Risks of Lynch Syndrome Cancers for MSH6 Mutation Carriers

Laura Baglietto; Noralane M. Lindor; James G. Dowty; Darren M. White; Anja Wagner; Encarna B. Gomez Garcia; Annette H. J. T. Vriends; Nicola R. Cartwright; Rebecca A. Barnetson; Susan M. Farrington; Albert Tenesa; Heather Hampel; Daniel D. Buchanan; Sven Arnold; Joanne P. Young; Michael D. Walsh; Jeremy Jass; Finlay Macrae; Yoland Antill; Ingrid M. Winship; Graham G. Giles; Jack Goldblatt; Susan Parry; Graeme Suthers; Barbara Leggett; Malinda Butz; Melyssa Aronson; Jenny N. Poynter; John A. Baron; Loic Le Marchand; Robert Haile; Steve Gallinger; John L. Hopper; John Potter; Albert de la Chapelle; Hans F. A. Vasen; Malcolm G. Dunlop; Stephen N. Thibodeau; Mark A. Jenkins

doi:10.1093/jnci/djp473

Risks of Lynch Syndrome Cancers for MSH6 Mutation Carriers

Laura Baglietto, Noralane M. Lindor^*, James G. Dowty, Darren M. White, Anja Wagner, Encarna B. Gomez Garcia, Annette H. J. T. Vriends, Nicola R. Cartwright, Rebecca A. Barnetson, Susan M. Farrington, Albert Tenesa, Heather Hampel, Daniel D. Buchanan, Sven Arnold, Joanne P. Young, Michael D. Walsh, Jeremy Jass, Finlay Macrae, Yoland Antill, Ingrid M. WinshipGraham G. Giles, Jack Goldblatt, Susan Parry, Graeme Suthers, Barbara Leggett, Malinda Butz, Melyssa Aronson, Jenny N. Poynter, John A. Baron, Loic Le Marchand, Robert Haile, Steve Gallinger, John L. Hopper, John Potter, Albert de la Chapelle, Hans F. A. Vasen, Malcolm G. Dunlop, Stephen N. Thibodeau, Mark A. Jenkins

^*Corresponding author for this work

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

Abstract

Background Germline mutations in MSH6 account for 10%-20% of Lynch syndrome colorectal cancers caused by hereditary DNA mismatch repair gene mutations. Because there have been only a few studies of mutation carriers, their cancer risks are uncertain. Methods We identified 113 families of MSH6 mutation carriers from five countries that we ascertained through family cancer clinics and population-based cancer registries. Mutation status, sex, age, and histories of cancer, polypectomy, and hysterectomy were sought from 3104 of their relatives. Age-specific cumulative risks for carriers and hazard ratios (HRs) for cancer risks of carriers, compared with those of the general population of the same country, were estimated by use of a modified segregation analysis with appropriate conditioning depending on ascertainment. Results For MSH6 mutation carriers, the estimated cumulative risks to ages 70 and 80 years, respectively, were as follows: for colorectal cancer, 22% (95% confidence interval [CI] = 14% to 32%) and 44% (95% CI = 28% to 62%) for men and 10% (95% CI = 5% to 17%) and 20% (95% CI = 11% to 35%) for women; for endometrial cancer, 26% (95% CI = 18% to 36%) and 44% (95% CI = 30% to 58%); and for any cancer associated with Lynch syndrome, 24% (95% CI = 16% to 37%) and 47% (95% CI = 32% to 66%) for men and 40% (95% CI = 32% to 52%) and 65% (95% CI = 53% to 78%) for women. Compared with incidence for the general population, MSH6 mutation carriers had an eightfold increased incidence of colorectal cancer (HR = 7.6, 95% CI = 5.4 to 10.8), which was independent of sex and age. Women who were MSH6 mutation carriers had a 26-fold increased incidence of endometrial cancer (HR = 25.5, 95% CI = 16.8 to 38.7) and a sixfold increased incidence of other cancers associated with Lynch syndrome (HR = 6.0, 95% CI = 3.4 to 10.7). Conclusion We have obtained precise and accurate estimates of both absolute and relative cancer risks for MSH6 mutation carriers.

Original language	English
Pages (from-to)	193-201
Journal	Journal of the National Cancer Institute
Volume	102
Issue number	3
DOIs	https://doi.org/10.1093/jnci/djp473
Publication status	Published - 3 Feb 2010

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Baglietto, L., Lindor, N. M., Dowty, J. G., White, D. M., Wagner, A., Garcia, E. B. G., Vriends, A. H. J. T., Cartwright, N. R., Barnetson, R. A., Farrington, S. M., Tenesa, A., Hampel, H., Buchanan, D. D., Arnold, S., Young, J. P., Walsh, M. D., Jass, J., Macrae, F., Antill, Y., ... Jenkins, M. A. (2010). Risks of Lynch Syndrome Cancers for MSH6 Mutation Carriers. Journal of the National Cancer Institute, 102(3), 193-201. https://doi.org/10.1093/jnci/djp473

