. 2017 Sep;66(9):1657-1664.

doi: 10.1136/gutjnl-2016-311403. Epub 2016 Jun 3.

Incidence of and survival after subsequent cancers in carriers of pathogenic MMR variants with previous cancer: a report from the prospective Lynch syndrome database

Pål Møller^{1

2

3}, Toni Seppälä⁴, Inge Bernstein^{5

6}, Elke Holinski-Feder^{7

8}, Paola Sala⁹, D Gareth Evans^{10

11}, Annika Lindblom¹², Finlay Macrae^{13

14}, Ignacio Blanco¹⁵, Rolf Sijmons¹⁶, Jacqueline Jeffries¹⁷, Hans Vasen¹⁸, John Burn¹⁹, Sigve Nakken², Eivind Hovig^{2

20

21}, Einar Andreas Rødland², Kukatharmini Tharmaratnam²², Wouter H de Vos Tot Nederveen Cappel²³, James Hill²⁴, Juul Wijnen²⁵, Mark Jenkins²⁶, Kate Green¹⁰, Fiona Lalloo¹⁰, Lone Sunde^{5

27

28}, Miriam Mints²⁹, Lucio Bertario⁹, Marta Pineda¹⁵, Matilde Navarro¹⁵, Monika Morak^{7

8}, Laura Renkonen-Sinisalo^{30

31}, Ian M Frayling¹⁷, John-Paul Plazzer¹³, Kirsi Pylvanainen³², Maurizio Genuardi³³, Jukka-Pekka Mecklin^{32

34}, Gabriela Möslein³, Julian R Sampson¹⁷, Gabriel Capella¹⁵; Mallorca Group (http://mallorca-group.org)

Affiliations

¹ Research Group Inherited Cancer, Department of Medical Genetics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
² Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Part of Oslo University Hospital, Oslo, Norway.
³ Surgical Center for Hereditary Tumors, HELIOS University Clinic Wuppertal, University Witten-Herdecke, Wuppertal, Germany.
⁴ Department of Surgery, Central Finland Health Care District, Jyväskylä, Finland.
⁵ The Danish Hereditary Non-polyposis Colorectal Cancer Register, Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark.
⁶ Department Surgical Gastroenterology, Aalborg University Hospital, Aalborg, Denmark.
⁷ Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany.
⁸ MGZ-Medizinisch Genetisches Zentrum, Munich, Germany.
⁹ Unit of Hereditary Digestive Tract Tumors IRCCS, Istituto Nazionale Tumori, Milan, Italy.
¹⁰ Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
¹¹ Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK.
¹² Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
¹³ Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melbourne, Victoria, Australia.
¹⁴ Department of Medicine, Melbourne University, Melbourne, Australia.
¹⁵ Hereditary Cancer Program, Institut Català d'Oncologia-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
¹⁶ Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
¹⁷ Institute of Medical Genetics, Cardiff University School of Medicine, Cardiff, UK.
¹⁸ Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands.
¹⁹ Institute of Genetic Medicine Newcastle University, Newcastle upon Tyne, UK.
²⁰ Institute of Cancer Genetics and Informatics, The Norwegian Radium Hospital, Part of Oslo University Hospital, Oslo, Norway.
²¹ Department of Informatics, University of Oslo, Oslo, Norway.
²² Department of Mathematics and Statistics, Lancaster University, Lancaster, UK.
²³ Department of Gastroenterology and Hepatology, Isala Clinics, Zwolle, The Netherlands.
²⁴ Department of Surgery, Central Manchester University Hospitals NHS Foundation Trust and University of Manchester, Manchester, UK.
²⁵ Department of Clinical Genetics and Department of Human Genetics Leiden University Medical Centre, Leiden, The Netherlands.
²⁶ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
²⁷ Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.
²⁸ Department of Biomedicine, Aarhus University, Aarhus, Denmark.
²⁹ Division of Obstetrics and Gynecology, Department of Women's and Children's health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
³⁰ Department of Surgery, Helsinki University Hospital, Helsinki, Finland.
³¹ Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland.
³² Department of Education and Science, Central Finland Health Care District, Jyväskylä, Finland.
³³ Institute of Genomic Medicine, "A. Gemelli" Faculty of Medicine, Catholic University of the Sacred Heart, Rome, Italy.
³⁴ University of Eastern Finland, Jyvaskyla, Finland.

PMID: 27261338
PMCID: PMC5561364
DOI: 10.1136/gutjnl-2016-311403

Incidence of and survival after subsequent cancers in carriers of pathogenic MMR variants with previous cancer: a report from the prospective Lynch syndrome database

Pål Møller et al. Gut. 2017 Sep.

