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

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Variation in the risk of colorectal cancer in families with Lynch syndrome : a retrospective cohort study. / The International Mismatch Repair Consortium.

In: The Lancet Oncology, Vol. 22, No. 7, 07.2021, p. 1014-1022.

Research output: Contribution to journalJournal articlepeer-review

Harvard

The International Mismatch Repair Consortium 2021, 'Variation in the risk of colorectal cancer in families with Lynch syndrome: a retrospective cohort study', The Lancet Oncology, vol. 22, no. 7, pp. 1014-1022. https://doi.org/10.1016/S1470-2045(21)00189-3

APA

The International Mismatch Repair Consortium (2021). Variation in the risk of colorectal cancer in families with Lynch syndrome: a retrospective cohort study. The Lancet Oncology, 22(7), 1014-1022. https://doi.org/10.1016/S1470-2045(21)00189-3

Vancouver

The International Mismatch Repair Consortium. Variation in the risk of colorectal cancer in families with Lynch syndrome: a retrospective cohort study. The Lancet Oncology. 2021 Jul;22(7):1014-1022. https://doi.org/10.1016/S1470-2045(21)00189-3

Author

The International Mismatch Repair Consortium. / Variation in the risk of colorectal cancer in families with Lynch syndrome : a retrospective cohort study. In: The Lancet Oncology. 2021 ; Vol. 22, No. 7. pp. 1014-1022.

Bibtex

@article{447019e0945b46bb9f04c3fff4f4c195,
title = "Variation in the risk of colorectal cancer in families with Lynch syndrome: a retrospective cohort study",
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.",
author = "Win, {Aung Ko} and Dowty, {James G.} and Reece, {Jeanette C.} and Grant Lee and Templeton, {Allyson S.} and Plazzer, {John Paul} and Buchanan, {Daniel D.} and Kiwamu Akagi and Se{\c c}il Aksoy and Angel Alonso and Karin Alvarez and Amor, {David J.} and Ravindran Ankathil and Stefan Aretz and Arnold, {Julie L.} and Melyssa Aronson and Rachel Austin and Backman, {Ann Sofie} and {Bajwa-ten Broeke}, {Sanne W.} and Ver{\'o}nica Barca-Tierno and Julian Barwell and Inge Bernstein and Pascaline Berthet and Beate Betz and Bignon, {Yves Jean} and Talya Boisjoli and Val{\'e}rie Bonadona and Laurent Briollais and Joan Brunet and Karolin Bucksch and Bruno Buecher and Reinhard Buettner and John Burn and Trinidad Cald{\'e}s and Gabriel Capella and Olivier Caron and Graham Casey and Chew, {Min H.} and Choi, {Yun hee} and James Church and Mark Clendenning and Chrystelle Colas and Cops, {Elisa J.} and Isabelle Coupier and Marcia Cruz-Correa and {de la Chapelle}, Albert and {de Wind}, Niels and Gerdes, {Anne Marie} and Rasmussen, {Lene J.} and Wadt, {Karin A.W.} and {The International Mismatch Repair Consortium}",
note = "Publisher Copyright: {\textcopyright} 2021 Elsevier Ltd",
year = "2021",
month = jul,
doi = "10.1016/S1470-2045(21)00189-3",
language = "English",
volume = "22",
pages = "1014--1022",
journal = "The Lancet Oncology",
issn = "1470-2045",
publisher = "TheLancet Publishing Group",
number = "7",

}

RIS

TY - JOUR

T1 - Variation in the risk of colorectal cancer in families with Lynch syndrome

T2 - a retrospective cohort study

AU - Win, Aung Ko

AU - Dowty, James G.

AU - Reece, Jeanette C.

AU - Lee, Grant

AU - Templeton, Allyson S.

AU - Plazzer, John Paul

AU - Buchanan, Daniel D.

AU - Akagi, Kiwamu

AU - Aksoy, Seçil

AU - Alonso, Angel

AU - Alvarez, Karin

AU - Amor, David J.

AU - Ankathil, Ravindran

AU - Aretz, Stefan

AU - Arnold, Julie L.

AU - Aronson, Melyssa

AU - Austin, Rachel

AU - Backman, Ann Sofie

AU - Bajwa-ten Broeke, Sanne W.

AU - Barca-Tierno, Verónica

AU - Barwell, Julian

AU - Bernstein, Inge

AU - Berthet, Pascaline

AU - Betz, Beate

AU - Bignon, Yves Jean

AU - Boisjoli, Talya

AU - Bonadona, Valérie

AU - Briollais, Laurent

AU - Brunet, Joan

AU - Bucksch, Karolin

AU - Buecher, Bruno

AU - Buettner, Reinhard

AU - Burn, John

AU - Caldés, Trinidad

AU - Capella, Gabriel

AU - Caron, Olivier

AU - Casey, Graham

AU - Chew, Min H.

AU - Choi, Yun hee

AU - Church, James

AU - Clendenning, Mark

AU - Colas, Chrystelle

AU - Cops, Elisa J.

AU - Coupier, Isabelle

AU - Cruz-Correa, Marcia

AU - de la Chapelle, Albert

AU - de Wind, Niels

AU - Gerdes, Anne Marie

AU - Rasmussen, Lene J.

AU - Wadt, Karin A.W.

AU - The International Mismatch Repair Consortium

N1 - Publisher Copyright: © 2021 Elsevier Ltd

PY - 2021/7

Y1 - 2021/7

N2 - 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.

AB - 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.

U2 - 10.1016/S1470-2045(21)00189-3

DO - 10.1016/S1470-2045(21)00189-3

M3 - Journal article

C2 - 34111421

AN - SCOPUS:85108809980

VL - 22

SP - 1014

EP - 1022

JO - The Lancet Oncology

JF - The Lancet Oncology

SN - 1470-2045

IS - 7

ER -

ID: 285949850