Cancer Risks for MLH1 and MSH2 Mutation Carriers

James G. Dowty; Aung K. Win; Daniel D. Buchanan; Noralane M. Lindor; Finlay A. Macrae; Mark Clendenning; Yoland C. Antill; Stephen N. Thibodeau; Graham Casey; Steve Gallinger; Loic Le Marchand; Polly A. Newcomb; Robert W. Haile; Graeme P. Young; Paul A. James; Graham G. Giles; Shanaka R. Gunawardena; Barbara A. Leggett; Michael Gattas; Alex Boussioutas; Dennis J. Ahnen; John A. Baron; Susan Parry; Jack Goldblatt; Joanne P. Young; John L. Hopper; Mark A. Jenkins

doi:10.1002/humu.22262

Cancer Risks for MLH1 and MSH2 Mutation Carriers

James G. Dowty, Aung K. Win, Daniel D. Buchanan, Noralane M. Lindor, Finlay A. Macrae, Mark Clendenning, Yoland C. Antill, Stephen N. Thibodeau, Graham Casey, Steve Gallinger, Loic Le Marchand, Polly A. Newcomb, Robert W. Haile, Graeme P. Young, Paul A. James, Graham G. Giles, Shanaka R. Gunawardena, Barbara A. Leggett, Michael Gattas, Alex BoussioutasDennis J. Ahnen, John A. Baron, Susan Parry, Jack Goldblatt, Joanne P. Young, John L. Hopper, Mark A. Jenkins

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

149 Scopus citations

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 (US)
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
State	Published - Mar 2013

Keywords

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

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1002/humu.22262

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

Dowty, JG, Win, AK, Buchanan, DD, Lindor, NM, Macrae, FA, Clendenning, M, Antill, YC, Thibodeau, SN, Casey, G, Gallinger, S, Marchand, LL, Newcomb, PA, Haile, RW, Young, GP, James, PA, Giles, GG, Gunawardena, SR, Leggett, BA, Gattas, M, Boussioutas, A, Ahnen, DJ, Baron, JA, Parry, S, Goldblatt, J, Young, JP, Hopper, JL & Jenkins, MA 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

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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 = "Dowty, {James G.} and Win, {Aung K.} and Buchanan, {Daniel D.} and Lindor, {Noralane M.} and Macrae, {Finlay A.} and Mark Clendenning and Antill, {Yoland C.} and Thibodeau, {Stephen N.} and Graham Casey and Steve Gallinger and Marchand, {Loic Le} and Newcomb, {Polly A.} and Haile, {Robert W.} and Young, {Graeme P.} and James, {Paul A.} and Giles, {Graham G.} and Gunawardena, {Shanaka R.} and Leggett, {Barbara A.} and Michael Gattas and Alex Boussioutas and Ahnen, {Dennis J.} and Baron, {John A.} and Susan Parry and Jack Goldblatt and Young, {Joanne P.} and Hopper, {John L.} and Jenkins, {Mark A.}",

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AU - Dowty, James G.

AU - Win, Aung K.

AU - Buchanan, Daniel D.

AU - Lindor, Noralane M.

AU - Macrae, Finlay A.

AU - Clendenning, Mark

AU - Antill, Yoland C.

AU - Thibodeau, Stephen N.

AU - Casey, Graham

AU - Gallinger, Steve

AU - Marchand, Loic Le

AU - Newcomb, Polly A.

AU - Haile, Robert W.

AU - Young, Graeme P.

AU - James, Paul A.

AU - Giles, Graham G.

AU - Gunawardena, Shanaka R.

AU - Leggett, Barbara A.

AU - Gattas, Michael

AU - Boussioutas, Alex

AU - Ahnen, Dennis J.

AU - Baron, John A.

AU - Parry, Susan

AU - Goldblatt, Jack

AU - Young, Joanne P.

AU - Hopper, John L.

AU - Jenkins, Mark A.

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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.

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KW - Colon CFR

KW - Colorectal cancer

KW - Endometrial cancer

KW - Lynch syndrome

KW - MLH1

KW - MSH2

KW - Penetrance

KW - Risk

KW - Segregation analysis

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DO - 10.1002/humu.22262

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C2 - 23255516

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SN - 1059-7794

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JO - Human mutation

JF - Human mutation

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ER -

Cancer Risks for MLH1 and MSH2 Mutation Carriers

Abstract

Keywords

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