Incidence of and survival after subsequent cancers in carriers of pathogenic MMR variants with previous cancer: a report from the prospective Lynch syndrome database.
Today most patients with Lynch syndrome (LS) survive their first cancer. There is limited information on the incidences and outcome of subsequent cancers. The present study addresses three questions: (i) what is the cumulative incidence of a subsequent cancer; (ii) in which organs do subsequent cancers occur; and (iii) what is the survival following these cancers?



Information was collated on prospectively organised surveillance and prospectively observed outcomes in patients with LS who had cancer prior to inclusion and analysed by age, gender and genetic variants.



1273 patients with LS from 10 countries were followed up for 7753 observation years. 318 patients (25.7%) developed 341 first subsequent cancers, including colorectal (n=147, 43%), upper GI, pancreas or bile duct (n=37, 11%) and urinary tract (n=32, 10%). The cumulative incidences for any subsequent cancer from age 40 to age 70 years were 73% for pathogenicMLH1(path_MLH1), 76% forpath_MSH2carriers and 52% forpath_MSH6carriers, and for colorectal cancer (CRC) the cumulative incidences were 46%, 48% and 23%, respectively. Crude survival after any subsequent cancer was 82% (95% CI 76% to 87%) and 10-year crude survival after CRC was 91% (95% CI 83% to 95%).



Relative incidence of subsequent cancer compared with incidence of first cancer was slightly but insignificantly higher than cancer incidence in patients with LS without previous cancer (range 0.94-1.49). The favourable survival after subsequent cancers validated continued follow-up to prevent death from cancer. The interactive website http://lscarisk.org was expanded to calculate the risks by gender, genetic variant and age for subsequent cancer for any patient with LS with previous cancer.
Research Group Inherited Cancer, Department of Medical Genetics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.|Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Part of Oslo University Hospital, Oslo, Norway.|Surgical Center for Hereditary Tumors, HELIOS University Clinic Wuppertal, University Witten-Herdecke, Wuppertal, Germany.
Pål
P
Møller
Department of Surgery, Central Finland Health Care District, Jyväskylä, Finland.
Toni
T
Seppälä
The Danish Hereditary Non-polyposis Colorectal Cancer Register, Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark.|Department Surgical Gastroenterology, Aalborg University Hospital, Aalborg, Denmark.
Inge
I
Bernstein
Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany.|MGZ-Medizinisch Genetisches Zentrum, Munich, Germany.
Elke
E
Holinski-Feder
Unit of Hereditary Digestive Tract Tumors IRCCS, Istituto Nazionale Tumori, Milan, Italy.
Paola
P
Sala
Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.|Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK.
D Gareth
DG
Evans
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Annika
A
Lindblom
Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melbourne, Victoria, Australia.|Department of Medicine, Melbourne University, Melbourne, Australia.
Finlay
F
Macrae
Hereditary Cancer Program, Institut Català d'Oncologia-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
Ignacio
0000-0002-7414-7481
I
Blanco
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Rolf
R
Sijmons
Institute of Medical Genetics, Cardiff University School of Medicine, Cardiff, UK.
Jacqueline
J
Jeffries
Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands.
Hans
H
Vasen
Institute of Genetic Medicine Newcastle University, Newcastle upon Tyne, UK.
John
J
Burn
Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Part of Oslo University Hospital, Oslo, Norway.
Sigve
S
Nakken
Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Part of Oslo University Hospital, Oslo, Norway.|Institute of Cancer Genetics and Informatics, The Norwegian Radium Hospital, Part of Oslo University Hospital, Oslo, Norway.|Department of Informatics, University of Oslo, Oslo, Norway.
Eivind
E
Hovig
Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Part of Oslo University Hospital, Oslo, Norway.
Einar Andreas
EA
Rødland
Department of Mathematics and Statistics, Lancaster University, Lancaster, UK.
Kukatharmini
K
Tharmaratnam
Department of Gastroenterology and Hepatology, Isala Clinics, Zwolle, The Netherlands.
Wouter H
WH
de Vos Tot Nederveen Cappel
Department of Surgery, Central Manchester University Hospitals NHS Foundation Trust and University of Manchester, Manchester, UK.
James
J
Hill
Department of Clinical Genetics and Department of Human Genetics Leiden University Medical Centre, Leiden, The Netherlands.
Juul
J
Wijnen
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
Mark
M
Jenkins
Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
Kate
K
Green
Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
Fiona
F
Lalloo
The Danish Hereditary Non-polyposis Colorectal Cancer Register, Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark.|Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.|Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Lone
L
Sunde
Division of Obstetrics and Gynecology, Department of Women's and Children's health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Miriam
M
Mints
Unit of Hereditary Digestive Tract Tumors IRCCS, Istituto Nazionale Tumori, Milan, Italy.
Lucio
L
Bertario
Hereditary Cancer Program, Institut Català d'Oncologia-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
Marta
M
Pineda
Hereditary Cancer Program, Institut Català d'Oncologia-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
Matilde
M
Navarro
Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany.|MGZ-Medizinisch Genetisches Zentrum, Munich, Germany.
Monika
M
Morak
Department of Surgery, Helsinki University Hospital, Helsinki, Finland.|Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland.
Laura
L
Renkonen-Sinisalo
Institute of Medical Genetics, Cardiff University School of Medicine, Cardiff, UK.
Ian M
IM
Frayling
Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melbourne, Victoria, Australia.
John-Paul
JP
Plazzer
Department of Education and Science, Central Finland Health Care District, Jyväskylä, Finland.
Kirsi
K
Pylvanainen
Institute of Genomic Medicine, "A. Gemelli" Faculty of Medicine, Catholic University of the Sacred Heart, Rome, Italy.
Maurizio
M
Genuardi
Department of Education and Science, Central Finland Health Care District, Jyväskylä, Finland.|University of Eastern Finland, Jyvaskyla, Finland.
Jukka-Pekka
JP
Mecklin
Surgical Center for Hereditary Tumors, HELIOS University Clinic Wuppertal, University Witten-Herdecke, Wuppertal, Germany.
Gabriela
G
Möslein
Institute of Medical Genetics, Cardiff University School of Medicine, Cardiff, UK.
Julian R
JR
Sampson
Hereditary Cancer Program, Institut Català d'Oncologia-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
Gabriel
G
Capella
D000328:Adult; D000368:Aged; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D053843:DNA Mismatch Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D018450:Disease Progression; D005060:Europe / Q000453:epidemiology; D005260:Female; D014644:Genetic Variation; D018095:Germ-Line Mutation; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1 / Q000235:genetics*; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009367:Neoplasm Staging; D018570:Risk Assessment / Q000379:methods / Q000706:statistics & numerical data; D016019:Survival Analysis
D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein
CANCER GENETICS; COLORECTAL CANCER GENES; EPIDEMIOLOGY; INHERITED CANCERS; SCREENING