Abstract
Literature suggests that genetic variants associated with increased susceptibility to gastric cancer (GCa) are mostly located in genes involved in carcinogenesis and possibly tumor progression. Therefore, we hypothesize that high genetic susceptibility is also associated with prognosis of the patients. To test this hypothesis, we selected a total of 42 common genetic variants that were reportedly associated with GCa risk with a high level of evidence obtained from either genome-wide association studies (GWASs) or meta-analyses and performed survival analysis of patients used in a case-control analysis. We first used 1115 GCa cases and 1172 cancer-free controls of ethnic Han Chinese to construct a weighted genetic risk score (GRS). Then, we included 633 GCa cases with available clinical information, fit GRS in a fractional polynomial Cox proportional hazards regression model to investigate whether there is a dose-dependent effect of GRS on risk of death in survival analysis. Dynamic predictive value of genetic risk for prognosis was also calculated. The results showed that the increase of GRS had no effect on risk of death in these GCa patients. Compared with GCa patients with the medium GRS, there was no significant difference in survival in patients with either a low (P = 0.349) or a high (P = 0.847) GRS. The results unchanged when data were stratified by tumor stage and Laurens classification. Time-dependent predictive value for prognosis in considering both clinical factors and GRS was comparable with that in considering clinical factors alone, for either all patients (P = 0.986) or stage- and Laruen type-based subgroups (P > 0.05 for all). In conclusion, higher polygenic susceptibility loci for GCa may not indicate worse prognosis of Chinese patients. Additional variants of relevant genes modulating GCa patients survival need to be further identified.
Highlights
Gastric cancer (GCa) is the second commonly diagnosed cancer and the second leading cause of cancer-related deaths in China [1]
It has been shown that there is no association between genetic risk score (GRS) of prostate cancer and risk of radiotherapy toxicity, some susceptibility genes were involved in cellular radiation response [27]
We first used a case-control study to develop a population-specific GRS based on 42 well-established GCa susceptibility loci derived from published genome-wide association studies (GWASs) and meta-analysis and used this GRS in a survival analysis of the patients www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget
Summary
Gastric cancer (GCa) is the second commonly diagnosed cancer and the second leading cause of cancer-related deaths in China [1]. The high recurrence rate makes it the necessary to identify additional markers for prognosis, which may facilitate individualized treatment and management Some clinical factors, such as Lauren’s classification, have been shown to be associated with GCa prognosis. Single nucleotide polymorphisms (SNPs), presented more than 1% in the general population, have been reported to be associated with GCa risk [8,9,10] These findings provide tools for early detection, diagnosis and prevention at the genetic level in the at-risk populations. Five large published genome-wide association studies (GWASs) have revealed a series of genetic variants associated with susceptibility to GCa [11,12,13,14,15] Some of these results have been successfully reproduced by subsequent large case-control studies with sufficient statistical power [16, 17]. We used the available genotyping data from an ongoing case-control study of GCa and survival data from the same patients in a single institution
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