Dataset Information

The Key Genes for Perineural Invasion in Pancreatic Ductal Adenocarcinoma Identified With Monte-Carlo Feature Selection Method.

ABSTRACT: Background:Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive form of pancreatic cancer. Its 5-year survival rate is only 3-5%. Perineural invasion (PNI) is a process of cancer cells invading the surrounding nerves and perineural spaces. It is considered to be associated with the poor prognosis of PDAC. About 90% of pancreatic cancer patients have PNI. The high incidence of PNI in pancreatic cancer limits radical resection and promotes local recurrence, which negatively affects life quality and survival time of the patients with pancreatic cancer. Objectives:To investigate the mechanism of PNI in pancreatic cancer, we analyzed the gene expression profiles of tumors and adjacent tissues from 50 PDAC patients which included 28 patients with perineural invasion and 22 patients without perineural invasion. Method:Using Monte-Carlo feature selection and Incremental Feature Selection (IFS) method, we identified 26 key features within which 15 features were from tumor tissues and 11 features were from adjacent tissues. Results:Our results suggested that not only the tumor tissue, but also the adjacent tissue, was informative for perineural invasion prediction. The SVM classifier based on these 26 key features can predict perineural invasion accurately, with a high accuracy of 0.94 evaluated with leave-one-out cross validation (LOOCV). Conclusion:The in-depth biological analysis of key feature genes, such as TNFRSF14, XPO1, and ATF3, shed light on the understanding of perineural invasion in pancreatic ductal adenocarcinoma.

SUBMITTER: Zhu JH

PROVIDER: S-EPMC7593847 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The Key Genes for Perineural Invasion in Pancreatic Ductal Adenocarcinoma Identified With Monte-Carlo Feature Selection Method.

Zhu Jin-Hui JH Yan Qiu-Liang QL Wang Jian-Wei JW Chen Yan Y Ye Qing-Huang QH Wang Zhi-Jiang ZJ Huang Tao T

Frontiers in genetics 20201015

<h4>Background</h4>Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive form of pancreatic cancer. Its 5-year survival rate is only 3-5%. Perineural invasion (PNI) is a process of cancer cells invading the surrounding nerves and perineural spaces. It is considered to be associated with the poor prognosis of PDAC. About 90% of pancreatic cancer patients have PNI. The high incidence of PNI in pancreatic cancer limits radical resection and promotes local recurrence, which negatively affec ...[more]

PMID: 33193628

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Project description:BACKGROUND:Cachexia is responsible for the low quality of life in pancreatic adenocarcinoma (PDAC). The rapid disease progression and patient deterioration seems related to perineural invasion, but the relationship between cachexia and perineural invasion for the evolution of the disease has been rarely studied. As perineural invasion is difficult to be highlighted, a biomarker such as the neurotrophic factor Midkine (MK) which promotes the neuronal differentiation and the cell migration could be helpful. Also, Activin (ACV) has been described as cachexia related to PDAC. However, their role for assessing and predicting the disease course in daily practice is not known. AIM:To assess the relationship between perineural invasion and cachexia and their biomarkers, MK and ACV, respectively, and their prognostic value. METHODS:This study included prospectively enrolled patients with proven adenocarcinoma and a matched group of controls without any malignancies. Patients with other causes of malnutrition were excluded. The plasma levels of ACV and MK were analyzed using western blotting and were correlated with the clinicopathological features and survival data. These results were validated by immunohistochemical analyses of the pancreatic tumor tissue of the patients included in the study and a supplementary group of surgically resected specimens from patients with a benign disease. RESULTS:The study comprised 114 patients with PDAC, 125 controls and a supplementary group of 14 benign pancreatic tissue samples. ACV and MK were both overexpressed more frequently in the plasma of patients with PDAC than in the controls (63% vs 32% for ACV, P < 0.001; 47% vs 16% for MK, P < 0.001), with similar levels in pancreatic tissue the MK protein expression was closely related to the advanced clinical stage (P = 0.006), the presence of metastasis (P = 0.04), perineural invasion (P = 0.03) and diabetes (P = 0.002), but with no influence on survival. No correlation between clinicopathological factors and ACV expression was noted. Cachexia, present in 19% of patients, was unrelated to ACV or MK level. Higher ACV expression was associated with a shorter survival (P = 0.008). CONCLUSION:The MK was a biomarker of perineural invasion, associated with tumor stage and diabetes, but without prognostic value as ACV. Cachexia was unrelated to perineural invasion, ACV level or survival.

Project description:Background: High nerve density in tumors and metastasis via nerves (perineural invasion-PNI) have been reported extensively in solid tumors throughout the body including pancreatic, head and neck, gastric, prostate, breast, and colorectal cancers. Ablation of tumor nerves results in improved disease outcomes, suggesting that blocking nerve-tumor communication could be a novel treatment strategy. However, the molecular mechanisms underlying this remain poorly understood. Thus, the aim here was to identify molecular pathways underlying nerve-tumor crosstalk and to determine common molecular features between PNI-associated cancers. Results: Analysis of head and neck (HNSCC), pancreatic, and gastric (STAD) cancer Gene Expression Omnibus datasets was used to identify differentially expressed genes (DEGs). This revealed extracellular matrix components as highly dysregulated. To enrich for pathways associated with PNI, genes previously correlated with PNI in STAD and in 2 HNSCC studies where tumor samples were segregated by PNI status were analyzed. Neurodevelopmental genes were found to be enriched with PNI. In datasets where tumor samples were not segregated by PNI, neurodevelopmental pathways accounted for 12%-16% of the DEGs. Further dysregulation of axon guidance genes was common to all cancers analyzed. By examining paralog genes, a clear pattern emerged where at least one family member from several axon guidance pathways was affected in all cancers examined. Overall 17 different axon guidance gene families were disrupted, including the ephrin-Eph, semaphorin-neuropilin/plexin, and slit-robo pathways. These findings were validated using The Cancer Genome Atlas and cross-referenced to other cancers with a high incidence of PNI including colon, cholangiocarcinoma, prostate, and breast cancers. Survival analysis revealed that the expression levels of neurodevelopmental gene families impacted disease survival. Conclusion: These data highlight the importance of the tumor as a source of signals for neural tropism and neural plasticity as a common feature of cancer. The analysis supports the hypothesis that dysregulation of neurodevelopmental programs is a common feature associated with PNI. Furthermore, the data suggested that different cancers may have evolved to employ alternative genetic strategies to disrupt the same pathways. Overall, these findings provide potential druggable targets for novel therapies of cancer management and provide multi-cancer molecular biomarkers.

Dataset Information

The Key Genes for Perineural Invasion in Pancreatic Ductal Adenocarcinoma Identified With Monte-Carlo Feature Selection Method.

Publications

The Key Genes for Perineural Invasion in Pancreatic Ductal Adenocarcinoma Identified With Monte-Carlo Feature Selection Method.

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