Cancer Risks for MLH1 and MSH2 Mutation Carriers

James G. Dowty, Aung K. Win, Daniel D. Buchanan, Noralane Morey 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 journalArticle

105 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 languageEnglish (US)
Pages (from-to)490-497
Number of pages8
JournalHuman Mutation
Volume34
Issue number3
DOIs
StatePublished - Mar 2013

Fingerprint

Mutation
Neoplasms
Colorectal Neoplasms
Endometrial Neoplasms
Colonic Neoplasms
Registries
Confidence Intervals
Genes

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Dowty, J. G., Win, A. K., Buchanan, D. D., Lindor, N. M., Macrae, F. A., Clendenning, 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

Cancer Risks for MLH1 and MSH2 Mutation Carriers. / Dowty, James G.; Win, Aung K.; Buchanan, Daniel D.; Lindor, Noralane Morey; Macrae, Finlay A.; Clendenning, Mark; Antill, Yoland C.; Thibodeau, Stephen N; Casey, Graham; Gallinger, Steve; Marchand, Loic Le; Newcomb, Polly A.; Haile, Robert W.; Young, Graeme P.; James, Paul A.; Giles, Graham G.; Gunawardena, Shanaka R.; Leggett, Barbara A.; Gattas, Michael; Boussioutas, Alex; Ahnen, Dennis J.; Baron, John A.; Parry, Susan; Goldblatt, Jack; Young, Joanne P.; Hopper, John L.; Jenkins, Mark A.

In: Human Mutation, Vol. 34, No. 3, 03.2013, p. 490-497.

Research output: Contribution to journalArticle

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
Dowty JG, Win AK, Buchanan DD, Lindor NM, Macrae FA, Clendenning M et al. Cancer Risks for MLH1 and MSH2 Mutation Carriers. Human Mutation. 2013 Mar;34(3):490-497. https://doi.org/10.1002/humu.22262
Dowty, James G. ; Win, Aung K. ; Buchanan, Daniel D. ; Lindor, Noralane Morey ; Macrae, Finlay A. ; Clendenning, Mark ; Antill, Yoland C. ; Thibodeau, Stephen N ; Casey, Graham ; Gallinger, Steve ; Marchand, Loic Le ; Newcomb, Polly A. ; Haile, Robert W. ; Young, Graeme P. ; James, Paul A. ; Giles, Graham G. ; Gunawardena, Shanaka R. ; Leggett, Barbara A. ; Gattas, Michael ; Boussioutas, Alex ; Ahnen, Dennis J. ; Baron, John A. ; Parry, Susan ; Goldblatt, Jack ; Young, Joanne P. ; Hopper, John L. ; Jenkins, Mark A. / Cancer Risks for MLH1 and MSH2 Mutation Carriers. In: Human Mutation. 2013 ; Vol. 34, No. 3. pp. 490-497.
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