The HOXB13 p.Gly84Glu variant observed in an extended five generation high-risk prostate cancer pedigree supports risk association for multiple cancer sites

HOXB13 p.Gly84Glu is recognized as a rare variant associated with increased risk for prostate cancer; risk association for other cancers is uncertain. This HOXB13 variant was originally reported in several 3-generation prostate cancer pedigrees and has been reported to be associated with increased risk for bladder and colorectal cancer and leukemia in GWAS. A HOXB13 pGly84Glu variant carrier was identified in a set of Utah individuals born more than 100 years ago who were members of high-risk cancer pedigrees. The proband carrier was diagnosed with colon cancer and is a member of a high-risk prostate cancer pedigree. The HOXB13 pGLY84Glu variant was assayed in other sampled relatives in the pedigree and was observed to segregate in relatives of the proband carrier in the extended pedigree; this pedigree showed significant excess of prostate cancer, cervical cancer, leukemia, colorectal cancer, and gastric cancer among descendants. Multiple additional variant carriers were identified, diagnosed with prostate, bladder, and colon cancers in the 5-generation high-risk cancer pedigree. This study shows the power and efficiency of a biorepository of samples with known genealogy from extended high-risk pedigrees for definition of cancer-associated risks. Association of HOXB13 p.Gly84Glu with risk of colon and bladder cancers in this extended pedigree confirms previous reports for risk association for both cancers.