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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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.

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Most cited references 15

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Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database

Pål Møller, Toni Seppälä, Inge Bernstein … (2015)

Objective Estimates of cancer risk and the effects of surveillance in Lynch syndrome have been subject to bias, partly through reliance on retrospective studies. We sought to establish more robust estimates in patients undergoing prospective cancer surveillance. Design We undertook a multicentre study of patients carrying Lynch syndrome-associated mutations affecting MLH1, MSH2, MSH6 or PMS2. Standardised information on surveillance, cancers and outcomes were collated in an Oracle relational database and analysed by age, sex and mutated gene. Results 1942 mutation carriers without previous cancer had follow-up including colonoscopic surveillance for 13 782 observation years. 314 patients developed cancer, mostly colorectal (n=151), endometrial (n=72) and ovarian (n=19). Cancers were detected from 25 years onwards in MLH1 and MSH2 mutation carriers, and from about 40 years in MSH6 and PMS2 carriers. Among first cancer detected in each patient the colorectal cancer cumulative incidences at 70 years by gene were 46%, 35%, 20% and 10% for MLH1, MSH2, MSH6 and PMS2 mutation carriers, respectively. The equivalent cumulative incidences for endometrial cancer were 34%, 51%, 49% and 24%; and for ovarian cancer 11%, 15%, 0% and 0%. Ten-year crude survival was 87% after any cancer, 91% if the first cancer was colorectal, 98% if endometrial and 89% if ovarian. Conclusions The four Lynch syndrome-associated genes had different penetrance and expression. Colorectal cancer occurred frequently despite colonoscopic surveillance but resulted in few deaths. Using our data, a website has been established at http://LScarisk.org enabling calculation of cumulative cancer risks as an aid to genetic counselling in Lynch syndrome.

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Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer.

Francis Giardiello, John I Allen, Jennifer E Axilbund … (2014)

The Multi-Society Task Force, in collaboration with invited experts, developed guidelines to assist health care providers with the appropriate provision of genetic testing and management of patients at risk for and affected with Lynch syndrome as follows: Figure 1 provides a colorectal cancer risk assessment tool to screen individuals in the office or endoscopy setting; Figure 2 illustrates a strategy for universal screening for Lynch syndrome by tumor testing of patients diagnosed with colorectal cancer; Figures 3,4,5,6 provide algorithms for genetic evaluation of affected and at-risk family members of pedigrees with Lynch syndrome; Table 10 provides guidelines for screening at-risk and affected persons with Lynch syndrome; and Table 12 lists the guidelines for the management of patients with Lynch syndrome. A detailed explanation of Lynch syndrome and the methodology utilized to derive these guidelines, as well as an explanation of, and supporting literature for, these guidelines are provided.

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Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk.

N. Abramson, Joseph Fraumeni, R Tarone … (1997)

There is a substantial risk of a second cancer for persons with hereditary retinoblastoma, which is enhanced by radiotherapy. To examine long-term risk of new primary cancers in survivors of childhood retinoblastoma and quantify the role of radiotherapy in sarcoma development. Cohort incidence study of patients with retinoblastoma followed for a median of 20 years, and nested case-control study of a radiation dose-response relationship for bone and soft tissue sarcomas. A total of 1604 patients with retinoblastoma who survived at least 1 year after diagnosis, identified from hospital records in Massachusetts and New York during 1914 to 1984. Incidence of subsequent cancers was statistically significantly elevated only in the 961 patients with hereditary retinoblastoma, in whom 190 cancers were diagnosed, vs 6.3 expected in the general population (relative risk [RR], 30 [95% confidence interval, 26-47]). Cumulative incidence (+/-SE) of a second cancer at 50 years after diagnosis was 51.0% (+/-6.2%) for hereditary retinoblastoma, and 5.0% (+/-3.0%) for nonhereditary retinoblastoma. All 114 sarcomas of diverse histologic types occurred in patients with hereditary retinoblastoma. For soft tissue sarcomas, the RRs showed a stepwise increase at all dose categories, and were statistically significant at 10 to 29.9 Gy and 30 to 59.9 Gy. A radiation risk for all sarcomas combined was evident at doses above 5 Gy, rising to 10.7-fold at doses of 60 Gy or greater (P<.05). Genetic predisposition has a substantial impact on risk of subsequent cancers in retinoblastoma patients, which is further increased by radiation treatment. A radiation dose-response relationship is demonstrated for all sarcomas and, for the first time in humans, for soft tissue sarcomas. Retinoblastoma patients should be examined for new cancers and followed into later life to determine whether their extraordinary cancer risk extends to common cancers of adulthood.