@article{ba282d399f414f14accce96b720edbb7,

title = "Risks of Lynch Syndrome Cancers for MSH6 Mutation Carriers",

abstract = "Background Germline mutations in MSH6 account for 10%-20% of Lynch syndrome colorectal cancers caused by hereditary DNA mismatch repair gene mutations. Because there have been only a few studies of mutation carriers, their cancer risks are uncertain. Methods We identified 113 families of MSH6 mutation carriers from five countries that we ascertained through family cancer clinics and population-based cancer registries. Mutation status, sex, age, and histories of cancer, polypectomy, and hysterectomy were sought from 3104 of their relatives. Age-specific cumulative risks for carriers and hazard ratios (HRs) for cancer risks of carriers, compared with those of the general population of the same country, were estimated by use of a modified segregation analysis with appropriate conditioning depending on ascertainment. Results For MSH6 mutation carriers, the estimated cumulative risks to ages 70 and 80 years, respectively, were as follows: for colorectal cancer, 22% (95% confidence interval [CI] = 14% to 32%) and 44% (95% CI = 28% to 62%) for men and 10% (95% CI = 5% to 17%) and 20% (95% CI = 11% to 35%) for women; for endometrial cancer, 26% (95% CI = 18% to 36%) and 44% (95% CI = 30% to 58%); and for any cancer associated with Lynch syndrome, 24% (95% CI = 16% to 37%) and 47% (95% CI = 32% to 66%) for men and 40% (95% CI = 32% to 52%) and 65% (95% CI = 53% to 78%) for women. Compared with incidence for the general population, MSH6 mutation carriers had an eightfold increased incidence of colorectal cancer (HR = 7.6, 95% CI = 5.4 to 10.8), which was independent of sex and age. Women who were MSH6 mutation carriers had a 26-fold increased incidence of endometrial cancer (HR = 25.5, 95% CI = 16.8 to 38.7) and a sixfold increased incidence of other cancers associated with Lynch syndrome (HR = 6.0, 95% CI = 3.4 to 10.7). Conclusion We have obtained precise and accurate estimates of both absolute and relative cancer risks for MSH6 mutation carriers.",

author = "Laura Baglietto and Lindor, {Noralane M.} and Dowty, {James G.} and White, {Darren M.} and Anja Wagner and Garcia, {Encarna B. Gomez} and Vriends, {Annette H. J. T.} and Cartwright, {Nicola R.} and Barnetson, {Rebecca A.} and Farrington, {Susan M.} and Albert Tenesa and Heather Hampel and Buchanan, {Daniel D.} and Sven Arnold and Young, {Joanne P.} and Walsh, {Michael D.} and Jeremy Jass and Finlay Macrae and Yoland Antill and Winship, {Ingrid M.} and Giles, {Graham G.} and Jack Goldblatt and Susan Parry and Graeme Suthers and Barbara Leggett and Malinda Butz and Melyssa Aronson and Poynter, {Jenny N.} and Baron, {John A.} and {Le Marchand}, Loic and Robert Haile and Steve Gallinger and Hopper, {John L.} and John Potter and {de la Chapelle}, Albert and Vasen, {Hans F. A.} and Dunlop, {Malcolm G.} and Thibodeau, {Stephen N.} and Jenkins, {Mark A.}",

year = "2010",

month = feb,

day = "3",

doi = "10.1093/jnci/djp473",

language = "English",

volume = "102",

pages = "193--201",

journal = "Journal of the National Cancer Institute",

issn = "0027-8874",

publisher = "Oxford University Press",

number = "3",

}

Baglietto, L, Lindor, NM, Dowty, JG, White, DM, Wagner, A, Garcia, EBG, Vriends, AHJT, Cartwright, NR, Barnetson, RA, Farrington, SM, Tenesa, A, Hampel, H, Buchanan, DD, Arnold, S, Young, JP, Walsh, MD, Jass, J, Macrae, F, Antill, Y, Winship, IM, Giles, GG, Goldblatt, J, Parry, S, Suthers, G, Leggett, B, Butz, M, Aronson, M, Poynter, JN, Baron, JA, Le Marchand, L, Haile, R, Gallinger, S, Hopper, JL, Potter, J, de la Chapelle, A, Vasen, HFA, Dunlop, MG, Thibodeau, SN & Jenkins, MA 2010, 'Risks of Lynch Syndrome Cancers for MSH6 Mutation Carriers', Journal of the National Cancer Institute, vol. 102, no. 3, pp. 193-201. https://doi.org/10.1093/jnci/djp473

TY - JOUR

T1 - Risks of Lynch Syndrome Cancers for MSH6 Mutation Carriers

AU - Baglietto, Laura

AU - Lindor, Noralane M.

AU - Dowty, James G.

AU - White, Darren M.

AU - Wagner, Anja

AU - Garcia, Encarna B. Gomez

AU - Vriends, Annette H. J. T.

AU - Cartwright, Nicola R.

AU - Barnetson, Rebecca A.

AU - Farrington, Susan M.

AU - Tenesa, Albert

AU - Hampel, Heather

AU - Buchanan, Daniel D.

AU - Arnold, Sven

AU - Young, Joanne P.

AU - Walsh, Michael D.

