBERONC), 28029, Mad id, Spain c Depa men o Su ge y, Cen al Finland Heal h Ca e Dis ic , Jy äskylä, Finland cu Coope a ion Uni Applied Tumou Biology, Ge man Cance Resea ch Cen e (DKFZ), Heidelbe g, Ge many c Ge man Cance Conso ium (DKTK) D esden and Ge man Cance Resea ch Cen e (DKFZ) Heidelbe g, Heidelbe g, Ge many cw Ins i u e o Clinical Gene ics, Facul y o Medicine and Uni e si y Hospi al Ca l Gus a Ca us, TU D esden, D esden, Ge many cx He edi a y Cance Synd ome Cen e D esden, Facul y o Medicine and Uni e si y Hospi al Ca l Gus a Ca us, TU D esden, D esden, Ge many cy MGZ - Medical Gene ics Cen e , Munich, Ge many cz Di ision o Cance Sciences, Uni e si y o Manches e , Manches e , UK Summa y Backg ound The P ospec i e Lynch Synd ome Da abase (PLSD) colla es in o ma ion on ca ie s o pa hogenic o likely pa hogenic MMR a ian s (pa h_MMR) who a e ecei ing medical ollow-up, including colonoscopy su eillance, which aims o he achie e ea ly diagnosis and ea men o cance s. He e we use he mos ecen PLSD coho ha is la ge and has wide geog aphical ep esen a ion han p e ious e sions, allowing us o p esen mo ali y as an ou come, and median ages a cance diagnoses o he fi s ime. Me hods The PLSD is a p ospec i e obse a ional s udy wi hou a con ol g oup ha was designed in 2012 and upda ed up o Oc obe 2022. Da a o 8500 ca ie s o pa h_MMR a ian s om 25 coun ies we e included, p o iding 71,713 yea s o ollow up. Cumula i e cance incidences a 65 yea s o age we e combined wi h 10-yea c ude su i al ollowing cance , o de i e es ima es o mo ali y up o 75 yea s o age by o gan, gene, and gende . Findings Gynaecological cance s we e mo e equen han colo ec al cance s in pa h_MSH2, pa h_MSH6 and pa h_PMS2 ca ie s [cumula i e incidence: 53.3%, 49.6% and 23.3% a 75 yea s, espec i ely]. Endome ial, colon and o a ian cance had low mo ali y [8%, 13% and 15%, espec i ely] and p os a e cance s we e equen in male pa h_MSH2 ca ie s [cumula i e incidence: 39.7% a 75 yea s]. Panc ea ic, b ain, bilia y ac and u e e and kidney and u ina y bladde cance s we e associa ed wi h high mo ali y [83%, 66%, 58%, 27%, and 29%, espec i ely]. Among pa h_MMR ca ie s unde going colonoscopy su eillance, pa icula ly pa h_MSH2 ca ie s, mo e dea hs ollowed non-colo ec al Lynch synd ome cance s han colo ec al cance s. In e p e a ion In pa h_MMR ca ie s unde going colonoscopy su eillance, non-colo ec al Lynch synd ome cance s we e associa ed wi h mo e dea hs han we e colo ec al cance s. Reducing dea hs om non-colo ec al cance s p esen s a key challenge in con empo a y medical ca e in Lynch synd ome. eClinicalMedicine 2023;▪: 101909 Published Online XXX h ps://doi.o g/10. 1016/j.eclinm.2023. 101909 A icles www. helance .com Vol ▪▪, 2023 3 Funding We acknowledge unding om he No wegian Cance Socie y, con ac 194751-2017. Copy igh © 2023 The Au ho (s). Published by Else ie L d. This is an open access a icle unde he CC BY license (h p://c ea i ecommons.o g/licenses/by/4.0/). Keywo ds: Mo ali y; Su i al; Lynch synd ome; Cance isk; MLH1;MSH2;MSH6;PMS2; P ospec i e s udy In oduc ion Lynch synd ome (LS) is caused by pa hogenic a ian s in any o he ou misma ch epai genes, MLH1, MSH2,MSH6 o PMS2 o by dele ion o he 3′end o EPCAM (TACSTD1) which esul s in hype me hyla ion o he MSH2 p omo e (pa h_MMR). 