The online version of this article (doi:10.1186/s12885-017-3257-x) contains supplementary material, which is available to authorized users.
Cervical cancer is the second most common cause of cancer deaths in women worldwide. The aim of this study is to exploit novel pathogenic genes in cervical carcinogenesis.
The somatic mutations from 194 patients with cervical cancer were obtained from the Cancer Genome Atlas (TCGA) publically accessible exome-sequencing database. We investigated mutated gene enrichment in the 12 cancer core pathways and predicted possible post-translational modifications. Additionally, we predicted the impact of mutations by scores quantifying the deleterious effects of the mutations. We also examined the immunogenicity of the mutations based on the mutant peptides’ strong binding with major histocompatibility complex class I molecules (MHC-I). The Kaplan-Meier method was used for the survival analysis.
We observed that the chromatin modification pathway was significantly mutated across all clinical stages. Among the mutated genes involved in this pathway, we observed that the histone modification regulators were primarily mutated. Interestingly, of the 197 mutations in the 26 epigenetic regulators in this pathway, 25 missense mutations in 13 genes were predicted in or around the phosphorylation sites. Only mutations in the histone methyltransferase MLL2 exhibited poor survival. Compared to other mutations in MLL2 mutant patients, we noticed that the mutational scores prioritized mutations in MLL2, which indicates that it is more likely to have deleterious effects to the human genome. Around half of all of the mutations were found to bind strongly to MHC-I, suggesting that patients are likely to benefit from immunotherapy.
Our results highlight the emerging role of mutations in epigenetic regulators, particularly MLL2, in cervical carcinogenesis, which suggests a potential disruption of histone modifications. These data have implications for further investigation of the mechanism of epigenetic dysregulation and for treatment of cervical cancer.
Additional file 1: Table S1. All mutated genes and nonsynonymous mutations. (XLS 3318 kb)12885_2017_3257_MOESM1_ESM.xls
Additional file 2: Figure S1. Correlation between the somatic mutations and nonsynonymous mutations. For each clinical stage, the number of total somatic mutations and the nonsynonymous mutations in each patient were plotted. The correlation coefficient and the significant p value are shown. (PDF 148 kb)12885_2017_3257_MOESM2_ESM.pdf
Additional file 3: Figure S2. Correlation between the nonsynonymous mutations with patients’ clinical stage. Distribution of patients’ nonsynonymous mutations number with the patients’ disease stages is exhibited. P value was calculated by a two-sided Student’s t test (mean ± s.d.; n = 194 subjects). (EPS 487 kb)12885_2017_3257_MOESM3_ESM.eps
Additional file 4: Table S2. Driver genes and core pathways. (XLS 33 kb)12885_2017_3257_MOESM4_ESM.xls
Additional file 5: Table S3. Mutated driver genes and variants in patients. (XLS 99 kb)12885_2017_3257_MOESM5_ESM.xls
Additional file 6: Figure S3. Mutated genes involved in the PI3K, RAS, apoptosis, and NOTCH pathways. The heatmaps show the distribution of the mutated genes involved in the four pathways across all clinical stages. Each column represents an individual, and each row denotes a gene. The bar graph on the top shows the patients’ subgroup at Stage I, Stage II, Stage III, and Stage IV as red, blue, orange, and purple, respectively. (EPS 2420 kb)12885_2017_3257_MOESM6_ESM.eps
Additional file 7: Figure S4. Another 8 epigenetic regulators harboring mutations destroying phosphorylation sites. The 8 epigenetic regulators are shown in the context of protein domain models derived from UniProt. Each filled circle represents a mutated patient. Somatic mutations destroying the phosphorylation sites are marked in red. Domains are depicted with various colors. (EPS 1080 kb)12885_2017_3257_MOESM7_ESM.eps
Additional file 8: Table S4. Details of the 25 missense mutations destroying phosphorylation sites. (XLS 26 kb)12885_2017_3257_MOESM8_ESM.xls
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- Emerging role of mutations in epigenetic regulators including MLL2 derived from The Cancer Genome Atlas for cervical cancer
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