BRCA1 missense polymorphisms are associated with poor prognosis of pancreatic cancer patients in a Chinese population.

Ying Zhu,Kan Zhai,Yajie Gong,Yi Zhang,Rong Zhong,Danyi Zou,Jiang Chang,Jianbo Tian,Xiaoping Miao,Jiaoyuan Li,Kun Huang,Xiating Peng,Juntao Ke,Yang Yang,Jing Gong

doi:10.18632/oncotarget.16422

Abstract

Pancreatic cancer is a highly lethal disease with limited prognostic marker. BRAC1 and BRCA2 are two classic tumor suppressor genes which play an important role in DNA repair. Somatic mutations and germline genetic variants on BRCA1/2 have been found associated with the tumorigenesis of pancreatic cancer. However, the correlations between BRCA1/2 polymorphism and pancreatic cancer prognosis remained unknown. In this study, we genotyped three tag missense variants on BRCA1/2 in 603 sporadic pancreatic cancer patients in a Chinese population. We found rs1799966 on BRCA1 was associated with poor prognosis of pancreatic cancer patients with hazard ratio being 1.23 (95% CI: 1.09–1.40, P = 0.0010). Further stratification analyses showed that significant correlation was particularly in locally advanced stage patients with hazard ratio being 1.36 (95% CI: 1.13–1.64, P = 0.0014), but not in patients in local stage (P = 0.1139) or metastatic stage (P = 0.5185). Two missense variants (rs766173 and rs144848) on BRAC2 showed no significant correlation with pancreatic cancer patients’ overall survival. In conclusion, we identified a germline missense variant on BRAC1 significantly associated with poor prognosis of pancreatic cancer patients with locally advanced stage. These results may contribute to the precision medicine of this disease.

Highlights

Pancreatic cancer is the thirteenth most common cancer in the world with mortality closely parallels incidence [1, 2]
We observed that rs1799966 (BRCA1) was significantly associated with pancreatic cancer patients’ overall survival with HR being 1.24 under an additive model (95% CI: 1.09–1.40, Figure 1: Linkage disequilibrium (LD) of single nucleotide polymorphisms (SNP) at the BRCA1/2 gene locus. rs766173 and rs1799944 on BRCA2 are in complete linkage disequilibrium (LD), but independent with the rest SNP rs144848
Through genotyping of three tag missense variants on BRCA1/2 in 603 Chinese pancreatic cancer patients, we discovered the prognostic value of rs1799966 (c.4837A>G [p.Ser1613Gly]) on BRCA1

Summary

Introduction

Pancreatic cancer is the thirteenth most common cancer in the world with mortality closely parallels incidence [1, 2]. Accumulating evidences have shown that germline variation such as single nucleotide polymorphisms (SNP) can affect cancer susceptibility [4, 5], and confer patients with different prognosis in multiple cancers [6,7,8]. Genetic variation relating to transcription regulation and DNA damage repair have effects on patient survival . Mutations in BRCA1/2 have been confirmed to give rise to multiple cancers including pancreatic adenocarcinoma [11,12,13,14]. Germline variants on BRCA2 have been identified to be associated with pancreatic cancer risk [20]. Correlation between variants on BRCA and pancreatic cancer patients’ survival are rarely studied

Methods

Results

Conclusion