1 Colonoscopy wi h polypec omy has been ad oca ed o p e en colo ec al cance (CRC) in pa h_MMR ca ie s 2 ; bu se e al epo s ha e ound high CRC incidence in pa h_MMR ca ie s despi e su eillance colonoscopy, as well as high gynaecological cance incidence. 3–8 The e ficacy o su - eillance o non-colo ec al cance s in LS is no well e idenced. 9 Su i al ollowing cance diagnosis has been epo ed, 4 guidelines o clinical in e en ions ha e been issued 10 and he ex en o which managemen p ac ices align wi h esea ch findings and wi h he guidelines based upon hem has been discussed. 11 The main goal o in e en ion in a pe son wi h an inhe i ed cance isk is o p e en p ema u e dea h, 12 bu success in achie ing his has been di ficul o measu e in LS, and he epo s men ioned abo e ha e ocused la gely on cance incidence as a su oga e endpoin o su i al. Recen ly, he USA Na ional Comp ehensi e Cance Ne wo k (NCCN) guidelines desc ibed he gene- and o gan-specific cumula i e cance isks in pa h_MMR ca ie s based on a ious da a sou ces, including he P ospec i e Lynch Synd ome Da abase (PLSD). 13 How- e e , when ad oca ing colonoscopy o he p e en ion o CRC, NCCN did no acknowledge ha he CRC in- cidences epo ed by PLSD we e de e mined in in- di iduals unde going colonoscopy su eillance. I was also s a ed ha he incidences o some o he cance s had no been epo ed in he li e a u e and he a e age ages a diagnosis o cance s we e desc ibed wi hou indi- ca ing how hey we e ob ained. The e is a lack o e idence ha su eillance p e en s ex acolonic cance s, bu cu en guidelines do include su eillance ecommenda ions o some o he many ex acolonic cance s associa ed wi h LS. 10,13–16 The e is limi ed in o ma ion on CRC and ex acolonic cance mo ali y in pa h_MMR ca ie s who ecei e colonos- copy su eillance. P o iding new da a on mo ali y was he ocus o his s udy. The upda ed e sion o PLSD upon which he cu - en s udy is based includes 71,713 p ospec i e ollow- up yea s, allowing us o he fi s ime o p esen mo - ali y ou comes by gene and gende , o each o gan in which LS-associa ed cance s occu . We also p esen da a ha will help o fill he knowledge gaps in he ecen NCCN guidelines when hey a e nex upda ed, including he median age a cance diagnosis in each o gan by gene and gende . Me hods The PLSD design The PLSD is a p ospec i e obse a ional s udy wi hou a con ol g oup ha was designed in 2012 and ha p o ides an agg ega ed compila ion o combined gene ic and clin- ical in o ma ion om all con ibu o s up o Oc obe 2022. The eligibili y c i e ia include pa h_MMR ca ie s wi h o wi hou a p e ious cance who a e aged 25 yea s o olde on he day o hei fi s p ospec i ely planned and comple ed su eillance colonoscopy. 