Variation in the risk of colorectal cancer in families with Lynch syndrome: a retrospective cohort study

The International Mismatch Repair Consortium

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Existing clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the mean age-specific cumulative risk (penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate the variation in the penetrance of colorectal cancer between carriers of pathogenic variants in the same gene by sex and continent of residence. Methods: In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero. Findings: 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (p<0·0001 for each of the three three continents). These familial risk factors resulted in a wide within-gene variation in the risk of colorectal cancer for men and women from each continent who all carried pathogenic variants in the same gene or the MSH2 c.942+3A>T variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7–56% of carriers having a colorectal cancer penetrance of less than 20%, 9–44% having a penetrance of more than 80%, and only 10–19% having a penetrance of 40–60%. Interpretation: Our study findings highlight the important role of risk modifiers, which could lead to personalised risk assessments for precision prevention and early detection of colorectal cancer for people with Lynch syndrome. Funding: National Health and Medical Research Council, Australia.

Original languageEnglish
Pages (from-to)1014-1022
Number of pages9
JournalThe Lancet Oncology
Volume22
Issue number7
DOIs
StatePublished - Jul 2021

Bibliographical note

Funding Information:
This work was supported by project grant 1063840 from the National Health and Medical Research Council (NHMRC), Australia. The Colon Cancer Family Registry is supported, in part, by funding from the National Cancer Institute (NCI), National Institutes of Health (NIH) award U01 CA167551. Additional support for case ascertainment was provided, in part, from the Surveillance, Epidemiology, and End Results Program, US state cancer registries in Arizona, Colorado, Minnesota, North Carolina, and New Hampshire, the Victoria Cancer Registry (Australia), and the Ontario Cancer Registry (Canada). The German Consortium for Familial Intestinal Cancer is supported by grants from the German Cancer Aid. The Inherited Cancer Connect Partnership is funded by the Cancer Council New South Wales Strategic Research Partnership scheme. Data collection for Wales was supported by Wales Gene Park, funded by Health and Care Research Wales. Data collection for the Hereditary Cancer Center at Creighton University was supported by revenue from Nebraska cigarette taxes awarded to Creighton University by the Nebraska Department of Health and Human Services. This work is also funded by the following grants: NHMRC Career Development Fellowship 1141746 (AKW), Early Career Fellowship 1120081 (JCR), Career Development Fellowship 1125268 (DDB), Senior Research Fellowship 1061779 and Investigator Grant 1177524 (ABS), Senior Research Fellowship 1117611 (MAJ), Senior Principal Research Fellowship 1137349 (JLH), NIH/NCI R01 CA132829 (SS); NIH U01/U24 CA074800 (RKP), NIH/NCI RC4CA153828 (JWe), University Sains Malaysia Research University grant 1001/CIPPT/813005 (RAn); German Cancer Aid Grant No.190370 (SAr), the Bengt Ihre Research Foundation and the Swedish Society of Medicine (AB), Dutch Cancer Society Grant UL-2012–5515 (SWB-tB); Fondo Investigación Sanitaria PI 16/01292 Instituto Salud Carlos III (TC), the Genesis Foundation, Montevideo, Uruguay (ADValle), the National Institute for Health Research Manchester Biomedical Research Centre Grant (reference number 1215–200074; DGE), Canadian Institutes of Health Research Foundation Grant 148390 (WF), Fondo Investigación Sanitaria PI 19/1366 Instituto Salud Carlos III (PG), Cancer Council NSW RG 19–01 (MRJK-C); Cancer Research UK, the Southampton Centre C328/A25139 (AML), the German Research Foundation Deutsche Forschungsgemeinschaft, SFB TR57, SPP1937, and the Hector-Foundation M89 (JNa), the South African Medical Research Council (RR), Nordea-fonden, the Novo Nordisk Foundation, the Olav Thon Foundation, and Sven Wewers fond (LJR), FINEP-CT-INFRA (02/2010) and PRONON/MS (25000.056766/2015–64; RMR), Fondazione AIRC per la Ricerca Sul Cancro investigator grant 21723 (LR); German Cancer Aid (WS), the Danish Cancer Society A-14570 (CT), Dr. Norman & Melinda Payson Professorship in Medical Oncology (JNW), the Norwegian Cancer Society Contract 194751–2017 (MD-V), the Jane and Aatos Erkko Foundation, the Emil Aaltonen Foundation, the Finnish Medical Foundation, the Sigrid Juselius Foundation, the Instrumentarium Science Foundation, and the iCAN Flagship of the Academy of Finland and Cancer Foundation Finland (TTS and JM), and the National Medical Research Council Singapore Clinical Scientist Award NMRC/CSA-INV/0017/2017 (JNg). The content of this Article does not necessarily reflect the views or policies of any of the sponsors or collaborating centres in the IMRC, nor does mention of trade names, commercial products, or organisations imply endorsement by the IMRC. We thank all study participants and staff from all collaborative centres of the IMRC for their contributions to this work, including, but not limited to, Donna Job (Newcastle University, Newcastle, UK) and Chris Michael-Lovatt (Peter MacCallum Cancer Centre, Melbourne, VIC, Australia).

