Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database

doi:10.1136/gutjnl-2017-314057

Observational Study

. 2018 Jul;67(7):1306-1316.

doi: 10.1136/gutjnl-2017-314057. Epub 2017 Jul 28.

Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database

Pål Møller^{1

2

3}, Toni T Seppälä⁴, Inge Bernstein^{5

6}, Elke Holinski-Feder^{7

8}, Paulo Sala⁹, D Gareth Evans^{10

11}, Annika Lindblom¹², Finlay Macrae^{13

14}, Ignacio Blanco¹⁵, Rolf H Sijmons¹⁶, Jacqueline Jeffries¹⁷, Hans F A 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 T Wijnen²⁵, Mark A Jenkins²⁶, Kate Green^{10

11}, Fiona Lalloo^{10

11}, Lone Sunde^{6

27

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

8}, Laura Renkonen-Sinisalo^{4

30}, Mev Dominguez Valentin^{1

2}, Ian M Frayling, John-Paul Plazzer¹³, Kirsi Pylvanainen³¹, Maurizio Genuardi³², Jukka-Pekka Mecklin³³, Gabriela Moeslein, Julian R Sampson¹⁷, Gabriel Capella^{15

3}; Mallorca Group

Affiliations

¹ 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, Olso, Norway.
³ Center for Hereditary Tumors, HELIOS-Klinikum Wuppertal, University of Witten-Herdecke, Wuppertal, Germany.
⁴ Department of Gastrointestinal Surgery, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
⁵ The Danish Hereditary Non-polyposis Colorectal Cancer Register, Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark.
⁶ Department of Surgical Gastroenterology, Aalborg University Hospital, Aalborg, Denmark.
⁷ Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Ziemssenstr, Germany.
⁸ MGZ - Medizinisch Genetisches Zentrum, Munich, Germany.
⁹ Unit of Hereditary Digestive Tract Tumors IRCCS Istituto Nazionale Tumori Milan, Milano, Italy.
¹⁰ Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, London, UK.
¹¹ Manchester Centre for Genomic Medicine, University of Manchester, London, UK.
¹² Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
¹³ Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melborne, Australia.
¹⁴ Department of Medicine, Melbourne University, Melborne, 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 Division of Cancer and Genetics, Institute of Medical Genetics, Cardiff University School of Medicine, Heath Park, 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, Olso, Norway.
²¹ Department of Informatics, University of Oslo, Olso, 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, London, 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 Department of Women's and Children's health, Division of Obstetrics and Gyneacology, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden.
³⁰ Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland.
³¹ Department of Education and Science, Central Finland Health Care District, yväskylä, Finland.
³² Institute of Genomic Medicine, "A. Gemelli" Faculty of Medicine, Catholic University of the Sacred Heart, Rome, Italy.
³³ University of Eastern Finland, Kuopio, Finland.

PMID: 28754778
PMCID: PMC6031262
DOI: 10.1136/gutjnl-2017-314057

Observational Study

Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database

Pål Møller et al. Gut. 2018 Jul.

. 2018 Jul;67(7):1306-1316.

doi: 10.1136/gutjnl-2017-314057. Epub 2017 Jul 28.

