Cancer risks for MLH1 and MSH2 mutation carriers

J Dowty; Aung Ko Win; Daniel Buchanan; N Lindor; Finlay Macrae; Mark Clendenning; Yoland Antill; S Thibodeau; Graham Casey; Steven Gallinger; Loic Le Marchand; Polly Newcomb; Robert Haile; Graeme Young; Paul James; Graham Giles; Shanaka Gunawardena; Barbara Leggett; Michael Gattas; Alex Boussioutas; D Ahnen; John Baron; Susan Parry; Jack Goldblatt; Joanne Young; John Hopper; Mark Jenkins

doi:10.1002/humu.22262

Cancer risks for MLH1 and MSH2 mutation carriers

J Dowty, Aung Ko Win, Daniel Buchanan, N Lindor, Finlay Macrae, Mark Clendenning, Yoland Antill, S Thibodeau, Graham Casey, Steven Gallinger, Loic Le Marchand, Polly Newcomb, Robert Haile, Graeme Young, Paul James, Graham Giles, Shanaka Gunawardena, Barbara Leggett, Michael Gattas, Alex BoussioutasD Ahnen, John Baron, Susan Parry, Jack Goldblatt, Joanne Young, John Hopper, Mark Jenkins

Research output: Contribution to journal › Article › peer-review

175 Citations (Scopus)

Abstract

We studied 17,576 members of 166 MLH1 and 224 MSH2 mutation-carrying families from the Colon Cancer Family Registry. Average cumulative risks of colorectal cancer (CRC), endometrial cancer (EC), and other cancers for carriers were estimated using modified segregation analysis conditioned on ascertainment criteria. Heterogeneity in risks was investigated using a polygenic risk modifier. Average CRC cumulative risks at the age of 70 years (95% confidence intervals) for MLH1 and MSH2 mutation carriers, respectively, were estimated to be 34% (25%-50%) and 47% (36%-60%) for male carriers and 36% (25%-51%) and 37% (27%-50%) for female carriers. Corresponding EC risks were 18% (9.1%-34%) and 30% (18%-45%). A high level of CRC risk heterogeneity was observed (P < 0.001), with cumulative risks at the age of 70 years estimated to follow U-shaped distributions. For example, 17% of male MSH2 mutation carriers have estimated lifetime risks of 0%-10% and 18% have risks of 90%-100%. Therefore, average risks are similar for the two genes but there is so much individual variation about the average that large proportions of carriers have either very low or very high lifetime cancer risks. Our estimates of CRC and EC cumulative risks for MLH1 and MSH2 mutation carriers are the most precise currently available.

Original language	English
Pages (from-to)	490-497
Number of pages	8
Journal	Human Mutation
Volume	34
Issue number	3
DOIs	https://doi.org/10.1002/humu.22262
Publication status	Published - Mar 2013

Keywords

Cancer
Colon CFR
Colorectal cancer
Endometrial cancer
Lynch syndrome
MLH1
MSH2
Penetrance
Risk
Segregation analysis

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10.1002/humu.22262

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Dowty, J., Win, A. K., Buchanan, D., Lindor, N., Macrae, F., Clendenning, M., Antill, Y., Thibodeau, S., Casey, G., Gallinger, S., Le Marchand, L., Newcomb, P., Haile, R., Young, G., James, P., Giles, G., Gunawardena, S., Leggett, B., Gattas, M., ... Jenkins, M. (2013). Cancer risks for MLH1 and MSH2 mutation carriers. Human Mutation, 34(3), 490-497. https://doi.org/10.1002/humu.22262

@article{23598b074e6f4a66b8ca1cc7b16411cf,

title = "Cancer risks for MLH1 and MSH2 mutation carriers",

abstract = "We studied 17,576 members of 166 MLH1 and 224 MSH2 mutation-carrying families from the Colon Cancer Family Registry. Average cumulative risks of colorectal cancer (CRC), endometrial cancer (EC), and other cancers for carriers were estimated using modified segregation analysis conditioned on ascertainment criteria. Heterogeneity in risks was investigated using a polygenic risk modifier. Average CRC cumulative risks at the age of 70 years (95% confidence intervals) for MLH1 and MSH2 mutation carriers, respectively, were estimated to be 34% (25%-50%) and 47% (36%-60%) for male carriers and 36% (25%-51%) and 37% (27%-50%) for female carriers. Corresponding EC risks were 18% (9.1%-34%) and 30% (18%-45%). A high level of CRC risk heterogeneity was observed (P < 0.001), with cumulative risks at the age of 70 years estimated to follow U-shaped distributions. For example, 17% of male MSH2 mutation carriers have estimated lifetime risks of 0%-10% and 18% have risks of 90%-100%. Therefore, average risks are similar for the two genes but there is so much individual variation about the average that large proportions of carriers have either very low or very high lifetime cancer risks. Our estimates of CRC and EC cumulative risks for MLH1 and MSH2 mutation carriers are the most precise currently available.",

keywords = "Cancer, Colon CFR, Colorectal cancer, Endometrial cancer, Lynch syndrome, MLH1, MSH2, Penetrance, Risk, Segregation analysis",