4–8,10,11,17–19 Cance s a e Resea ch in con ex E idence be o e his s udy We sea ched PubMed up o Oc obe , 2022 o a icles in English published using he sea ch e ms “Lynch synd ome and cance isk”,“Lynch synd ome and su i al”,“Lynch synd ome and mo ali y”,“ex a colonic Lynch synd ome umo ”,“Lynch synd ome and colo ec al cance incidence” and “su eillance and Lynch synd ome”in he i le o abs ac . Howe e , educ ion o colo ec al cance incidence by colonoscopy su eillance has no been documen ed and he e a e limi ed da a ega ding isks o o he cance ypes and he e ec i eness o wide cance su eillance in indi iduals wi h Lynch synd ome. P e iously, ou comes om in e en ions including colonoscopy ha e been epo ed as cance incidences, no su i al. Added alue o his s udy In ca ie s o MMR a ian s unde going colonoscopy su eillance, colo ec al cance was equen bu associa ed wi h low mo ali y whilesomeo he cance s,no ablybileduc ,panc easandb ain, we e associa ed wi h high mo ali y and mo e dea hs ollowed non-colo ec al han colo ec al cance s. Implica ions o all he a ailable e idence P e en ion and ea men o non-colo ec al cance s should be p io i ised o u he educe mo ali y in pa h_MMR ca ie s. A icles 4 www. helance .com Vol ▪▪, 2023 g ouped by he h ee fi s posi ions in he ICD9 classifi- ca ion sys em. This ails o iden i y sebaceous gland can- ce s. Os eosa comas a e ecognised as pa o LS, 20 bu we e ound oo in equen ly o be included in he p e- sen a ion o cance incidences. In his s udy, cance s in he ollowing o gans a e deno ed as LS cance s: colon, ec um, endome ium, o a y, small in es ine, bile duc , panc eas, s omach, p os a e, u ina y bladde , u e e , b ain and os- eosa coma. Adenoca cinomas sha e some pheno ypic cha ac e is ics, and he e is a small possibili y ha a sub- sequen cance migh ha e been a ecu ence om a p e ious cance in he same o ano he o gan. Howe e , local ecu ences a e usually clinically dis inguished om me ach onous p ima ies. The pa h_MMR ca ie s in he cu en s udy we e ollowed up wi h colonoscopy and gynaecological su eillance acco ding o local imple- men a ion o in e na ional ecommenda ions. The gynae- cological ollow-up ca ied ou by PLSD con ibu ing cen es has been epo ed p e iously and is no e idence- based. 4,17 S a is ical analysis Annual incidence a es in 5-yea coho s by gene and gende o cance in each o gan and in g oups o o gans we e calcula ed in MySQL80©. O e all su i al was es ima ed using he Nelson-Aalen algo i hm in R. 21 Ca ego iza ion o ca ie s as dead o ali e was made a las obse a ion and was made o all ca ie s. C ude mo ali y a 75 yea s o age ollowing cance in specific o gans was calcula ed as cumula i e incidence a 65 yea s o cance in each o gan mul iplied by (1–10-yea su i al) ollowing cance diagnosis in ha o gan. The epo ed mo ali y is an empi ical obse a ion which in- cludes no assump ions, and includes dea h om any cause, including synch onous and me ach onous cance s associa ed wi h LS. Possible o e diagnosis o colon cance due o colonoscopy 21 was