The pancreatic cancer risk variant rs3790844 of the nuclear receptor NR5A2 modulates genetic susceptibility of cholangiocarcinoma

Background:

There is limited information on risk factors modulating genetic susceptibility to cholangiocarcinoma (CCA), the second most common primary liver cancer fraught with a poor prognosis and ill-defined pathogenesis.[1] A common variant in the liver receptor homologe-1 (LRH-1) gene, alternatively referred to as NR5A2, has been identified as a genetic risk factor for pancreatic cancer.[2] Since the nuclear receptor (NR) 5A2 is critically involved in embryonic development, bile salt metabolism and cholesterol transport, we assessed a potential contribution of rs3790844 in genetic CCA risk.[3]

Patients & Methods: In a large European-based CCA cohort, we genotyped 226 CCA individuals (58.9% males, PSC < 2%, age 66.2 +/- 11.7 years, 79.2% extrahepatic CCAs) and a total of 350 CCA-free controls. The single nucleotide variant (SNV) rs3790844 in the NR5A2 gene was genotyped by a PCR-based assay with 5'-nuclease and fluorescence detection. Statistical analyses included assessment for consistency with the Hardy-Weinberg equilibrium (HWE) by exact tests and association testing in contingency tables. In addition, NR5A2 expression analyses were performed on different CCA cell lines by quantitative PCR.

Results: Allele and genotype distributions in the control group were consistent with HWE (p > 0.05). The rs3790844 [T] allele was overrepresented in the CCA group (78.1 vs. 72.7%), providing consistent association signals in allele- and genotype-based tests (chi2: OR = 1.34, 95% CI = 1.01 – 1.77, p = 0.039; Armitage: OR = 1.29, p = 0.041). Of interest, exploratory subgroup analyses yielded an association with a larger effect size for rs3790844 in the comparatively small intrahepatic CCA subgroup (n = 47, OR = 1.84, 95% CI = 1.05 – 3.24, p = 0.03). Compared to HepG2 cells, NR5A2 was prominently overexpressed in SK-CHA1 and CH9 cells, while expression was low in TFK-1, and Egi 1 cell lines.

Conclusions: These findings in the currently largest CCA cohort provide first evidence for genetic risk modulation by the common variant rs3790844, and suggest a novel role of NR5A2 in cholangiocarcinogenesis. However, confirmation and extension of our results in independent cohorts is warranted.

References:

[1] Tyson Hepatol 2011

[2] Petersen Nat Genet 2010

[3] Lee Front Biosci 2008