| 英文摘要 |
PartⅠ. Characteristics of keratinocyte and relevant clinical significance in digestive system cancer microenvironment Backgrounds The digestive system is one of the systems with the highest incidence of cancer. Among the cancer incidence and mortality in China, the incidence of gastric cancer, colorectal cancer, liver cancer and pancreatic cancer are all in the top ten. Pancreatic cancer has one of the highest mortality rates in the world. Most patients with pancreatic cancer are asymptomatic until the disease develops to an advanced stage when surgery cannot be performed. Worse still, due to insensitivity to chemotherapy or radiotherapy, the prognosis of pancreatic cancer patients is poor. Keratinocytes or their characteristics influence prognosis in a variety of tumors. Recently with the development of large-scale sequencing databases and novel algorithms, we could explore the cellular components of tumor bulks including keratinocytes from genomic level. Methods We utilized a novel algorithm which digitally portrays the tissue cellular heterogeneity landscape from transcriptomes. By selecting characteristic gene sets of stromal or immune cells and analyzing datasets from TCGA and ICGC, the algorithm gives adjusted score of keratinocytes for each one. We inspected the prognostic value of keratinocytes in gastric cancer, liver cancer, colorectal cancer and pancreatic cancer. Cox regression, Log-rank test and Pearson-χ2 test were used. Results Our study showed the significant prognostic value of keratinocyte scores among all 64 types of cells in pancreatic cancer. Its marker gene, KRT14, could also be used as an independent prognostic factor. Moreover, keratinocyte scores had negative correlations with tumor grade but no correlations with age, sex, size, stage etc. were found. Conclusions There exists the characteristic of keratinocytes in the expression of digestive system tumors and the keratinocyte scores could be used as a negative prognostic factor in pancreatic cancer, which is of potential research value. Keywords: digestive system, characteristic of keratinocytes, pancreatic cancer, prognosis. CLC: R656. Part Ⅱ. Molecular subtypes in pancreatic cancer based on characteristic genes of keratinocytes Backgrounds There have already been reports on molecular subtyping in digestive system tumors, however, current subtypes of pancreatic cancer do not inform treatment decisions. For the first time we discovered that characteristic of keratinocytes in pancreatic cancer was a significant negative prognostic factor. Since this algorithm needs complete standardized transcriptome data, to find representative characteristic genes and to perform molecular subtypes were necessary. Methods We selected characteristic gene sets from different sources. After filtered with Venn diagrams, the genes are then screened with Cox regression and Lasso regression and two significant genes were picked out. We performed the molecular subtypes with the two genes and get the most representative double positive (DP) and double negative (DN) groups. Afterwards, we analyzed the difference between the groups from the perspectives of overall survival, genomic alterations, signal pathways and immune cells portion. Finally, we assessed the prognostic value of subgroups in patients who received adjuvant chemotherapy. Results Characteristic genes GJB4 and DSG3 were distinguished and used for molecular subtypes. Patients from DN group had significantly better than DP groups. Comparatively, DP group showed more tumor mutational burden and higher mutation rate in diver genes like KRAS or TP53. As for cancer-associated signal pathways, we found DP group had more mutations and higher expression on the many pathways. DP group had higher ratio of Treg and Macrophage M0 while DN group had more CD8+ T cells and monocytes. Moreover, patients received adjuvant chemotherapy from DN group had better survival outcomes than those from DP groups. Conclusions Molecular subtypes based on keratinocyte-associated genes GJB4 and DSG3 could successfully distinguish the survival outcomes and therapeutic effects of pancreatic patients. The subtypes were closely related to tumor mutational burden, signal pathways and immune cell components, which had potential value of application and worth further exploration. Keywords: characteristic of keratinocytes, pancreatic cancer, molecular subtyping, clinical prognosis. CLC: R656. Part Ⅲ. A brief view of immune infiltration status in pancreatic cancer Backgrounds Microenvironment in pancreatic cancer has close relationship with the progression, treatment and prognosis. In this part, we optimized the research model to explore the infiltration status of immune cells in the microenvironment of pancreatic cancer as a whole. Methods We simplified the model from 64 to 27 immune and stromal cell types in microenvironment. After the scores of all cell types were output, we grouped patients with finite gaussian mixture model. Then we utilized Cox regression model, Log-rank test and Pearson-χ2 test to study the relationship between the groups and clinical phenotypes, overall survival and others. Finally, we applied algorithms including ESTIMATE, MATH and EMT signature methods to further study it's connection with tumor purity, intratumor heterogeneity and EMT status. Results All pancreatic cancer patients were categorized into groups of high immune infiltration (C2) and low immune infiltration (C1). Although there was no significant difference in overall survival of all patients, however, patients who received gemcitabine treatment in C2 group had better survival than those in C1 group. Also, patients from C2 group had high ratio of G2 grade, N1 stage and position in pancreas body and tail, while patients from C1 group had high ratio of G1 grade, N0 stage and position in pancreas head. Moreover, C1 group had significant higher ESTMATE score, MATH value and lower EMT score. Conclusions Immune infiltration classification was a significant prognostic factor in overall survival in pancreatic patients who received gemcitabine treatment. There was significant difference in grade, N, M status and tumor position between two groups. C2 group had higher tumor purity and C1 group had higher intratumor heterogeneity. As for EMT status. C1 group was more epithelial and C2 was relatively mesenchymal. Keywords: immune infiltration, pancreatic cancer, subtyping, clinical prognosis. CLC: R656.
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