Pleiotropic effect of rare mutation in HOXB13 on multiple cancers detected in a cohort of >100K individuals via imputation. J. Witte1, T. Hoffmann1, L. Sakoda2, L. Shen2, E. Jorgenson2, M. Asgari2, D. Corley2, L. Habel2, L. Kushi2, M. Kwan2, C. Schaffer2, S. Van Den Eeden2, N. Risch1 1) Epidemiology & Biostatistics, Univ California,San Francisco, San Francisco, CA; 2) Division of Research, Kaiser Permanente, Northern California, Oakland, CA.

   A rare, high penetrance mutation for prostate cancer was recently identified in the HOXB13 gene (G84E). We successfully imputed this mutation into the Kaiser Permanente/UCSF Genetic Epidemiology Research Study on Adult Health and Aging, a large cohort of >100,000 individuals with genome-wide genotype data. The imputation reference panel included data from the 1000 Genomes Project supplemented with sequence data from 22 known G84E mutation carriers. To verify that the mutation was imputing accurately from the reference panel, we developed a classification and regression tree method based on pointwise linkage disequilibrium to identify a founder haplotype. We found that the HOXB13 mutation (G84E) was associated not only with prostate cancer (p=3.2x10^-13), but also with an increased risk of the following cancers in the cohort: breast, colon, melanoma, non-Hodgkin lymphoma, and endometrium (combined odds ratio=1.58, P-value=0.025; adjusted for multiple testing). In addition to providing evidence of a pleiotropic effect of the G84E HOXB13 mutation on cancer, our observations show that with a sufficiently large reference sample one can successfully impute very rare variants into large cohorts, and confirm these with novel classification methods.