Risks of lynch syndrome cancers for msh6 mutation carriers

Laura Baglietto, Noralane Morey 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 Buchanan, Sven Arnold, Joanne 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. Vasen, Malcolm G. Dunlop, Stephen N Thibodeau, Mark A. Jenkins

Research output: Contribution to journalArticle

207 Citations (Scopus)

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).ConclusionWe have obtained precise and accurate estimates of both absolute and relative cancer risks for MSH6 mutation carriers. The Author 2009. Published by Oxford University Press.2010

Original languageEnglish (US)
Pages (from-to)193-201
Number of pages9
JournalJournal of the National Cancer Institute
Volume102
Issue number3
DOIs
StatePublished - Feb 2010

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Hereditary Nonpolyposis Colorectal Neoplasms
Confidence Intervals
Mutation
Neoplasms
Colorectal Neoplasms
Incidence
Endometrial Neoplasms
Population
DNA Mismatch Repair
Germ-Line Mutation
Hysterectomy
Registries

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Baglietto, L., Lindor, N. M., Dowty, J. G., White, D. M., Wagner, A., Gomez Garcia, E. B., ... 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

Risks of lynch syndrome cancers for msh6 mutation carriers. / Baglietto, Laura; Lindor, Noralane Morey; Dowty, James G.; White, Darren M.; Wagner, Anja; Gomez Garcia, Encarna B.; Vriends, Annette H J T; Cartwright, Nicola R.; Barnetson, Rebecca A.; Farrington, Susan M.; Tenesa, Albert; Hampel, Heather; Buchanan, Daniel; Arnold, Sven; Young, Joanne; Walsh, Michael D.; Jass, Jeremy; MacRae, Finlay; Antill, Yoland; Winship, Ingrid M.; Giles, Graham G.; Goldblatt, Jack; Parry, Susan; Suthers, Graeme; Leggett, Barbara; Butz, Malinda; Aronson, Melyssa; Poynter, Jenny N.; Baron, John A.; Le Marchand, Loic; Haile, Robert; Gallinger, Steve; Hopper, John L.; Potter, John; De La Chapelle, Albert; Vasen, Hans F.; Dunlop, Malcolm G.; Thibodeau, Stephen N; Jenkins, Mark A.

In: Journal of the National Cancer Institute, Vol. 102, No. 3, 02.2010, p. 193-201.

Research output: Contribution to journalArticle

Baglietto, L, Lindor, NM, Dowty, JG, White, DM, Wagner, A, Gomez Garcia, EB, Vriends, AHJT, Cartwright, NR, Barnetson, RA, Farrington, SM, Tenesa, A, Hampel, H, Buchanan, D, Arnold, S, Young, J, 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, HF, 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
Baglietto, Laura ; Lindor, Noralane Morey ; Dowty, James G. ; White, Darren M. ; Wagner, Anja ; Gomez Garcia, Encarna B. ; Vriends, Annette H J T ; Cartwright, Nicola R. ; Barnetson, Rebecca A. ; Farrington, Susan M. ; Tenesa, Albert ; Hampel, Heather ; Buchanan, Daniel ; Arnold, Sven ; Young, Joanne ; Walsh, Michael D. ; Jass, Jeremy ; MacRae, Finlay ; Antill, Yoland ; Winship, Ingrid M. ; Giles, Graham G. ; Goldblatt, Jack ; Parry, Susan ; Suthers, Graeme ; Leggett, Barbara ; Butz, Malinda ; Aronson, Melyssa ; Poynter, Jenny N. ; Baron, John A. ; Le Marchand, Loic ; Haile, Robert ; Gallinger, Steve ; Hopper, John L. ; Potter, John ; De La Chapelle, Albert ; Vasen, Hans F. ; Dunlop, Malcolm G. ; Thibodeau, Stephen N ; Jenkins, Mark A. / Risks of lynch syndrome cancers for msh6 mutation carriers. In: Journal of the National Cancer Institute. 2010 ; Vol. 102, No. 3. pp. 193-201.
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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).ConclusionWe have obtained precise and accurate estimates of both absolute and relative cancer risks for MSH6 mutation carriers. The Author 2009. Published by Oxford University Press.2010",
author = "Laura Baglietto and Lindor, {Noralane Morey} and Dowty, {James G.} and White, {Darren M.} and Anja Wagner and {Gomez Garcia}, {Encarna B.} 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 Daniel Buchanan and Sven Arnold and Joanne Young 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.} and Dunlop, {Malcolm G.} and Thibodeau, {Stephen N} and Jenkins, {Mark A.}",
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TY - JOUR

T1 - Risks of lynch syndrome cancers for msh6 mutation carriers

AU - Baglietto, Laura

AU - Lindor, Noralane Morey

AU - Dowty, James G.

AU - White, Darren M.

AU - Wagner, Anja

AU - Gomez Garcia, Encarna B.

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

AU - Arnold, Sven

AU - Young, Joanne

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.

AU - Dunlop, Malcolm G.

AU - Thibodeau, Stephen N

AU - Jenkins, Mark A.

PY - 2010/2

Y1 - 2010/2

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).ConclusionWe have obtained precise and accurate estimates of both absolute and relative cancer risks for MSH6 mutation carriers. The Author 2009. Published by Oxford University Press.2010

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).ConclusionWe have obtained precise and accurate estimates of both absolute and relative cancer risks for MSH6 mutation carriers. The Author 2009. Published by Oxford University Press.2010

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