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

Research output: Contribution to journalResearch articleContributed

Contributors

  • Mev Dominguez-Valentin - , Institute of Cancer Research (Author)
  • Saskia Haupt - , University Hospital Heidelberg (Author)
  • Toni T Seppälä - , Tampere University Hospital (Author)
  • Julian R Sampson - , Cardiff University (Author)
  • Lone Sunde - , Aalborg University (Author)
  • Inge Bernstein - , Department of Molecular and Clinical Cancer Medicine and. (Author)
  • Mark A Jenkins - , University of Melbourne (Author)
  • Christoph Engel - , University Hospital Leipzig (Author)
  • Stefan Aretz - , University of Bonn Medical Center (Author)
  • Maartje Nielsen - , University Hospital Carl Gustav Carus Dresden (Author)
  • Gabriel Capella - , Hospitalet de Llobregat (Author)
  • Francesc Balaguer - , Barcelona Institute for Global Health (ISGlobal) Hospital Clínic (Author)
  • Dafydd Gareth Evans - , Manchester University NHS Foundation Trust (Author)
  • John Burn - , Newcastle University (Author)
  • Elke Holinski-Feder - , Campus Innenstadt (Author)
  • Lucio Bertario - , IRCCS Istituto Europeo di Oncologia - Milano (Author)
  • Bernardo Bonanni - , IRCCS Istituto Europeo di Oncologia - Milano (Author)
  • Annika Lindblom - , Karolinska Institutet (Author)
  • Zohar Levi - , Rabin Medical Center Israel (Author)
  • Finlay Macrae - , Royal Melbourne Hospital (Author)
  • Ingrid Winship - , Royal Melbourne Hospital (Author)
  • John-Paul Plazzer - , Royal Melbourne Hospital (Author)
  • Rolf Sijmons - , University of Groningen (Author)
  • Luigi Laghi - , University of Parma (Author)
  • Adriana Della Valle - , Hospital Fuerzas Armadas (Author)
  • Karl Heinimann - , University Hospital Basel (Author)
  • Tadeusz Dębniak - , International Hereditary Cancer Center (Author)
  • Robert Fruscio - , University of Milan - Bicocca (Author)
  • Francisco Lopez-Koestner - , Clínica Universidad de los Andes (Author)
  • Karin Alvarez-Valenzuela - , Clínica Universidad de los Andes (Author)
  • Lior H Katz - , Hebrew University of Jerusalem (Author)
  • Ido Laish - , Hebrew University of Jerusalem (Author)
  • Elez Vainer - , Hadassah Medical Center (Author)
  • Carlos Vaccaro - , Hospital Italiano de Buenos Aires (Author)
  • Dirce Maria Carraro - , A.C.Camargo Cancer Center (Author)
  • Kevin Monahan - , St. Mark's Hospital and Academic Institute (Author)
  • Elizabeth Half - , Gastrointestinal Cancer Prevention Unit (Author)
  • Aine Stakelum - , St Vincent's University Hospital (Author)
  • Des Winter - , St Vincent's University Hospital (Author)
  • Rory Kennelly - , St Vincent's University Hospital (Author)
  • Nathan Gluck - , Tel Aviv University (Author)
  • Harsh Sheth - , Institute of Medical and Human Genetics (Author)
  • Naim Abu-Freha - , Soroka Medical Center (Author)
  • Marc Greenblatt - , University of Vermont (Author)
  • Benedito Mauro Rossi - , Hospital Sirio-Libanes (Author)
  • Mabel Bohorquez - , Universidad del Tolima (Author)
  • Giulia Martina Cavestro - , Vita-Salute San Raffaele University (Author)
  • Leonardo S Lino-Silva - , Surgical Pathology (Author)
  • Karoline Horisberger - , University Hospital Zurich (Author)
  • Maria Grazia Tibiletti - , Ospedale di Circolo ASST Settelaghi (Author)
  • Ivana do Nascimento - , Universidade Federal do Recôncavo da Bahia (Author)
  • Huw Thomas - , Imperial College London (Author)
  • Norma Teresa Rossi - , Fundación para el Progreso de la Medicina" y "Sanatorio Allende" (Author)
  • Leandro Apolinário da Silva - , Hospital Universitário Oswaldo Cruz (Author)
  • Attila Zaránd - , Semmelweis University (Author)
  • Juan Ruiz-Bañobre - , University of Santiago de Compostela (Author)
  • Vincent Heuveline - , University Hospital Heidelberg (Author)
  • Jukka-Pekka Mecklin - , University of Jyväskylä (Author)
  • Kirsi Pylvänäinen - , TUD Dresden University of Technology (Author)
  • Laura Renkonen-Sinisalo - , University of Helsinki (Author)
  • Anna Lepistö - , University of Helsinki (Author)
  • Päivi Peltomäki - , University of Helsinki (Author)
