Tumor heterogeneity is a major contributing factor in the adverse clinical outcome of gliomas. Consequently, the latest edition (2016 edition) of the WHO glioma classification incorporates molecular features into the classification criteria, thereby improving the homogeneity of clinical outcomes in patients with the same subtype. However, as one of histological subtype of glioma, LGG has substantial variation in patient survival and lacks effective prognostic markers. In the current study, we analyzed the survival and gene expression information of 955 patients with LGG and found the five-PCG signature could be a good prognostic molecular marker. In addition to predicting prognosis of LGG patients, the five-PCG signature has also been found to have a role in guiding radiotherapy.
Tumor heterogeneity and therapeutic advancements have prompted clinicians to make individualized prognosis and treatment choices for cancer patients, thereby achieving precision medicine. Gene expression has always been at the forefront of the development of personalized medicine, especially in the field of cancer. Gene expression signatures obtained by analyzing gene expression profiling have been shown to predict the tumor behavior and to distinguish patients with specific tumor grades and / or prognosis in various types of cancer, such as esophageal squamous cell carcinoma, hepatocellular carcinoma, bladder carcinoma, breast cancer, and glioblastoma. In the current study, we aimed to analyze the gene expression profile and develop an effective gene signature for accurate prognosis prediction of LGG patients. After a detailed analysis of gene expression profiles of 955 patients with LGG from the TCGA training set and CGGA validation set, a five PCGs based prognostic risk model and the five-PCG signature that could distinguish LGG patients with high risk of poor prognosis from patients with low risk were developed. The five-PCG signature has the following two advantages in prognosis prediction: First, it is an independent factor and does not depend on known prognostic factors such as IDH mutation and tumor grade; second, it has excellent prediction performance for its AUC value was higher than IDH mutation and tumor grade.
Notably, the five-PCG signature was found to be a predictive marker for radiotherapy in LGG patients. More specifically, the marker can identify who can benefit from radiotherapy or who is suitable for radiotherapy. As a result, LGG patients have more scientific guidance on whether to accept radiotherapy, and clinicians can also have more standardized guidelines for radiotherapy to facilitate their implementation. This finding shows that the five-PCG signature not only makes the prognosis assessment of patients more precise, but also can play the role of individualized treatment.In addition, we noted that the five PCGs in the signature had positive risk factors, meaning they were all prognostic risk factors. By searching the existing literature, we found that the important role of these genes in prognosis prediction had been reported in a variety of tumors. ATP binding cassette subfamily C member 3(ABCC3), also named multidrug resistance-associated protein 3(MRP3), is an organic anion transporter and contributes to drug resistance of cancer cells. Consistent with the results in this article, the poor prognosis predictive role of ABCC3 has been reported not only in acute myeloid leukemia, gastric cancer, pancreatic cancer and lung cancer, but also in gliomas. In addition to being found as a prognostic marker for gliomas in this article, structural maintenance of chromosomes 4(SMC4) has also been found to be a survival marker for colorectal cancer, breast cancer and prostate cancer. Epithelial membrane protein 3(EMP3) is considered to be a tumor suppressor, but this article found that this gene is a prognostic risk gene for LGG. Similar to our results, Haiwei Wang et al also found that EMP3 was associated with the worse prognosis of LGG patients and Xiao-Xia Guo et al discovered EMP3 was also a risk gene in the process of developing a prognostic 4-gene panel for glioblastoma patients. WEE1 G2 checkpoint kinase(WEE1) is reported to be an oncogenic nuclear kinase and a regulator of the G2 checkpoint. Expression of WEE1 has been found to be associated with poor prognosis in a variety of tumor types including gliomas. Two other gene signatures constructed to predict the prognosis of LGG are also consistent with the results of this article, and found that WEE1 is a prognostic risk factor[26, 27]. H2B clustered histone 12(H2BC12 or HIST1H2BK) is a replication-dependent histone and belongs to the histone H2B family. The prognostic role of HIST1H2BK was identified in ovarian cancer, breast cancer and pancreatic ductal adenocarcinoma.Although we had some findings on the function of the five prognostic genes by KEGG and GO analysis, further functional exploration of these genes is needed.