AU - Jass, Jeremy

AU - Macrae, Finlay

AU - Antill, Yoland

AU - Winship, Ingrid M.

AU - Giles, Graham G.

AU - Goldblatt, Jack

AU - Parry, Susan

AU - Suthers, Graeme

AU - Leggett, Barbara

AU - Butz, Malinda

AU - Aronson, Melyssa

AU - Poynter, Jenny N.

AU - Baron, John A.

AU - Le Marchand, Loic

AU - Haile, Robert

AU - Gallinger, Steve

AU - Hopper, John L.

AU - Potter, John

AU - de la Chapelle, Albert

AU - Vasen, Hans F. A.

AU - Dunlop, Malcolm G.

AU - Thibodeau, Stephen N.

AU - Jenkins, Mark A.

PY - 2010/2/3

Y1 - 2010/2/3

N2 - Background Germline mutations in MSH6 account for 10%-20% of Lynch syndrome colorectal cancers caused by hereditary DNA mismatch repair gene mutations. Because there have been only a few studies of mutation carriers, their cancer risks are uncertain. Methods We identified 113 families of MSH6 mutation carriers from five countries that we ascertained through family cancer clinics and population-based cancer registries. Mutation status, sex, age, and histories of cancer, polypectomy, and hysterectomy were sought from 3104 of their relatives. Age-specific cumulative risks for carriers and hazard ratios (HRs) for cancer risks of carriers, compared with those of the general population of the same country, were estimated by use of a modified segregation analysis with appropriate conditioning depending on ascertainment. Results For MSH6 mutation carriers, the estimated cumulative risks to ages 70 and 80 years, respectively, were as follows: for colorectal cancer, 22% (95% confidence interval [CI] = 14% to 32%) and 44% (95% CI = 28% to 62%) for men and 10% (95% CI = 5% to 17%) and 20% (95% CI = 11% to 35%) for women; for endometrial cancer, 26% (95% CI = 18% to 36%) and 44% (95% CI = 30% to 58%); and for any cancer associated with Lynch syndrome, 24% (95% CI = 16% to 37%) and 47% (95% CI = 32% to 66%) for men and 40% (95% CI = 32% to 52%) and 65% (95% CI = 53% to 78%) for women. Compared with incidence for the general population, MSH6 mutation carriers had an eightfold increased incidence of colorectal cancer (HR = 7.6, 95% CI = 5.4 to 10.8), which was independent of sex and age. Women who were MSH6 mutation carriers had a 26-fold increased incidence of endometrial cancer (HR = 25.5, 95% CI = 16.8 to 38.7) and a sixfold increased incidence of other cancers associated with Lynch syndrome (HR = 6.0, 95% CI = 3.4 to 10.7). Conclusion We have obtained precise and accurate estimates of both absolute and relative cancer risks for MSH6 mutation carriers.

AB - Background Germline mutations in MSH6 account for 10%-20% of Lynch syndrome colorectal cancers caused by hereditary DNA mismatch repair gene mutations. Because there have been only a few studies of mutation carriers, their cancer risks are uncertain. Methods We identified 113 families of MSH6 mutation carriers from five countries that we ascertained through family cancer clinics and population-based cancer registries. Mutation status, sex, age, and histories of cancer, polypectomy, and hysterectomy were sought from 3104 of their relatives. Age-specific cumulative risks for carriers and hazard ratios (HRs) for cancer risks of carriers, compared with those of the general population of the same country, were estimated by use of a modified segregation analysis with appropriate conditioning depending on ascertainment. Results For MSH6 mutation carriers, the estimated cumulative risks to ages 70 and 80 years, respectively, were as follows: for colorectal cancer, 22% (95% confidence interval [CI] = 14% to 32%) and 44% (95% CI = 28% to 62%) for men and 10% (95% CI = 5% to 17%) and 20% (95% CI = 11% to 35%) for women; for endometrial cancer, 26% (95% CI = 18% to 36%) and 44% (95% CI = 30% to 58%); and for any cancer associated with Lynch syndrome, 24% (95% CI = 16% to 37%) and 47% (95% CI = 32% to 66%) for men and 40% (95% CI = 32% to 52%) and 65% (95% CI = 53% to 78%) for women. Compared with incidence for the general population, MSH6 mutation carriers had an eightfold increased incidence of colorectal cancer (HR = 7.6, 95% CI = 5.4 to 10.8), which was independent of sex and age. Women who were MSH6 mutation carriers had a 26-fold increased incidence of endometrial cancer (HR = 25.5, 95% CI = 16.8 to 38.7) and a sixfold increased incidence of other cancers associated with Lynch syndrome (HR = 6.0, 95% CI = 3.4 to 10.7). Conclusion We have obtained precise and accurate estimates of both absolute and relative cancer risks for MSH6 mutation carriers.

U2 - 10.1093/jnci/djp473

DO - 10.1093/jnci/djp473

M3 - Article

SN - 0027-8874

VL - 102

SP - 193

EP - 201

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

IS - 3

ER -

Risks of Lynch Syndrome Cancers for MSH6 Mutation Carriers

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