Novel HOXB13 gene variant linked to hereditary prostate cancer risk
MedWire News: A novel variant in the homeobox B13 gene (HOXB13) is associated with a significantly increased risk for hereditary prostate cancer, shows a study published in the New England Journal of Medicine.
"This is the first major genetic variant associated with inherited prostate cancer," said Kathleen Cooney (University of Michigan, Ann Arbor, USA), a lead author of the study, in a press statement.
"We found that the mutation was significantly more common in men with a family history and early diagnosis compared with men diagnosed later, after age 55, without a family history," she said.
The findings come from a genomic analysis of the 17q21-22 chromosome, one of the regions of the genome most intensely investigated for its association with prostate cancer susceptibility.
In a previous study, the authors used data from the Prostate Cancer Genetics Project and John Hopkins University to identify 453 families with a pedigree of prostate cancer. Among these they found a subset of 147 families with at least four members with prostate cancer who showed evidence of linkage to a particular genomic interval.
In the current study, the researchers selected the youngest of the patients with available DNA from 94 of the families for further analysis.
They screened 202 genes in the genomic interval of interest, which included HOXB13, a gene known to play an important role in prostate development.
Members from four of the families were found to have the same substitution mutation (G84E) in HOXB13, prompting the researchers to test the other family members with prostate cancer.
All 18 of the men with available DNA from the four families were found to carry the HOXB13 G84E mutation.
The researchers then analyzed genotype data for the same mutation in a population of 5083 unrelated men who had prostate cancer and 1401 men who were free of prostate cancer (controls).
Among those in the control population only one man was found to be carrying the mutation (carrier frequency, 0.1%) compared with 72 of the men who had prostate cancer (carrier frequency, 1.4%).
Carrier frequency of the HOXB13 G84E mutation was significantly higher among men with early-onset prostate cancer and a family history of the disease (3.1%) than it was in those with early-onset prostate cancer without a family history (1.0%) or in men with a family history but who were not diagnosed until after the age of 55 years (1.2%).
The lowest carrier frequency was among men with late-onset, nonfamilial prostate cancer (0.6%).
"We had never seen anything like this before. It all came together to suggest that this single change may account for at least a portion of the hereditary form of the disease," said co-author Patrick Walsh (John Hopkins University, Baltimore, Maryland, USA).
The authors say that future DNA sequencing studies using next-generation technology and study populations enriched for genetic influence may identify additional rare variants that contribute to familial clustering of prostate cancer.
"Although HOXB13 mutations will be indentified in a minority of men with prostate cancer, rare genetic lesions can identify pathways that are found to be abnormal in more common, sporadic cases," say Cooney et al.
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By Sally Robertson