TY - JOUR

T1 - Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment

T2 - a report from the prospective Lynch syndrome database

AU - Dominguez-Valentin, Mev

AU - Haupt, Saskia

AU - Seppälä, Toni T.

AU - Sampson, Julian R.

AU - Sunde, Lone

AU - Bernstein, Inge

AU - Jenkins, Mark A.

AU - Engel, Christoph

AU - Aretz, Stefan

AU - Nielsen, Maartje

AU - Capella, Gabriel

AU - Balaguer, Francesc

AU - Evans, Dafydd Gareth

AU - Burn, John

AU - Holinski-Feder, Elke

AU - Bertario, Lucio

AU - Bonanni, Bernardo

AU - Lindblom, Annika

AU - Levi, Zohar

AU - Macrae, Finlay

AU - Winship, Ingrid

AU - Plazzer, John Paul

AU - Sijmons, Rolf

AU - Laghi, Luigi

AU - Della Valle, Adriana

AU - Heinimann, Karl

AU - Dębniak, Tadeusz

AU - Fruscio, Robert

AU - Lopez-Koestner, Francisco

AU - Alvarez-Valenzuela, Karin

AU - Katz, Lior H.

AU - Laish, Ido

AU - Vainer, Elez

AU - Vaccaro, Carlos

AU - Carraro, Dirce Maria

AU - Monahan, Kevin

AU - Half, Elizabeth

AU - Stakelum, Aine

AU - Winter, Des

AU - Kennelly, Rory

AU - Gluck, Nathan

AU - Sheth, Harsh

AU - Abu-Freha, Naim

AU - Greenblatt, Marc

AU - Rossi, Benedito Mauro

AU - Bohorquez, Mabel

AU - Cavestro, Giulia Martina

AU - Lino-Silva, Leonardo S.

AU - Horisberger, Karoline

AU - Tibiletti, Maria Grazia

AU - Nascimento, Ivana do

AU - Thomas, Huw

AU - Rossi, Norma Teresa

AU - Apolinário da Silva, Leandro

AU - Zaránd, Attila

AU - Ruiz-Bañobre, Juan

AU - Heuveline, Vincent

AU - Mecklin, Jukka Pekka

AU - Pylvänäinen, Kirsi

AU - Renkonen-Sinisalo, Laura

AU - Lepistö, Anna

AU - Peltomäki, Päivi

AU - Therkildsen, Christina

AU - Madsen, Mia Gebauer

AU - Burgdorf, Stefan Kobbelgaard

AU - Hopper, John L.

AU - Win, Aung Ko

AU - Haile, Robert W.

AU - Lindor, Noralane

AU - Gallinger, Steven

AU - Le Marchand, Loïc

AU - Newcomb, Polly A.

AU - Figueiredo, Jane

AU - Buchanan, Daniel D.

AU - Thibodeau, Stephen N.

AU - von Knebel Doeberitz, Magnus

AU - Loeffler, Markus

AU - Rahner, Nils

AU - Schröck, Evelin

AU - Steinke-Lange, Verena

AU - Schmiegel, Wolff

AU - Vangala, Deepak

AU - Perne, Claudia

AU - Hüneburg, Robert

AU - Redler, Silke

AU - Büttner, Reinhard

AU - Weitz, Jürgen

AU - Pineda, Marta

AU - Duenas, Nuria

AU - Vidal, Joan Brunet

AU - Moreira, Leticia

AU - Sánchez, Ariadna

AU - Hovig, Eivind

AU - Nakken, Sigve

AU - Green, Kate

AU - Lalloo, Fiona

AU - Hill, James

AU - Crosbie, Emma

AU - Mints, Miriam

AU - Goldberg, Yael

AU - Tjandra, Douglas

AU - ten Broeke, Sanne W.

AU - Kariv, Revital

AU - Rosner, Guy

AU - Advani, Suresh H.

AU - Thomas, Lidiya

AU - Shah, Pankaj

AU - Shah, Mithun

AU - Neffa, Florencia

AU - Esperon, Patricia

AU - Pavicic, Walter

AU - Torrezan, Giovana Tardin

AU - Bassaneze, Thiago

AU - Martin, Claudia Alejandra

AU - Moslein, Gabriela

AU - Moller, Pål

N1 - Publisher Copyright: © 2023 The Author(s)

PY - 2023

Y1 - 2023

N2 - 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. Funding: We acknowledge funding from the Norwegian Cancer Society, contract 194751-2017.

AB - 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. Funding: We acknowledge funding from the Norwegian Cancer Society, contract 194751-2017.

KW - Cancer risk

KW - Lynch syndrome

KW - MLH1

KW - Mortality

KW - MSH2

KW - MSH6

KW - PMS2

KW - Prospective study

KW - Survival

U2 - 10.1016/j.eclinm.2023.101909

DO - 10.1016/j.eclinm.2023.101909

M3 - Journal article

C2 - 37181409

AN - SCOPUS:85153285119

VL - 58

JO - EClinicalMedicine

JF - EClinicalMedicine

SN - 2589-5370

M1 - 101909

ER -