adjus ed o when calcula ing su i al: incidence and su i al a e o be measu ed simul aneously when combined like his. PLSD incidences should no be compa ed wi h su i al measu ed in o he ways. We a e no awa e o any s udies o measu e mo - ali y by o he means and o ou knowledge he e is no p e ious epo on mo ali y as an ou come o sc eening o ea ly cance diagnosis in LS. Con ounde s o ou me hod o es ima ing su i al include ime- ends in ea men s ha may educe mo ali y, which his epo did no conside . The poin es ima es o pa h_PMS2 ca ie sha ewideconfidence in e als because o he low numbe o ca ie s and ollow-up yea s colla ed by he PLSD. Cance s de ec ed p ospec i ely we e sco ed as he fi s umo in each o gan in ca ie s who had no had cance in ha o gan be o e o a inclusion (igno ing p ospec i ely diagnosed cance s in o he o gans and excluding p e ious cance s and p e alen cance s iden ified a inclusion). No synch onous o subsequen cance in he same o gan was sco ed as an e en . Cumula i e isk o cance was se o ze o a age 25 yea s, and annual incidence a es (AIRs) o fi e-yea coho s om 25 o 75 yea s o age we e calcula ed as he s a ing poin o u he calcula ions in R© ( e sion 4.2.0). In he cu en epo , he cumula i e incidences ( isks) and hei 95% confidence in e als (CIs) we e calcula ed using Nelson-Aalen es ima es wi h an unde lying Poisson dis ibu ion. Fo calcula ing he median age o cance diagnosis, he isk has o be condi ioned on hose pa ien s who de eloped any cance du ing hei li e ime. Fo his, he condi ional isk was compu ed by di iding he isk es- ima e in each fi e-yea age coho by he li e ime isk (app oxima ed by he isk a 75 yea s o age), mapping he isk on he in e al [0%; 100%]. The co esponding condi ional 95% CIs we e compu ed acco dingly, condi ioned on he li e- ime isk and unca ed o he in e al [0%; 100%]. We hen pe o med a piecewise linea in e pola ion o he condi ional isk and condi- ional 95% CIs o he fi e-yea age coho s o de e mine he median age o cance onse . The la e co esponds o he age a which he in e pola ed condi ional isk hi s he 50% condi ional isk limi . The same in e sec ion calcula ions we e pe o med o he co esponding 95% confidence in e als. E hics s a emen The s udy adhe ed o he p inciples se ou in he Decla a ion o Helsinki. I was app o ed by he No - wegian Da a P o ec ion Au ho i y ( e e ence 2001/2988- 2) and he E hics Commi ee ( e e ence S-02030). Ge- ne ic es ing was pe o med wi h in o med consen ac- co ding o local and na ional equi emen s and all epo ing cen es expo ed only de-iden ified da a o PLSD. Pa ien s had been ollowed up p ospec i ely ac- co ding o in e na ional and local clinical guidelines, as p e iously desc ibed. 3–7,17–19,22 Role o he unding sou ce The unding body had no ole in he design o he s udy and collec ion, analysis, and in e p e a ion o da a and in w i ing he manusc ip . MD-V and PM had access o da ase and all au ho s con ibu ed da a o he PLSD and e iewed and app o ed he manusc ip . All au ho s ha e ead and ag eed