Abstract 1312: Genetic variation in the Hippo pathway and breast cancer risk in women of African ancestry in the ROOT Consortium
Authors: Wang Shengfeng , Zheng Yonglan , Ogundiran Temidayo O. , Ojengbede Oladosu , Zheng Wei , Nathanson Katherine L. , Nemesure Barbara , Ambs Stefan , Huo Dezheng , Olopade Olufunmilayo I. 
Published: July 2017

Background: The Hippo pathway controls organ growth by regulating cell proliferation and apoptosis. To our knowledge, it is still unclear about its role in the development of breast cancer. Identifying the relevant genes and single-nucleotide polymorphisms (SNPs) should shed light on the pathway’s mechanism in carcinogenesis. Methods: We examined 47,419 SNPs in 37 Hippo pathway genes in the genome wide association study of breast cancer conducted in the African Diaspora (ROOT consortium), which included 3,686 participants of African ancestry from Nigeria, USA, and Barbados (1,657 cases and 2,029 controls). Gene-level analyses were conducted using the adaptive rank truncated product (ARTP) test for 10,771 SNPs that weren’t highly correlated (r2 &lt; 0.8), and SNP-level analyses were conducted with logistic regression. Results: The Hippo pathway was significantly associated with risk of estrogen receptor positive (ER+) breast cancer (pathway-level P=0.028). Gene-based analyses revealed that WWC1 (gene-level P=0.001) was responsible for this association, with rs116516633 in this gene being statistically significant after gene-level adjustment for multiple comparisons [odds ratio (OR) =0.53 for each G allele, 95% confidence interval (CI) =0.41-0.70, Padj=0.002]. In addition, two SNPs in LATS2 (rs142900440, OR=0.42, 95% CI: 0.28-0.64; rs58674288, OR=0.38, 95% CI =0.24-0.61) were associated with risk of ER+ breast cancer. In the analysis of ER- breast cancer risk, rs2579161 in DLG5 (OR=1.38, 95% CI: 1.17-1.63) and rs11062429 in TEAD4 (OR=1.39, 95% CI: 1.17-1.64) were statistically significant. These associations remained significant after Bonferroni-correction at the gene-wide level (all P&lt; 0.05). Conclusions: We found evidence of associations of the Hippo pathway with ER+ breast cancer risk in women of African ancestry. Our findings supported the potential mechanism that WWC1 functions as an upstream member of the pathway, and highlighted the importance of further studies.

Table 1.Gene-wide significant tested SNPs for all breast cancer, ER+ tumors or ER- tumorsAll cases vs controlsER+ cases vs controlsER- cases vs controlsGene-SNPFunctionMajor/minor allelesMinor allele frequency among controlsOR (95% CI)PadjOR (95% CI)PadjOR (95% CI)PadjOverallTEAD1-rs16911695IntronG/A0.241.24 (1.11-1.39)0.101.30 (1.07-1.58)1.001.34 (1.10-1.63)1.00ER+LATS2-rs142900440IntronT/C0.040.78 (0.61-0.98)1.000.42 (0.28-0.64)0.010.80 (0.54-1.19)1.00LATS2-rs58674288IntronC/T0.030.73 (0.56-0.95)1.000.38 (0.24-0.61)0.010.70 (0.45-1.08)1.00WWC1-rs116516633Non-coding transcript variantA/G0.100.82 (0.71-0.96)1.000.53 (0.41-0.70)0.0020.81 (0.62-1.06)1.00ER-DLG5-rs2579161Upstream gene variantG/A0.491.08 (0.98-1.19)1.000.99 (0.85-1.17)1.001.38 (1.17-1.63)0.03TEAD4-rs11062429Downstream gene variantC/G0.431.01 (0.92-1.11)1.000.94 (0.79-1.00)1.001.39 (1.17-1.64)0.047

Citation Format: Shengfeng Wang, Yonglan Zheng, Temidayo O. Ogundiran, Oladosu Ojengbede, Wei Zheng, Katherine L. Nathanson, Barbara Nemesure, Stefan Ambs, Dezheng Huo, Olufunmilayo I. Olopade. Genetic variation in the Hippo pathway and breast cancer risk in women of African ancestry in the ROOT Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1312. doi:10.1158/1538-7445.AM2017-1312