Abstract
The HOXB13 p.G84E mutation has been firmly established as a prostate cancer susceptibility allele. Although HOXB13 also plays a role in breast tumor progression, the association of HOXB13 p.G84E with breast cancer risk is less evident. Therefore, we comprehensively interrogated the entire HOXB13 coding sequence for mutations in 1,250 non-BRCA1/2 familial breast cancer cases and 800 controls. We identified two predicted deleterious missense mutations, p.G84E and p.R217C, that were recurrent among breast cancer cases and further evaluated their association with breast cancer risk in a larger study. Taken together, 4,520 familial non-BRCA1/2 breast cancer cases and 3,127 controls were genotyped including the cases and controls of the whole gene screen. The concordance rate for the genotyping assays compared with Sanger sequencing was 100%. The prostate cancer risk allele p.G84E was identified in 18 (0.56%) of 3,187 cases and 16 (0.70%) of 2,300 controls (OR = 0.81, 95% CI = 0.41–1.59, P = 0.54). Additionally, p.R217C was identified in 10 (0.31%) of 3,208 cases and 2 (0.087%) of 2,288 controls (OR = 3.57, 95% CI = 0.76–33.57, P = 0.14). These results imply that none of the recurrent HOXB13 mutations in the Dutch population are associated with breast cancer risk, although it may be worthwhile to evaluate p.R217C in a larger study.
Highlights
Breast cancer is the second leading cause of cancer death in Western countries and the most frequently diagnosed cancer in Western women
We evaluated the entire coding sequence of the HOXB13 gene for germline mutations in 1,250 non-BRCA1/2 breast cancer patients and 800 controls from the Rotterdam Breast Cancer Study (RBCS) study
It did appear that the prostate cancer risk variant p.G84E was less prevalent in breast cancer cases than controls, whereas the prevalence of the p.R217C variant appeared to be higher in breast cancer cases compared with controls
Summary
Breast cancer is the second leading cause of cancer death in Western countries and the most frequently diagnosed cancer in Western women. Taken together in a polygenic risk score (PRS; calculated from 77 SNPs) the lifetime risk of breast cancer for women in the highest quantile of this PRS was 17%9 These breast cancer susceptibility genes and alleles account for approximately 35% of the familial breast cancer risk, which means that the underlying cause of the majority of the familial breast cancer risk still remains unexplained. In this respect, the rare variant c.251G >A (p.G84E; rs138213197) in the HOXB13 gene was reported to be associated with prostate cancer[10]. All three studies only investigated the prostate cancer risk-associated variant p.G84E
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