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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
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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
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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