o he final e sion o he manusc ip . Ve sion. All au ho s had ull access o all he da a in he s udy and accep esponsibili y o he decision o sub- mi o publica ion. Resul s Cha ac e is ics o he PLSD pa ien s, ollow-up yea s, gene, gende , and coun y In addi ion o he 6350 ca ie s included in ou p e ious epo , 4 da a om 2150 new pa h_MMR ca ie s we e p o ided by 18 new con ibu ing cen es and by A icles www. helance .com Vol ▪▪, 2023 5 p e iously con ibu ing cen es ha p o ided in o ma- ion on newly ec ui ed ca ie s. In o al, 25 coun ies in fi e con inen s (Supplemen a y Table S1) we e ep e- sen ed in he cu en PLSD da ase ha comp ised 8500 pa h_MMR ca ie s (4588 emales and 3912 males) wi h a mean age o 42.5 and 43.6 yea s o pa h_MLH1/ MSH2 ca ie s compa ed o 48.3 and 49.9 yea s o pa h_MSH6/PMS2 ca ie s a inclusion. They we e ollowed up wi h su eillance colonoscopy and p o ided 71,713 p ospec i e obse a ion yea s, wi h a mean ollow-up ime o 8.4 yea s. When s a ified by gene, he e we e 3171 (37.3%) pa h_MSH2 ca ie s, 3131 (36.8%) pa h_MLH1, 1649 pa h_MSH6 (19.4%) and 549 (6.5%) pa h_PMS2 ca ie s in he s udy. Supplemen a y Table S1 desc ibes he numbe s o pa ien s, ollow-up yea s and age a inclu- sion, s a ified by gene, gende , and coun y. Du ing p ospec i e obse a ion, 1853 fi s cance s in any o gan we e diagnosed (Supplemen a y Table S2)o which 1436 (77.5%) we e LS-associa ed cance s (s om- ach, small in es ine, bilia y ac , panc eas, colon, ec um, endome ium, o a ies, os eosa coma, p os a e, b ain, u ina y bladde and u e e ). Cance s o he colon (n = 481, 26% o all cance s), endome ium (n = 237, 12.8%), skin (n = 155, 8.4%), and ec um (n = 137, 7.4%) we e mos equen , bu skin cance s we e no epo ed consis en ly. In Supplemen a y Tables S3–S6, we also p esen he incidence o b eas cance s. Al hough his cance is men ioned in he NCCN guidelines, 13 we do no conside b eas cance o be a pa o LS and hence do no discuss he findings. 23 Su i al and mo ali y Ten-yea c ude su i al a e cance o he colon ha occu ed be o e 65 yea s o age was 87% and 72% a e ec al, 92% a e endome ial, 85% a e o a ian, 73% a e uppe u ina y ac , 71% a e u ina y bladde , 76% a e p os a e, 42% a e bile duc , 63% a e s omach, 70% a e small bowel, 17% a e panc eas and 34% a e b ain cance s. Fi e- and 10-yea su i al a e de ailed in Supplemen a y Table S7. Figs. 1 and 2illus a e ha he e we e no significan di e ences by gene in he 10-yea su i al a e colon o endome ial cance . Fo colon cance his was 86% [80%– 92%] in pa h_MLH1, 89% [82%–96%] in pa h_MSH2 and 85% [67%–100%] in pa h_MSH6 ca ie s and o +++++++++++ +++++++++++ ++++ ++ +++ ++ 0.00 0.25 0.50 0.75 1.00 0510 Time Su i al p obabili y S a a ++++ 241 141 76 165 82 39 22 12 6 300 0510 Time S a a Numbe a isk pa h_MLH1 pa h_MSH2 pa h_MSH6 pa h_PMS2 pa h_MLH1 pa h_MSH2 pa h_MSH6 pa h_PMS2 Fig. 1: C ude su i al (%) in pa h_MLH1, pa h_MSH2, pa h_MSH6 and pa h_PMS2 ca ie s subjec ed o colonoscopy su eillance a e colon cance diagnosed be o e age o 65 