author = "J Dowty and Win, {Aung Ko} and Daniel Buchanan and N Lindor and Finlay Macrae and Mark Clendenning and Yoland Antill and S Thibodeau and Graham Casey and Steven Gallinger and {Le Marchand}, Loic and Polly Newcomb and Robert Haile and Graeme Young and Paul James and Graham Giles and Shanaka Gunawardena and Barbara Leggett and Michael Gattas and Alex Boussioutas and D Ahnen and John Baron and Susan Parry and Jack Goldblatt and Joanne Young and John Hopper and Mark Jenkins",

year = "2013",

month = mar,

doi = "10.1002/humu.22262",

language = "English",

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Dowty, J, Win, AK, Buchanan, D, Lindor, N, Macrae, F, Clendenning, M, Antill, Y, Thibodeau, S, Casey, G, Gallinger, S, Le Marchand, L, Newcomb, P, Haile, R, Young, G, James, P, Giles, G, Gunawardena, S, Leggett, B, Gattas, M, Boussioutas, A, Ahnen, D, Baron, J, Parry, S, Goldblatt, J, Young, J, Hopper, J & Jenkins, M 2013, 'Cancer risks for MLH1 and MSH2 mutation carriers', Human Mutation, vol. 34, no. 3, pp. 490-497. https://doi.org/10.1002/humu.22262

TY - JOUR

T1 - Cancer risks for MLH1 and MSH2 mutation carriers

AU - Dowty, J

AU - Win, Aung Ko

AU - Buchanan, Daniel

AU - Lindor, N

AU - Macrae, Finlay

AU - Clendenning, Mark

AU - Antill, Yoland

AU - Thibodeau, S

AU - Casey, Graham

AU - Gallinger, Steven

AU - Le Marchand, Loic

AU - Newcomb, Polly

AU - Haile, Robert

AU - Young, Graeme

AU - James, Paul

AU - Giles, Graham

AU - Gunawardena, Shanaka

AU - Leggett, Barbara

AU - Gattas, Michael

AU - Boussioutas, Alex

AU - Ahnen, D

AU - Baron, John

AU - Parry, Susan

AU - Goldblatt, Jack

AU - Young, Joanne

AU - Hopper, John

AU - Jenkins, Mark

PY - 2013/3

Y1 - 2013/3

N2 - We studied 17,576 members of 166 MLH1 and 224 MSH2 mutation-carrying families from the Colon Cancer Family Registry. Average cumulative risks of colorectal cancer (CRC), endometrial cancer (EC), and other cancers for carriers were estimated using modified segregation analysis conditioned on ascertainment criteria. Heterogeneity in risks was investigated using a polygenic risk modifier. Average CRC cumulative risks at the age of 70 years (95% confidence intervals) for MLH1 and MSH2 mutation carriers, respectively, were estimated to be 34% (25%-50%) and 47% (36%-60%) for male carriers and 36% (25%-51%) and 37% (27%-50%) for female carriers. Corresponding EC risks were 18% (9.1%-34%) and 30% (18%-45%). A high level of CRC risk heterogeneity was observed (P < 0.001), with cumulative risks at the age of 70 years estimated to follow U-shaped distributions. For example, 17% of male MSH2 mutation carriers have estimated lifetime risks of 0%-10% and 18% have risks of 90%-100%. Therefore, average risks are similar for the two genes but there is so much individual variation about the average that large proportions of carriers have either very low or very high lifetime cancer risks. Our estimates of CRC and EC cumulative risks for MLH1 and MSH2 mutation carriers are the most precise currently available.

AB - We studied 17,576 members of 166 MLH1 and 224 MSH2 mutation-carrying families from the Colon Cancer Family Registry. Average cumulative risks of colorectal cancer (CRC), endometrial cancer (EC), and other cancers for carriers were estimated using modified segregation analysis conditioned on ascertainment criteria. Heterogeneity in risks was investigated using a polygenic risk modifier. Average CRC cumulative risks at the age of 70 years (95% confidence intervals) for MLH1 and MSH2 mutation carriers, respectively, were estimated to be 34% (25%-50%) and 47% (36%-60%) for male carriers and 36% (25%-51%) and 37% (27%-50%) for female carriers. Corresponding EC risks were 18% (9.1%-34%) and 30% (18%-45%). A high level of CRC risk heterogeneity was observed (P < 0.001), with cumulative risks at the age of 70 years estimated to follow U-shaped distributions. For example, 17% of male MSH2 mutation carriers have estimated lifetime risks of 0%-10% and 18% have risks of 90%-100%. Therefore, average risks are similar for the two genes but there is so much individual variation about the average that large proportions of carriers have either very low or very high lifetime cancer risks. Our estimates of CRC and EC cumulative risks for MLH1 and MSH2 mutation carriers are the most precise currently available.

KW - Cancer

KW - Colon CFR

KW - Colorectal cancer

KW - Endometrial cancer

KW - Lynch syndrome

KW - MLH1

KW - MSH2

KW - Penetrance

KW - Risk

KW - Segregation analysis

UR - http://www.scopus.com/inward/record.url?scp=84873942317&partnerID=8YFLogxK

U2 - 10.1002/humu.22262

DO - 10.1002/humu.22262

M3 - Article

SN - 1059-7794

VL - 34

SP - 490

EP - 497

JO - Human Mutation

JF - Human Mutation

IS - 3

ER -

Cancer risks for MLH1 and MSH2 mutation carriers

Abstract

Keywords

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