Imputation of the Rare HOXB13 G84E Mutation and Cancer Risk in a Large Population-Based Cohort

Thomas J. Hoffmann, Lori C. Sakoda, Ling Shen, Eric Jorgenson, Laurel A. Habel, Jinghua Liu, Mark N. Kvale, Maryam M. Asgari, Yambazi Banda, Douglas Corley, Lawrence H. Kushi, Charles P. Quesenberry, Catherine Schaefer, Stephen K. Van Den Eeden, Neil Risch, John S. Witte

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

An efficient approach to characterizing the disease burden of rare genetic variants is to impute them into large well-phenotyped cohorts with existing genome-wide genotype data using large sequenced referenced panels. The success of this approach hinges on the accuracy of rare variant imputation, which remains controversial. For example, a recent study suggested that one cannot adequately impute the HOXB13 G84E mutation associated with prostate cancer risk (carrier frequency of 0.0034 in European ancestry participants in the 1000 Genomes Project). We show here that—by utilizing the 1000 Genomes Project data plus an enriched reference panel of mutation carriers—we were able to accurately impute the G84E mutation into a large cohort of 83,285 non-Hispanic White participants from the Kaiser Permanente Research Program on Genes, Environment and Health Genetic Epidemiology Research on Adult Health and Aging cohort. Imputation authenticity was confirmed via a novel classification and regression tree method, and then empirically validated analyzing a subset of these subjects plus an additional 1,789 men from the California Men’s Health Study specifically genotyped for the G84E mutation (r2 = 0.57, 95% CI = 0.37–0.77). We then show the value of this approach by using the imputed data to investigate the impact of the G84E mutation on age-specific prostate cancer risk and on risk of fourteen other cancers in the cohort. The age-specific risk of prostate cancer among G84E mutation carriers was higher than among non-carriers, and this difference increased with age. Risk estimates from Kaplan-Meier curves were 36.7% versus 13.6% by age 72, and 64.2% versus 24.2% by age 80, for G84E mutation carriers and non-carriers, respectively (p = 3.4×10−12). The G84E mutation was also suggestively associated with an increase in risk for the following cancer sites by approximately 50% in a pleiotropic manner: breast, non-Hodgkin’s lymphoma, kidney, bladder, melanoma, endometrium, and pancreas (p = 0.042).

Original languageEnglish (US)
Article numbere1004930
JournalPLoS Genetics
Volume11
Issue number1
DOIs
StatePublished - 2015
Externally publishedYes

Fingerprint

mutation
Mutation
neoplasms
Population
Neoplasms
prostatic neoplasms
cancer
Prostatic Neoplasms
genome
Genome
mens health
non-Hodgkin lymphoma
Men's Health
Genetic Research
burden of disease
risk estimate
Molecular Epidemiology
cancer risk
endometrium
Health

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Hoffmann, T. J., Sakoda, L. C., Shen, L., Jorgenson, E., Habel, L. A., Liu, J., ... Witte, J. S. (2015). Imputation of the Rare HOXB13 G84E Mutation and Cancer Risk in a Large Population-Based Cohort. PLoS Genetics, 11(1), [e1004930]. https://doi.org/10.1371/journal.pgen.1004930

Imputation of the Rare HOXB13 G84E Mutation and Cancer Risk in a Large Population-Based Cohort. / Hoffmann, Thomas J.; Sakoda, Lori C.; Shen, Ling; Jorgenson, Eric; Habel, Laurel A.; Liu, Jinghua; Kvale, Mark N.; Asgari, Maryam M.; Banda, Yambazi; Corley, Douglas; Kushi, Lawrence H.; Quesenberry, Charles P.; Schaefer, Catherine; Van Den Eeden, Stephen K.; Risch, Neil; Witte, John S.

In: PLoS Genetics, Vol. 11, No. 1, e1004930, 2015.

Research output: Contribution to journalArticle

Hoffmann, TJ, Sakoda, LC, Shen, L, Jorgenson, E, Habel, LA, Liu, J, Kvale, MN, Asgari, MM, Banda, Y, Corley, D, Kushi, LH, Quesenberry, CP, Schaefer, C, Van Den Eeden, SK, Risch, N & Witte, JS 2015, 'Imputation of the Rare HOXB13 G84E Mutation and Cancer Risk in a Large Population-Based Cohort', PLoS Genetics, vol. 11, no. 1, e1004930. https://doi.org/10.1371/journal.pgen.1004930
Hoffmann, Thomas J. ; Sakoda, Lori C. ; Shen, Ling ; Jorgenson, Eric ; Habel, Laurel A. ; Liu, Jinghua ; Kvale, Mark N. ; Asgari, Maryam M. ; Banda, Yambazi ; Corley, Douglas ; Kushi, Lawrence H. ; Quesenberry, Charles P. ; Schaefer, Catherine ; Van Den Eeden, Stephen K. ; Risch, Neil ; Witte, John S. / Imputation of the Rare HOXB13 G84E Mutation and Cancer Risk in a Large Population-Based Cohort. In: PLoS Genetics. 2015 ; Vol. 11, No. 1.
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