Abstract 2793: Not HOXB13 p.G84E, but p.R217C appears to be associated with increased breast cancer risk in the Dutch population

Recently, the germline mutation G84E in HOXB13 was shown to be associated with an increased risk for prostate cancer. In breast cancer, HOXB13 has been found to be overexpressed. Moreover, high expression of HOXB13 has been shown to mediate poor response to tamoxifen therapy by suppressing estrogen receptor α and inducing IL-6 expression. Based on these observations, the HOXB13 G84E mutation might also be associated with breast cancer risk. So far, the association between HOXB13 G84E and breast cancer risk has been investigated in three different studies and contradictory results were obtained. The goal of this study is to detect if HOXB13 gene mutations in general associate with breast cancer risk. To this end, we sequenced the whole HOXB13 coding region to find mutations in 1250 non-BRCA1&2 familial breast cancer cases and 800 controls. In total, thirteen variants were detected, including seven missense mutations. The G84E mutation was identified in 4 of 1215 cases (0.33%) and 6 of 759 controls (0.79%). Interestingly, we detected another mutation G217C in 6 of 1206 cases (0.50%) and 1 of 765 controls (0.13%). The other five missense mutations were only found once. Because both the HOXB13 G84E and R217C mutations were predicted to be probably damaging, we further evaluated if these two mutations were associated with breast cancer risk. Therefore we expanded our case-control study to include a total of 4520 non-BRCA1&2 familial breast cancer cases and 3127 controls by Taqman genotyping. Our preliminary results show that the HOXB13 G84E mutation was found in 22 of 4449 cases (0.49%) and 23 of 3089 controls (0.74%). The carrier allele frequency was higher in controls than in cases, but not significantly different (OR = 0.66, 95% CI = 0.37-1.19, p = 0.17). Our results indicate that the HOXB13 G84E mutation is not associated with breast cancer risk. The HOXB13 R217C mutation was identified in 15 of 4478 cases (0.33%) and 3 of 3077 controls (0.10%). This difference was borderline significant (OR = 3.44, 95% CI = 1.00-11.91, p = 0.052) most likely due to low population frequency in combination with a relatively small sample size. The HOXB13 R217C mutation could thus be a novel moderate-risk breast cancer susceptibility allele, however a larger study is needed to confirm these results. In conclusion, the R217C mutation rather than the G84E mutation in HOXB13 appears to be associated with breast cancer risk. Citation Format: Jingjing Liu, Wendy JC Prager-van der Smissen, Sten Cornelissen, Margriet J. Collee, Ans W.M. van den Ouweland, Marjanka K. Schmidt, John W.M. Martens, Antoinette Hollestelle. Not HOXB13 p.G84E, but p.R217C appears to be associated with increased breast cancer risk in the Dutch population. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2793. doi:10.1158/1538-7445.AM2015-2793