Whole-genome Sequencing Identifies New Potential Driver Mutations In Early-onset Gastric Cancer

Background and Purpose:Gastric cancer is one of the most common cancers around the world, with a relatively high mortality rate. The poor response to chemotherapies and poor prognosis are partially due to the fact that gastric cancer is a heterogeneous disease with marked molecular and phenotypic diversity. However, the specific pathogenesis of gastric cancer is still not clear so far. Since the rapid developments on molecular biology, genomics and bioinformatics, especially the arising of next-generation sequencing, there are more and more researches focusing on the molecular characteristics of gastric cancer. The oncogene activation or tumor-suppressor gene inactivation caused by somatic mutation could play an important role in the carcinogenesis, which is specially called the driver mutation. Thus screening for the potential driver mutations of gastric cancer can make good sense for the further studies on its molecular pathogenesis and founding corresponding targeted therapies. As with the age increasing, the influences of the outside environment on human increase, which somehow causes much interference while screening for driver mutations. Comparing to the elderly patients, younger patients are less exposed to environmental carcinogens, and their neoplasms reply more on genetic and molecular factors. Thus researches on younger cancer patients may better illustrate the underlying genetic pathogenesis of gastric cancer. Here we conducted the whole-genome sequencing of early-onset gastric cancer tissues, aiming to assess the genomic landscapes and explore the potential driver mutations in gastric cancer.Methods:We surveyed the spectrum of somatic alterations in early-onset gastric cancer by conducting the whole-genome sequencing of DNA from the neoplastic epitheliums of 5 surgically resected early-onset gastric cancer tissues (patients at the age of 45 years or younger) and their matched normal tissues. Then we used the bioinformatics instruments to analyze the potential susceptibility gene mutations, fusion genes and significantly mutated genes in early-onset gastric cancer, so that identifying potential driver mutations in gastric cancer.Results:Through the whole-genome sequencing and bioinformatics analysis in our study, we identified a total of 162 susceptibility gene mutations and 70 fusion genes related with gastric cancer. Compared with the known driver gene databases in cancer, we found 49 known driver gene mutations appeared in our early-onset gastric cancer samples, including TP53、NOTCH1、ARID1A、PIK3CA and CDH1, which were reported to be potential driver mutations in gastric cancer before. In addition, we identified 8 new significantly mutated genes related with gastric cancer in our samples, namely CYP4F2.MIOX、OCM2、OR11H1、MUC4、KLF2、GRM8 and CBWD3, and 2 mutated genes, KLF2 and SEMA5A, which had cluster mutant implying there might be positive selection in tumor development.Conclusion:We have identified several new potential driver mutations in our early-onset gastric cancer samples, which will probably need more gastric cancer samples to be verified. And it also provides some basis for our future researches on the molecular mechanisms of gastric cancer.