Abstract 1562: Germline polymorphisms in cancer stem cell genes associate with survival among women with high-grade serous ovarian cancer
Authors: Brett M. Reid, Jennifer B. Permuth, Zhihua Chen, Ann Chen, Thomas A. Sellers
Journal: Cancer Research (2019)

Abstract Background: Cancer stem cells (CSCs) are a rare population of tumor initiating cells associated with chemoresistance, recurrence and poor survival. Our group previously correlated germline variants in ovarian CSC-related genes with chemoresponse in 362 high-grade serous ovarian cancer (HGSOC) patients. Here, we evaluate CSC variants in a large, independent population to determine their association with overall (OS) and progression-free (PFS) survival. Methods: Over 2,500 women of European ancestry diagnosed with HGSOC who underwent cytoreductive surgery have been followed for clinical outcome and genotyped on the OncoArray. We identified 4,209 common (MAF&amp;gt;0.01) short polymorphisms (SNPs) that were genotyped or well-imputed (r2&amp;gt;0.70) within 26 CSC-related genes. Associations with OS and PFS were estimated with additive genetic cox proportional hazards models adjusted for ancestral principal components, age at diagnosis, and study. Residual disease after surgery (≤1cm vs. &amp;gt;1cm), and stage at diagnosis (advanced vs. local) were assessed for confounding (covariate), modification (interaction), and mediational (logistic regression) effects. For each SNP, the best fit model was adopted and p-values were adjusted for multiple testing using a false discovery rate (FDR) &amp;lt; 15% threshold. Primary analyses evaluated 1,254 patients who received standard chemotherapy; secondary analysis included 2,659 patients, regardless of chemotherapy regimen. Results: Two genes that were previously associated with response to chemotherapy (ESRRB, ALDH1A1) and two new genes (NOTCH2, CXCR4) were associated with OS and PFS. Eight variants within ESRRB were significantly associated with improved OS and comprised four independent (rsq&amp;lt;0.2) intronic variants. The top hit rs7160216 (HR=0.61, P=8.4x10-7, FDR=0.004) was modified by residual disease with the association attenuated in optimally debulked patients (HR=0.88, P interaction=0.05). One independent variant in ALDH1A1 was associated with an almost 2-fold lower OS (rs17563633 HR=1.80, P=7.2x10-5, FDR=0.03) and a ~6-fold lower OS in suboptimally debulked patients (HR=5.8, P interaction=9.2x10-4). Analysis of all patients, irrespective of chemotherapy, identified a significant association for rs17848385 in CXCR4 with reduced OS (HR=1.36, P=1.3x10-5, FDR=0.05). Aforementioned variants also displayed similar, significant associations with PFS though without modification. No significant SNP effects on survival were mediated through residual disease or stage; however, uncorrelated SNP blocks in ESRRB and ALDH1A1 associated with these factors proposing possible genomic interaction. Conclusion: Polymorphisms in CSC genes are associated with survival of HGSOC and more research is needed to clarify the prognostic value of these genes, particularly as carriers may benefit from emerging therapies targeting CSC pathways. Citation Format: Brett M. Reid, Jennifer B. Permuth, Zhihua Chen, Ann Chen, Thomas A. Sellers, on behalf of the Ovarian Cancer Association Consortium (OCAC). Germline polymorphisms in cancer stem cell genes associate with survival among women with high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1562.