yea s. The da k line showed he su i al p obabili y, and he ba s showed he 95% confidence in e al o each pa h_MMR ca ie : pa h_MLH1 (o ange), pa h_MSH2 (g een), pa h_MSH6 (blue) and pa h_PMS2 (pu ple). Ca ego iza ion o ca ie s as dead o ali e was made a las obse a ion and was made o all ca ie s. A icles 6 www. helance .com Vol ▪▪, 2023 endome ial cance : 93% [88%–99%],91% [85%–98%] and 89% [75%–100%], espec i ely. Supplemen a y Figs. S1– S10 show he 10-yea su i al by gene o ec al and ex acolonic cance s, including o a ian, u e e and kidney, u ina y bladde , p os a e, s omach, small bowel, bilia y ac , panc eas, and b ain cance s. Mo ali y by o gan, gene and gende a 75 yea s o age is p esen ed in Table 1. As shown, o male pa h_MLH1 and pa h_MSH6 ca ie s, mo ali y was simila a e CRC compa ed o mo ali y a e non-CRC cance s. Pa h_MSH2 ca ie s o bo h gende s and e- male pa h_MSH6 ca ie s had mo e dea hs a e non- CRC. Impo an ly, he combined incidences o dea hs a e colon and ec al cance o all pa h_MMR ca ie s comp ised less han hal o he o al dea hs ollowing any LS cance . Coun ing numbe s (no incidences) o dea hs in he o al se ies, dea hs ollowing CRC accoun ed o less han hal o all dea hs ollowing an LS cance (n = 76, 36%) (Table 2). Gyneacological cance (n = 31, 14.8%), u e e and kidney (n = 16, 7.7%), s omach cance (n = 16, 7.7%) and panc eas (n = 14, 6.7%) we e he o he cance s associa ed wi h a high numbe o dea hs (Table 2). Median age o cance diagnosis and cumula i e incidences o cance s by age, gene, gende , and o gan The median ages o cance diagnosis and he cumula i e incidences o cance s in pa h_ MLH1,pa h_MSH2, pa h_MSH6 and pa h_PMS2 ca ie s in di e en o gans by age, gene and gende a e gi en in Table 3 and Supplemen a y Tables S3–S6, espec i ely. We used he same o ma as he 2021 NCCN epo 13 and p esen LS- associa ed cance s only, based on p e ious PLSD epo s bu excluding os eosa coma ( he 11 cases ound we e insu ficien o s a is ical calcula ions). Incidences o g oups o cance s such as u ina y ac cance s, endo- me ial o o a ian cance s and uppe gas oin es inal ac cance s a e also gi en. Median ages a cance diagnoses by gene, o gan, and gende ha e no been epo ed be o e in LS. We ound a younge median age a diagnosis o cance s in pa h_MSH2 ca ie s han in pa h_MLH1 ca ie s, wi h he excep ion o CRC, u ina y bladde , bile duc /gall bladde and b ain cance s. An olde median age a diagnosis was obse ed o cance s in pa h_MSH6 and pa h_PMS2 ca ie s. +++++++++++ +++++++++++ ++ + ++ ++++ + ++ ++ 0.00 0.25 0.50 0.75 1.00 0510 Time Su i al p obabili y S a a +++ 93 58 38 82 54 27 36 15 6 541 0510 Time S a a Numbe a isk pa h_MLH1 pa h_MSH2 +pa h_MSH6 pa h_MLH1 pa h_MSH2 pa h_MSH6 pa h_PMS2 pa h_PMS2 Fig. 2: C ude su i al (%) in pa h_MLH1, pa h_MSH2,pa h_MSH6 and pa h_PMS2 ca ie s subjec ed o colonoscopy su eillance a e colon cance diagnosed be o e age o 65 yea s. The da k line showed he su i al p obabili y, and he ba s showed he 95% confidence in e al o each pa h_MMR