  • Christina Therkildsen - , Copenhagen University Hospitals (Author)
  • Mia Gebauer Madsen - , Aarhus University Hospital (AUH) (Author)
  • Stefan Kobbelgaard Burgdorf - , Copenhagen University Hospitals (Author)
  • John L Hopper - , University of Melbourne (Author)
  • Aung Ko Win - , University of Melbourne (Author)
  • Robert W Haile - , Stanford University (Author)
  • Noralane Lindor - , Mayo Clinic Scottsdale, AZ (Author)
  • Steven Gallinger - , University of Toronto (Author)
  • Loïc Le Marchand - , University of Hawai'i at Mānoa (Author)
  • Polly A Newcomb - , Fred Hutchinson Cancer Research Center (Author)
  • Jane Figueiredo - , Fred Hutchinson Cancer Research Center (Author)
  • Daniel D Buchanan - , University of Melbourne (Author)
  • Stephen N Thibodeau - , Department of Laboratory Medicine and Pathology (Author)
  • Magnus von Knebel Doeberitz - , University Hospital Heidelberg (Author)
  • Markus Loeffler - , University Hospital Leipzig (Author)
  • Nils Rahner - , University Hospital Duesseldorf (Author)
  • Evelin Schröck - , Institute of Clinical Genetics, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), University Hospital Carl Gustav Carus Dresden (Author)
  • Verena Steinke-Lange - , Department of internal Medicine I (Author)
  • Wolff Schmiegel - , Ruhr University Bochum (Author)
  • Deepak Vangala - , Ruhr University Bochum (Author)
  • Claudia Perne - , University of Bonn Medical Center (Author)
  • Robert Hüneburg - , University of Bonn Medical Center (Author)
  • Silke Redler - , University Hospital Duesseldorf (Author)
  • Reinhard Büttner - , Uniklinik Köln (Author)
  • Jürgen Weitz - , Department of Visceral, Thoracic and Vascular Surgery (Author)
  • Marta Pineda - , Hospitalet de Llobregat (Author)
  • Nuria Duenas - , Hospitalet de Llobregat (Author)
  • Joan Brunet Vidal - , Hospitalet de Llobregat (Author)
  • Leticia Moreira - , Barcelona Institute for Global Health (ISGlobal) Hospital Clínic (Author)
  • Ariadna Sánchez - , Barcelona Institute for Global Health (ISGlobal) Hospital Clínic (Author)
  • Eivind Hovig - , Institute of Cancer Research (Author)
  • Sigve Nakken - , Institute of Cancer Research (Author)
  • Kate Green - , Manchester University NHS Foundation Trust (Author)
  • Fiona Lalloo - , Manchester University NHS Foundation Trust (Author)
  • James Hill - , Central Manchester and Manchester Children's University Hospitals NHS Trust, University of Manchester (Author)
  • Emma Crosbie - , Manchester University NHS Foundation Trust (Author)
  • Miriam Mints - , Karolinska University Hospital (Author)
  • Yael Goldberg - , Raphael Recanati Genetic Institute (Author)
  • Douglas Tjandra - , Royal Melbourne Hospital (Author)
  • Sanne W Ten Broeke - , University of Groningen (Author)
  • Revital Kariv - , St Vincent's University Hospital (Author)
  • Guy Rosner - , St Vincent's University Hospital (Author)
  • Suresh H Advani - , Sushrut Hospital and Research Centre (Author)
  • Lidiya Thomas - , Sushrut Hospital and Research Centre (Author)
  • Pankaj Shah - , Zydus Cancer Centre (Author)
  • Mithun Shah - , Zydus Cancer Centre (Author)
  • Florencia Neffa - , University of Parma (Author)
  • Patricia Esperon - , University of Parma (Author)
  • Walter Pavicic - , Hospital Italiano de Buenos Aires (Author)
  • Giovana Tardin Torrezan - , Hospital Italiano de Buenos Aires (Author)
  • Thiago Bassaneze - , University of Vermont (Author)
  • Claudia Alejandra Martin - , Private University Hospital of Córdoba (Author)
  • Gabriela Moslein - , Witten/Herdecke University (Author)
  • Pål Moller - , Institute of Cancer Research (Author)

Abstract

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.

Details

Original languageEnglish
Article number101909
Pages (from-to)101909
JournalEClinicalMedicine
Volume58
Publication statusPublished - Apr 2023
Peer-reviewedNo

External IDs

PubMedCentral PMC10166779
Scopus 85153285119

Keywords

Sustainable Development Goals

ASJC Scopus subject areas

Keywords

  • Cancer risk, Lynch syndrome, MLH1, Mortality, MSH2, MSH6, PMS2, Prospective study, Survival

Library keywords