Germline mutations in HOXB13 and prostate-cancer risk

Abstract

Background: Family history is a significant risk factor for prostate cancer, although the molecular basis for this association is poorly understood. Linkage studies have implicated chromosome 17q21-22 as a possible location of a prostate-cancer susceptibility gene.

Methods: We screened more than 200 genes in the 17q21-22 region by sequencing germline DNA from 94 unrelated patients with prostate cancer from families selected for linkage to the candidate region. We tested family members, additional case subjects, and control subjects to characterize the frequency of the identified mutations.

Results: Probands from four families were discovered to have a rare but recurrent mutation (G84E) in HOXB13 (rs138213197), a homeobox transcription factor gene that is important in prostate development. All 18 men with prostate cancer and available DNA in these four families carried the mutation. The carrier rate of the G84E mutation was increased by a factor of approximately 20 in 5083 unrelated subjects of European descent who had prostate cancer, with the mutation found in 72 subjects (1.4%), as compared with 1 in 1401 control subjects (0.1%) (P=8.5x10(-7)). The mutation was significantly more common in men with early-onset, familial prostate cancer (3.1%) than in those with late-onset, nonfamilial prostate cancer (0.6%) (P=2.0x10(-6)).

Conclusions: The novel HOXB13 G84E variant is associated with a significantly increased risk of hereditary prostate cancer. Although the variant accounts for a small fraction of all prostate cancers, this finding has implications for prostate-cancer risk assessment and may provide new mechanistic insights into this common cancer. (Funded by the National Institutes of Health and others.).

Figure 1. Pedigrees of Four Subjects with the HOXB13 G84E Mutation on Initial Targeted Sequencing

The proband who was selected for sequencing is indicated by the arrow in each pedigree. The remaining symbols are described in the key. Squares indicate male sex, and circles female sex. Ages of subjects, rounded to the nearest 5-year interval, are shown under the symbols. A slash through the symbol indicates that the subject is deceased. Two subjects in two families, Family 1 from the University of Michigan Prostate Cancer Genetics Project (UM) and Family 1 from Johns Hopkins University (JHU), who were inferred to be obligate carriers of the HOXB13 G84E mutation, died from prostate cancer. The unaffected G84E carrier in JHU Family 1 was 70 years of age at last contact.

Figure 2. Structure of HOXB13

The HOXB13 gene is the most 5′ member of the HOXB gene cluster on chromosome 17q21-22. The locations of the five missense mutations are indicated in the two exons of HOXB13. The homeodomain region and MEIS interacting domains are indicated. CDS denotes coding sequences, and UTR untranslated regions.

Figure 3. DNA Sequence Chromatograms Obtained from Normal Prostate and Prostate-Cancer Tissue from a Heterozygous Carrier of the HOXB13 G84E Variant, with Associated Histologic Findings

Wild-type and mutant DNA are present in both normal prostate tissue and prostate-cancer tissue from HOXB13 G84E carriers. For this experiment, DNA was extracted from sections of paraffin-embedded blocks of tissue obtained during a radical prostatectomy performed in a patient who was heterozygous for the HOXB13 G84E variant. The blocks were selected and trimmed to contain either normal or tumor tissue, as shown on hematoxylin and eosin staining (at left), and were subjected to Sanger sequencing. The chromatograms (at right) show the presence of both wild-type (GGA) and mutant (GAA) alleles at codon 84 in normal prostate tissue (middle) and the maintenance of both alleles in the matched sample of prostate tumor tissue (bottom). The top chromatogram is a homozygous wild-type sequence from a subject without the G84E mutation. The genome position that is shown (44,160,704) is based on the National Center for Biotechnology Information database, build 36 (hg18).