ca ie : pa h_MLH1 (o ange), pa h_MSH2 (g een), pa h_MSH6 (blue) and pa h_PMS2 (pu ple). Ca ego iza ion o ca ie s as dead o ali e was made a las obse a ion and was made o all ca ie s. A icles www. helance .com Vol ▪▪, 2023 7 Cance ype Pa hogenic a ian s 10-yea su i al Males Females Cumula i e incidence 65 yea s Mo ali y 75 yea s Cumula i e incidence 65 yea s Mo ali y 75 yea s Colon pa h_MLH1 87% 48.4% [42.4–54.8] 6% 36.3% [31.0–42.3] 5% pa h_MSH2 41.5% [34.8–48.8] 5% 29.8% [24.6–35.8] 4% pa h_MSH6 12.7% [6.8–23.1] 2% 10.1% [5.8–17.1] 1% pa h_PMS2 9.5% [2.5–32.9] 1% 2.8% [0.4–18.2] 0% Rec um pa h_MLH1 72% 6.0% [3.8–9.3] 2% 4.6% [2.9–7.3] 1% pa h_MSH2 12.6% [9.2–17.3] 4% 7.6% [5.1–11.1] 2% pa h_MSH6 5.1% [2.3–11.1] 1% 3.9% [1.8–8.6] 1% pa h_PMS2 0% [NA] 0% 2.2% [0.3–14.6] 1% Endome ium pa h_MLH1 92% na 31.7% [26.5–37.7] 3% pa h_MSH2 37.6% [31.3–44.8] 3% pa h_MSH6 32.1% [24.2–41.7] 3% pa h_PMS2 12.7% [5.5–27.9] 1% O a y pa h_MLH1 85% na 8.0% [5.3–12.0] 1% pa h_MSH2 10.6% [7.2–15.6] 2% pa h_MSH6 2.9% [0.9–8.7] 0% pa h_PMS2 2.5% [0.4–16.3] 0% S omach pa h_MLH1 63% 2.8% [1.5–5.2] 1% 2.0% [1.0–4.2] 1% pa h_MSH2 4.3% [2.5–7.6] 2% 2.6% [1.4–5.0] 1% pa h_MSH6 0.7% [0.1–4.9] 0% 0.7% [0.1–4.7] 0% pa h_PMS2 2.7% [0.4–17.5] 1% 0% [NA] 0% Small in es ine pa h_MLH1 70% 4.4% [2.6–7.2] 1% 2.5% [1.3–4.6] 1% pa h_MSH2 4.5% [2.6–7.6] 1% 3.2% [1.8–5.6] 1% pa h_MSH6 0.7% [0.1–4.8] 0% 0.6% [0.1–4.0] 0% pa h_PMS2 3.3% [0.5–21.3] 1% 2.1% [0.3–14.0] 1% Bile duc pa h_MLH1 42% 2.9% [1.5–5.6] 2% 1.5% [0.7–3.3] 1% pa h_MSH2 1.0% [0.3–3.2] 1% 0.8% [0.3–2.4] 0% pa h_MSH6 0% [NA] 0% 0% [NA] 0% pa h_PMS2 0% [NA] 0% 0% [NA] 0% Panc eas pa h_MLH1 17% 1.1% [0.4–2.9] 1% 1.9% [0.9–4.0] 2% pa h_MSH2 1.4% [0.5–3.7] 1% 1.2% [0.5–3.3] 1% pa h_MSH6 0% [NA] 0% 0.7% [0.1–4.8] 1% pa h_PMS2 0% [NA] 0% 0% [NA] 0% U e e /kidney pa h_MLH1 73% 2.5% [1.3–5.1] 1% 1.7% [0.8–3.8] 0% pa h_MSH2 11.5% [8.2–16.0] 3% 9.7% [6.9–13.5] 3% pa h_MSH6 1.4% [0.3–5.4] 0% 3.2% [1.3–7.4] 1% pa h_PMS2 0% [NA] 0% 0% [NA] 0% U ina y bladde pa h_MLH1 71% 3.3% [1.8–6.1] 1% 1.3% [0.6–3.2] 0% pa h_MSH2 5.9% [3.7–9.4] 2% 4.7% [2.8–7.7] 1% pa h_MSH6 3.0% [1.1–7.9] 1% 1.8% [0.6–5.6] 1% pa h_PMS2 0% [NA] 0% 0% [NA] 0% P os a e pa h_MLH1 76% 5.3% [3.2–8.7] 1% na pa h_MSH2 10.6% [7.5–15.0] 3% pa h_MSH6 3.0% [1.1–7.7] 1% pa h_PMS2 3.3% [0.5–21.5] 1% B ain pa h_MLH1 34% 0% [NA] 0% 0.9% [0.3–2.4] 1% pa h_MSH2 3.3% [1.7–6.3] 2% 1.4% [0.5–3.8] 1% pa h_MSH6 0.8% [0.1–5.3] 1% 1.2% [0.3–4.6] 1% pa h_PMS2 0% [NA] 0% 7.3% [1.1–41.6] 5% a Mo ali y was calcula ed as cumula i e incidence a 65 yea s o age mul iplied by (1–10 yea s su i al) om Supplemen a y Table S4. a Caused by only one case a young age, which is no significan ly di e en om ze o, na: no applicable. Table 1: Mo ali y by cance , gene and gende a 75 yea s in pa h_MMR ca ie s: mo ali y a 75 yea s was calcula ed as cumula i e incidence a 65 yea s wi h [95% confidence in e als] mul iplied by (1 – en yea s su i al) ollowing cance in ha o gan. A icles 8 www. helance .com Vol ▪▪, 2023