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Genetic variations in stem cell-related genes and colorectal cancer prognosis.

ABSTRACT: Many properties of cancer cells are reminiscent of those in normal stem cells. Genes important to stem cell development have been significantly implicated in the etiology and clinical outcome of colorectal cancer (CRC). However, the associations of genetic variations in these genes with CRC prognosis have not yet been elucidated.We analyzed the effects of eight potentially functional single nucleotide polymorphisms (SNPs) in six stem cell-related genes on the prognosis of a well-characterized population of 380 Chinese CRC patients diagnosed from February 2006 to January 2010.The most significant finding was related to rs879882, a variant in the 5' region of POU5F1 gene which encodes a protein essential for embryonic stem cell self-renewal and pluripotency, and induced pluripotent stem cell reprogramming. The variant-containing genotypes of rs879882 were associated with an increased risk of recurrence (hazard ratio [HR]?=?2.10, 95% confidence interval [CI] 1.17-3.76, P?=?0.01). In chemotherapy-stratified analysis, the association remained borderline significant in patients receiving chemotherapy (HR?=?1.97, 95% CI 0.89-4.34, P?=?0.09). In addition, a nonsynonymous SNP of APC gene was also significantly associated with recurrence risk in chemotherapy-treated patients (HR?=?2.63, 95% CI 1.14-6.06 P?=?0.02). Further analyses showed a combined effect of the two SNPs in predicting CRC recurrence in patients receiving chemotherapy (P?=?0.04) but not in those without chemotherapy (P?=?0.43). Moreover, an exploratory multivariate assessment model indicated that these two variants enhanced the power to predict recurrence after chemotherapy.We presented one of the first epidemiologic studies showing that stem cell-related genetic variants may impact CRC clinical outcomes, especially in chemotherapy-treated patients.

SUBMITTER: Yang H

PROVIDER: S-EPMC3721524 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Genetic variations in stem cell-related genes and colorectal cancer prognosis.

Yang Hushan H Qu Falin F Myers Ronald E RE Bao Guoqiang G Hyslop Terry T Hu Guang G Fei Fei F Xing Jinliang J

Journal of gastrointestinal cancer 20121201 4

<h4>Background</h4>Many properties of cancer cells are reminiscent of those in normal stem cells. Genes important to stem cell development have been significantly implicated in the etiology and clinical outcome of colorectal cancer (CRC). However, the associations of genetic variations in these genes with CRC prognosis have not yet been elucidated.<h4>Methods</h4>We analyzed the effects of eight potentially functional single nucleotide polymorphisms (SNPs) in six stem cell-related genes on the p ...[more]

PMID: 22528324

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Project description:BackgroundCancer initiation and development are driven by key mutations in driver genes. Applying high-throughput sequencing technologies and bioinformatic analyses, The Cancer Genome Atlas (TCGA) project has identified panels of somatic mutations that contributed to the etiology of various cancers. However, there are few studies investigating the germline genetic variations in these significantly mutated genes (SMGs) and lung cancer susceptibility.Patients and methodsWe comprehensively evaluated 1655 tagged single nucleotide polymorphisms (SNPs) located in 127 SMGs identified by TCGA, and test their association with lung cancer risk in large-scale case-control study. Functional effect of the validated SNPs, gene mutation frequency and pathways were analyzed.ResultsWe found 11 SNPs in 8 genes showed consistent association (P < 0.1) and 8 SNPs significantly associated with lung cancer risk (P < 0.05) in both discovery and validation phases. The most significant association was rs10412613 in PPP2R1A, with the minor G allele associated with a decreased risk of lung cancer [odds ratio = 0.91, 95% confidence interval (CI): 0.87-0.96, P = 2.3 × 10-4]. Cumulative analysis of risk score built as a weight sum of the 11 SNPs showed consistently elevated risk with increasing risk score (P for trend = 9.5 × 10-9). In stratified analyses, the association of PPP2R1A:rs10412613 and lung cancer risk appeared stronger among population of younger age at diagnosis and never smokers. The expression quantitative trait loci analysis indicated that rs10412613, rs10804682, rs635469 and rs6742399 genotypes significantly correlated with the expression of PPP2R1A, ATR, SETBP1 and ERBB4, respectively. From TCGA data, expression of the identified genes was significantly different in lung tumors compared with normal tissues, and the genes' highest mutation frequency was found in lung cancers. Integrative pathway analysis indicated the identified genes were mainly involved in AKT/NF-κB regulatory pathway suggesting the underlying biological processes.ConclusionThis study revealed novel genetic variants in SMGs associated with lung cancer risk, which might contribute to elucidating the biological network involved in lung cancer development.

Project description:Background: Colorectal cancer (CRC) is one gastrointestinal malignancy, accounting for 10% of cancer diagnoses and cancer-related deaths worldwide each year. Therefore, it is urgent to identify genes involved in CRC predicting the prognosis. Methods: CRC's data were acquired from the Gene Expression Omnibus (GEO) database (GSE39582 and GSE41258 datasets) and The Cancer Genome Atlas (TCGA) database. The differentially expressed necroptosis-related genes (DENRGs) were sorted out between tumor and normal tissues. Univariate Cox regression analysis and least absolute shrinkage and selectionator operator (LASSO) analysis were applied to selected DENRGs concerning patients' overall survival and to construct a prognostic biomarker. The effectiveness of this biomarker was assessed by the Kaplan-Meier curve and the receiver operating characteristic (ROC) analysis. The GSE39582 dataset was utilized as external validation for the prognostic signature. Moreover, using univariate and multivariate Cox regression analyses, independent prognostic factors were identified to construct a prognostic nomogram. Next, signaling pathways regulated by the signature were explored through the gene set enrichment analysis (GSEA). The single sample gene set enrichment analysis (ssGSEA) algorithm and tumor immune dysfunction and exclusion (TIDE) were used to explore immune correlation in the two groups, high-risk and low-risk ones. Finally, prognostic genes' expression was examined in the GSE41258 dataset. Results: In total, 27 DENRGs were filtered, and a necroptosis-related prognostic signature based on 6 DENRGs was constructed, which may better understand the overall survival (OS) of CRC. The Kaplan-Meier curve manifested the effectiveness of the prognostic signature, and the ROC curve showed the same result. In addition, univariate and multivariate Cox regression analyses revealed that age, pathology T, and risk score were independent prognostic factors, and a nomogram was established. Furthermore, the prognostic signature was most significantly associated with the apoptosis pathway. Meanwhile, 24 immune cells represented significant differences between two groups, like the activated B cell. Furthermore, 32 immune checkpoints, TIDE scores, PD-L1 scores, and T-cell exclusion scores were significantly different between the two groups. Finally, a 6-gene prognostic signature represented different expression levels between tumor and normal samples significantly in the GSE41258 dataset. Conclusion: Our study established a signature including 6 genes and a prognostic nomogram that could significantly assess the prognosis of patients with CRC.

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Genetic variations in stem cell-related genes and colorectal cancer prognosis.

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Genetic variations in stem cell-related genes and colorectal cancer prognosis.

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