Authors

Affiliations

¹ 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, Olso, Norway.
³ Center for Hereditary Tumors, HELIOS-Klinikum Wuppertal, University of Witten-Herdecke, Wuppertal, Germany.
⁴ Department of Gastrointestinal Surgery, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
⁵ The Danish Hereditary Non-polyposis Colorectal Cancer Register, Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark.
⁶ Department of Surgical Gastroenterology, Aalborg University Hospital, Aalborg, Denmark.
⁷ Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Ziemssenstr, Germany.
⁸ MGZ - Medizinisch Genetisches Zentrum, Munich, Germany.
⁹ Unit of Hereditary Digestive Tract Tumors IRCCS Istituto Nazionale Tumori Milan, Milano, Italy.
¹⁰ Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, London, UK.
¹¹ Manchester Centre for Genomic Medicine, University of Manchester, London, UK.
¹² Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
¹³ Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melborne, Australia.
¹⁴ Department of Medicine, Melbourne University, Melborne, 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 Division of Cancer and Genetics, Institute of Medical Genetics, Cardiff University School of Medicine, Heath Park, 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, Olso, Norway.
²¹ Department of Informatics, University of Oslo, Olso, 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, London, 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 Department of Women's and Children's health, Division of Obstetrics and Gyneacology, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden.
³⁰ Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland.
³¹ Department of Education and Science, Central Finland Health Care District, yväskylä, Finland.
³² Institute of Genomic Medicine, "A. Gemelli" Faculty of Medicine, Catholic University of the Sacred Heart, Rome, Italy.
³³ University of Eastern Finland, Kuopio, Finland.

PMID: 28754778
PMCID: PMC6031262
DOI: 10.1136/gutjnl-2017-314057

Erratum in

Correction: Cancer risk and survival in path _MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database.
[No authors listed] [No authors listed] Gut. 2020 Jun;69(6):e4. doi: 10.1136/gutjnl-2017-314057corr1. Gut. 2020. PMID: 32381558 Free PMC article. No abstract available.

Abstract

Background: Most patients with path_MMR gene variants (Lynch syndrome (LS)) now survive both their first and subsequent cancers, resulting in a growing number of older patients with LS for whom limited information exists with respect to cancer risk and survival.

Objective and design: This observational, international, multicentre study aimed to determine prospectively observed incidences of cancers and survival in path_MMR carriers up to 75 years of age.

Results: 3119 patients were followed for a total of 24 475 years. Cumulative incidences at 75 years (risks) for colorectal cancer were 46%, 43% and 15% in path_MLH1, path_MSH2 and path_MSH6 carriers; for endometrial cancer 43%, 57% and 46%; for ovarian cancer 10%, 17% and 13%; for upper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancers 21%, 10% and 7%; for urinary tract cancers 8%, 25% and 11%; for prostate cancer 17%, 32% and 18%; and for brain tumours 1%, 5% and 1%, respectively. Ovarian cancer occurred mainly premenopausally. By contrast, upper gastrointestinal, urinary tract and prostate cancers occurred predominantly at older ages. Overall 5-year survival for prostate cancer was 100%, urinary bladder 93%, ureter 85%, duodenum 67%, stomach 61%, bile duct 29%, brain 22% and pancreas 0%. Path_PMS2 carriers had lower risk for cancer.

Conclusion: Carriers of different path_MMR variants exhibit distinct patterns of cancer risk and survival as they age. Risk estimates for counselling and planning of surveillance and treatment should be tailored to each patient's age, gender and path_MMR variant. We have updated our open-access website www.lscarisk.org to facilitate this.

Keywords: HNPCC syndrome; cancer prevention; clinical trials; colorectal cancer screening; inherited cancers.

PubMed Disclaimer

Conflict of interest statement

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

Figures

**Figure 1**
Cumulative incidences of colorectal cancer, upper gastrointestinal cancer (including stomach, duodenum, bile duct, gall bladder and pancreas) and urinary tract cancer (not including prostate).

**Figure 2**
Kaplan-Meier estimates of 10-year crude survival following colon cancer, sigmoid-rectal cancer, endometrial cancer or ovarian cancer that was diagnosed before 65 years of age after censoring for upper gastrointestinal or brain tumours. Solid line indicates point values; dotted lines indicate 95% CIs.

See this image and copyright information in PMC

Comment in

The study of Lynch syndrome in a special population reveals a strong founder effect and an unusual mutational mechanism in familial adenomatous polyposis.
Siraj AK, Masoodi T, Bu R, Parvathareddy SK, Siraj S, Alassiri A, Al-Dayel F, Alkuraya FS, Al-Kuraya KS. Siraj AK, et al. Gut. 2020 Nov;69(11):2048-2049. doi: 10.1136/gutjnl-2019-320511. Epub 2020 Jan 10. Gut. 2020. PMID: 31924657 Free PMC article. No abstract available.