Funding Information:
This work was supported by project grant 1063840 from the National Health and Medical Research Council (NHMRC), Australia. The Colon Cancer Family Registry is supported, in part, by funding from the National Cancer Institute (NCI), National Institutes of Health (NIH) award U01 CA167551. Additional support for case ascertainment was provided, in part, from the Surveillance, Epidemiology, and End Results Program, US state cancer registries in Arizona, Colorado, Minnesota, North Carolina, and New Hampshire, the Victoria Cancer Registry (Australia), and the Ontario Cancer Registry (Canada). The German Consortium for Familial Intestinal Cancer is supported by grants from the German Cancer Aid. The Inherited Cancer Connect Partnership is funded by the Cancer Council New South Wales Strategic Research Partnership scheme. Data collection for Wales was supported by Wales Gene Park, funded by Health and Care Research Wales. Data collection for the Hereditary Cancer Center at Creighton University was supported by revenue from Nebraska cigarette taxes awarded to Creighton University by the Nebraska Department of Health and Human Services. This work is also funded by the following grants: NHMRC Career Development Fellowship 1141746 (AKW), Early Career Fellowship 1120081 (JCR), Career Development Fellowship 1125268 (DDB), Senior Research Fellowship 1061779 and Investigator Grant 1177524 (ABS), Senior Research Fellowship 1117611 (MAJ), Senior Principal Research Fellowship 1137349 (JLH), NIH/NCI R01 CA132829 (SS); NIH U01/U24 CA074800 (RKP), NIH/NCI RC4CA153828 (JWe), University Sains Malaysia Research University grant 1001/CIPPT/813005 (RAn); German Cancer Aid Grant No.190370 (SAr), the Bengt Ihre Research Foundation and the Swedish Society of Medicine (AB), Dutch Cancer Society Grant UL-2012?5515 (SWB-tB); Fondo Investigaci?n Sanitaria PI 16/01292 Instituto Salud Carlos III (TC), the Genesis Foundation, Montevideo, Uruguay (ADValle), the National Institute for Health Research Manchester Biomedical Research Centre Grant (reference number 1215?200074; DGE), Canadian Institutes of Health Research Foundation Grant 148390 (WF), Fondo Investigaci?n Sanitaria PI 19/1366 Instituto Salud Carlos III (PG), Cancer Council NSW RG 19?01 (MRJK-C); Cancer Research UK, the Southampton Centre C328/A25139 (AML), the German Research Foundation Deutsche Forschungsgemeinschaft, SFB TR57, SPP1937, and the Hector-Foundation M89 (JNa), the South African Medical Research Council (RR), Nordea-fonden, the Novo Nordisk Foundation, the Olav Thon Foundation, and Sven Wewers fond (LJR), FINEP-CT-INFRA (02/2010) and PRONON/MS (25000.056766/2015?64; RMR), Fondazione AIRC per la Ricerca Sul Cancro investigator grant 21723 (LR); German Cancer Aid (WS), the Danish Cancer Society A-14570 (CT), Dr. Norman & Melinda Payson Professorship in Medical Oncology (JNW), the Norwegian Cancer Society Contract 194751?2017 (MD-V), the Jane and Aatos Erkko Foundation, the Emil Aaltonen Foundation, the Finnish Medical Foundation, the Sigrid Juselius Foundation, the Instrumentarium Science Foundation, and the iCAN Flagship of the Academy of Finland and Cancer Foundation Finland (TTS and JM), and the National Medical Research Council Singapore Clinical Scientist Award NMRC/CSA-INV/0017/2017 (JNg). The content of this Article does not necessarily reflect the views or policies of any of the sponsors or collaborating centres in the IMRC, nor does mention of trade names, commercial products, or organisations imply endorsement by the IMRC. We thank all study participants and staff from all collaborative centres of the IMRC for their contributions to this work, including, but not limited to, Donna Job (Newcastle University, Newcastle, UK) and Chris Michael-Lovatt (Peter MacCallum Cancer Centre, Melbourne, VIC, Australia).

Publisher Copyright:
© 2021 Elsevier Ltd

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