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Author and article information

Journal

Journal ID (nlm-ta): Gut

Journal ID (iso-abbrev): Gut

Journal ID (hwp): gutjnl

Journal ID (publisher-id): gut

Title: Gut

Publisher: Gut (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Print): 0017-5749

ISSN (Electronic): 1468-3288

Publication date (Print): July 2018

Publication date (Electronic): 28 July 2017

Volume: 67

Issue: 7

Pages: 1306-1316

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 ] departmentDepartment of Medicine , Melbourne University , Melborne, Australia

[15 ] departmentHereditary Cancer Program , Institut Català d’Oncologia-IDIBELL, L’Hospitalet de Llobregat , Barcelona, Spain

[16 ] departmentDepartment of Genetics , University of Groningen, University Medical Center Groningen , Groningen, The Netherlands

[17 ] departmentDivision of Cancer and Genetics , Institute of Medical Genetics, Cardiff University School of Medicine , Heath Park, UK

[18 ] departmentDepartment of Gastroenterology and Hepatology , Leiden University Medical Centre , Leiden, The Netherlands

[19 ] Institute of Genetic Medicine Newcastle University , Newcastle upon Tyne, UK

[20 ] departmentInstitute of Cancer Genetics and Informatics , The Norwegian Radium Hospital, part of Oslo University Hospital , Olso, Norway

[21 ] departmentDepartment of Informatics , University of Oslo , Olso, Norway

[22 ] departmentDepartment of Mathematics and Statistics , Lancaster University , Lancaster, UK

[23 ] departmentDepartment of Gastroenterology and Hepatology , Isala Clinics , Zwolle, The Netherlands

[24 ] departmentDepartment of Surgery , Central Manchester University Hospitals NHS Foundation Trust and University of Manchester , London, UK

[25 ] departmentDepartment of Clinical Genetics and Department of Human Genetics Leiden , University Medical Centre , Leiden, The Netherlands

[26 ] departmentCentre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health , The University of Melbourne , Parkville, Victoria, Australia

[27 ] departmentDepartment of Clinical Genetics , Aarhus University Hospital , Aarhus, Denmark

[28 ] Department of Biomedicine, Aarhus University , Aarhus, Denmark

[29 ] departmentDepartment of Women’s and Children’s health, Division of Obstetrics and Gyneacology , Karolinska Institutet, Karolinska University Hospital , Solna, Stockholm, Sweden

[30 ] departmentGenome-Scale Biology Research Program , University of Helsinki , Helsinki, Finland

[31 ] departmentDepartment of Education and Science , Central Finland Health Care District , yväskylä, Finland

[32 ] departmentInstitute of Genomic Medicine, “A. Gemelli” Faculty of Medicine , Catholic University of the Sacred Heart , Rome, Italy

[33 ] University of Eastern Finland , Kuopio, Finland

[34 ] Center for Hereditary Tumors, HELIOS-Klinikum Wuppertal, University of Witten-Herdecke , Wuppertal, Germany

Article

Publisher ID: gutjnl-2017-314057

DOI: 10.1136/gutjnl-2017-314057

PMC ID: 6031262

PubMed ID: 28754778

SO-VID: 5b81ee0b-9d46-46d3-8854-322f644a95c3

License:

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

History

Date received : 28 February 2017

Date revision received : 09 May 2017

Date accepted : 10 May 2017

Funding

Funded by: Finnish State Research Funding;

Funded by: Jane and Aatos Erkko Foundation;

Funded by: The Finnish Medical Foundation;

Funded by: The Sigrid Juselius Foundation;

Funded by: The Finnish Cancer Foundation;

Funded by: the Scientific Foundation AsociaciÃ³n EspaÃ±ola Contra el CÃ¡ncer;

Funded by: the Government of Catalonia;

Funded by: the Carlos III Health Institute;;

Funded by: the Norwegian Radium Hospital Foundation;

Funded by: the Wales Gene Park funded by Health and Care Research Wales;

Funded by: the Spanish Ministry of Economy and Competitiveness and co-funded by FEDER funds- a way to build Europe- (SAF2012-33636 and SAF2015-68016);;

Funded by: the Stockholm Cancer Society;

Funded by: the Swedish Research Council;

Funded by: the Swedish Cancer Society;

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ScienceOpen disciplines: Gastroenterology & Hepatology

Keywords: cancer prevention,clinical trials,colorectal cancer screening,inherited cancers,hnpcc syndrome

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ScienceOpen disciplines: Gastroenterology & Hepatology

Keywords: cancer prevention, clinical trials, colorectal cancer screening, inherited cancers, hnpcc syndrome

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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Abstract

Background

Objective and design

Results

Conclusion

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Karger: Gastroenterology

Most cited references 15

Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database

Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer.

Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk.

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