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Update on Genetic Testing in Gynecologic Cancer.
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References

1. Møller P, Seppälä T, Bernstein I, et al. . Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database. Gut 2017;66:464–72. 10.1136/gutjnl-2015-309675 - DOI - PMC - PubMed
1. Møller P, Seppälä T, Bernstein I, et al. . Mallorca Group (http://mallorca-group.org). Incidence of and survival after subsequent cancers in carriers of pathogenic MMR variants with previous cancer: a report from the prospective Lynch syndrome database. Gut 2017;66:1657–64. 10.1136/gutjnl-2016-311403 - DOI - PMC - PubMed
1. Vasen HF, Blanco I, Aktan-Collan K, et al. . Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut 2013;62:812–23. 10.1136/gutjnl-2012-304356 - DOI - PMC - PubMed
1. Giardiello FM, Allen JI, Axilbund JE, et al. . Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer. Am J Gastroenterol 2014;109:1159–79. 10.1038/ajg.2014.186 - DOI - PubMed
1. Warthin AS. Heredity with reference to carcinoma as shown by the study of the cases examined in the pathological laboratory of the University of Michigan, 1895-1913. CA: A Cancer J Clin 1985;35:348–59. 10.3322/canjclin.35.6.348 - DOI - PubMed

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[1] Møller P, Seppälä T, Bernstein I, et al. . Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database. Gut 2017;66:464–72. 10.1136/gutjnl-2015-309675 - DOI - PMC - PubMed

[2] Møller P, Seppälä T, Bernstein I, et al. . Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database. Gut 2017;66:464–72. 10.1136/gutjnl-2015-309675 - DOI - PMC - PubMed

[3] Møller P, Seppälä T, Bernstein I, et al. . Mallorca Group (http://mallorca-group.org). Incidence of and survival after subsequent cancers in carriers of pathogenic MMR variants with previous cancer: a report from the prospective Lynch syndrome database. Gut 2017;66:1657–64. 10.1136/gutjnl-2016-311403 - DOI - PMC - PubMed

[4] Møller P, Seppälä T, Bernstein I, et al. . Mallorca Group (http://mallorca-group.org). Incidence of and survival after subsequent cancers in carriers of pathogenic MMR variants with previous cancer: a report from the prospective Lynch syndrome database. Gut 2017;66:1657–64. 10.1136/gutjnl-2016-311403 - DOI - PMC - PubMed

[5] Vasen HF, Blanco I, Aktan-Collan K, et al. . Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut 2013;62:812–23. 10.1136/gutjnl-2012-304356 - DOI - PMC - PubMed

[6] Vasen HF, Blanco I, Aktan-Collan K, et al. . Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut 2013;62:812–23. 10.1136/gutjnl-2012-304356 - DOI - PMC - PubMed

[7] Giardiello FM, Allen JI, Axilbund JE, et al. . Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer. Am J Gastroenterol 2014;109:1159–79. 10.1038/ajg.2014.186 - DOI - PubMed

[8] Giardiello FM, Allen JI, Axilbund JE, et al. . Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer. Am J Gastroenterol 2014;109:1159–79. 10.1038/ajg.2014.186 - DOI - PubMed

[9] Warthin AS. Heredity with reference to carcinoma as shown by the study of the cases examined in the pathological laboratory of the University of Michigan, 1895-1913. CA: A Cancer J Clin 1985;35:348–59. 10.3322/canjclin.35.6.348 - DOI - PubMed

[10] Warthin AS. Heredity with reference to carcinoma as shown by the study of the cases examined in the pathological laboratory of the University of Michigan, 1895-1913. CA: A Cancer J Clin 1985;35:348–59. 10.3322/canjclin.35.6.348 - DOI - PubMed

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Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database

Affiliations

Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database

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