Abstract
Ovarian cancer survival varies considerably among patients, to which germline variation may also contribute in addition to mutational signatures. To identify genetic markers modulating ovarian cancer outcome, we performed a genome-wide association study in 2130 Chinese ovarian cancer patients and found a hitherto unrecognized locus at 3p26.1 to be associated with the overall survival (Pcombined = 8.90 × 10−10). Subsequent statistical fine-mapping, functional annotation, and eQTL mapping prioritized a likely casual SNP rs9311399 in the non-coding regulatory region. Mechanistically, rs9311399 altered its enhancer activity through an allele-specific transcription factor binding and a long-range interaction with the promoter of a lncRNA BHLHE40-AS1. Deletion of the rs9311399-associated enhancer resulted in expression changes in several oncogenic signaling pathway genes and a decrease in tumor growth. Thus, we have identified a novel genetic locus that is associated with ovarian cancer survival possibly through a long-range gene regulation of oncogenic pathways.
Highlights
Ovarian cancer is the second most lethal gynecological malignancy after cervical cancer in China[1]
Only rs7631664 met the conventional genome-wide significance threshold of P = 5 × 10−8, with hazard ratios (HRs) of 1.60 in the discovery stage, 1.56 (1.24–1.95) in the replication stage, and 1.58 (1.37–1.83) in the joint analysis (Fig. 1b and Supplementary Table S1)
The removal of rs9311399associated enhancer fragments led to an alteration in cancer-related pathways and tumorigenic capacity in ovarian cancer cells. In this two-stage genome-wide association studies (GWASs) study of 2130 ovarian cancer patients on genetic factors for survival, we used four different bioinformatics and experimental approaches and identified a hitherto unrecognized survival-associated locus at 3p26.1, where a putative causal SNP rs9311399 is located, which was found to be significantly associated with overall survival (OS) of the patients
Summary
Ovarian cancer is the second most lethal gynecological malignancy after cervical cancer in China[1]. Several clinical features and epidemiologic risk factors, including patient age, health status, lifestyle behaviors, tumor characteristics, and response to treatment, have been used to predict ovarian cancer survival[4,5,6]. These factors only partially explain the observed heterogeneity of survival among ovarian cancer patients. In family studies[8,9,10,11] and genome-wide association studies (GWASs)[12,13,14], many rare and common germline variants have been identified to confer susceptibility to ovarian cancer.
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