. 2017 Sep;66(9):1657-1664.

doi: 10.1136/gutjnl-2016-311403. Epub 2016 Jun 3.

Authors

Affiliations

¹ Research Group Inherited Cancer, Department of Medical Genetics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
² Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Part of Oslo University Hospital, Oslo, Norway.
³ Surgical Center for Hereditary Tumors, HELIOS University Clinic Wuppertal, University Witten-Herdecke, Wuppertal, Germany.
⁴ Department of Surgery, Central Finland Health Care District, Jyväskylä, Finland.
⁵ The Danish Hereditary Non-polyposis Colorectal Cancer Register, Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark.
⁶ Department Surgical Gastroenterology, Aalborg University Hospital, Aalborg, Denmark.
⁷ Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany.
⁸ MGZ-Medizinisch Genetisches Zentrum, Munich, Germany.
⁹ Unit of Hereditary Digestive Tract Tumors IRCCS, Istituto Nazionale Tumori, Milan, Italy.
¹⁰ Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
¹¹ Manchester Centre for Genomic Medicine, University of Manchester, Manchester, UK.
¹² Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
¹³ Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melbourne, Victoria, Australia.
¹⁴ Department of Medicine, Melbourne University, Melbourne, Australia.
¹⁵ Hereditary Cancer Program, Institut Català d'Oncologia-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
¹⁶ Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
¹⁷ Institute of Medical Genetics, Cardiff University School of Medicine, Cardiff, UK.
¹⁸ Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands.
¹⁹ Institute of Genetic Medicine Newcastle University, Newcastle upon Tyne, UK.
²⁰ Institute of Cancer Genetics and Informatics, The Norwegian Radium Hospital, Part of Oslo University Hospital, Oslo, Norway.
²¹ Department of Informatics, University of Oslo, Oslo, Norway.
²² Department of Mathematics and Statistics, Lancaster University, Lancaster, UK.
²³ Department of Gastroenterology and Hepatology, Isala Clinics, Zwolle, The Netherlands.
²⁴ Department of Surgery, Central Manchester University Hospitals NHS Foundation Trust and University of Manchester, Manchester, UK.
²⁵ Department of Clinical Genetics and Department of Human Genetics Leiden University Medical Centre, Leiden, The Netherlands.
²⁶ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
²⁷ Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.
²⁸ Department of Biomedicine, Aarhus University, Aarhus, Denmark.
²⁹ Division of Obstetrics and Gynecology, Department of Women's and Children's health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
³⁰ Department of Surgery, Helsinki University Hospital, Helsinki, Finland.
³¹ Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland.
³² Department of Education and Science, Central Finland Health Care District, Jyväskylä, Finland.
³³ Institute of Genomic Medicine, "A. Gemelli" Faculty of Medicine, Catholic University of the Sacred Heart, Rome, Italy.
³⁴ University of Eastern Finland, Jyvaskyla, Finland.

PMID: 27261338
PMCID: PMC5561364
DOI: 10.1136/gutjnl-2016-311403

Abstract

Objective: 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?

Design: 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.

Results: 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 pathogenic MLH1 (path_MLH1), 76% for path_MSH2 carriers and 52% for path_MSH6 carriers, 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%).

Conclusions: 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.

Keywords: CANCER GENETICS; COLORECTAL CANCER GENES; EPIDEMIOLOGY; INHERITED CANCERS; SCREENING.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

PubMed Disclaimer

Conflict of interest statement

Competing interests: JB has a patent for high-speed low-cost tumour profiling pending to JB and QuantuMDx.

Figures

**Figure 1**
Result of two-sample t-test of months since last colonoscopy to colorectal cancer in previous report and in this report: p=0.10.

**Figure 2**
Survival after subsequent cancer by genetic variants (with 95% CIs as dotted line in same colour) when cancer diagnosed <65 years of age. Dotted lines indicate upper 95% CIs and broken lines indicate lower 95% intervals. There was no death observed in *path_PMS2* carriers.

**Figure 3**
Survival after subsequent colorectal cancer by genetic variant (with 95% CIs as dotted line in same colour) when cancer diagnosed <65 years of age. Dotted lines indicate upper 95% CIs and broken lines indicate lower 95% intervals. There was no death observed in *path_MSH6* carriers.

See this image and copyright information in PMC

References

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Incidence of and survival after subsequent cancers in carriers of pathogenic MMR variants with previous cancer: a report from the prospective Lynch syndrome database

Affiliations

Incidence of and survival after subsequent cancers in carriers of pathogenic MMR variants with previous cancer: a report from the prospective Lynch syndrome database

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Miscellaneous