Dataset Information

Association Study between Polymorphisms in DNA Methylation-Related Genes and Testicular Germ Cell Tumor Risk.

ABSTRACT:

Background

Testicular germ cell tumors (TGCT), histologically classified as seminomas and nonseminomas, are believed to arise from primordial gonocytes, with the maturation process blocked when they are subjected to DNA methylation reprogramming. SNPs in DNA methylation machinery and folate-dependent one-carbon metabolism genes have been postulated to influence the proper establishment of DNA methylation.

Methods

In this pathway-focused investigation, we evaluated the association between 273 selected tag SNPs from 28 DNA methylation-related genes and TGCT risk. We carried out association analysis at individual SNP and gene-based level using summary statistics from the Genome Wide Association Study meta-analysis recently conducted by the international Testicular Cancer Consortium on 10,156 TGCT cases and 179,683 controls.

Results

In individual SNP analyses, seven SNPs, four mapping within MTHFR, were associated with TGCT risk after correction for multiple testing (q ≤ 0.05). Queries of public databases showed that three of these SNPs were associated with MTHFR changes in enzymatic activity (rs1801133) or expression level in testis tissue (rs12121543, rs1476413). Gene-based analyses revealed MTHFR (q = 8.4 × 10-4), methyl-CpG-binding protein 2 (MECP2; q = 2 × 10-3), and ZBTB4 (q = 0.03) as the top TGCT-associated genes. Stratifying by tumor histology, four MTHFR SNPs were associated with seminoma. In gene-based analysis MTHFR was associated with risk of seminoma (q = 2.8 × 10-4), but not with nonseminomatous tumors (q = 0.22).

Conclusions

Genetic variants within MTHFR, potentially having an impact on the DNA methylation pattern, are associated with TGCT risk.

Impact

This finding suggests that TGCT pathogenesis could be associated with the folate cycle status, and this relation could be partly due to hereditary factors.

SUBMITTER: Grasso C

PROVIDER: S-EPMC9444936 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Publications

Association Study between Polymorphisms in DNA Methylation-Related Genes and Testicular Germ Cell Tumor Risk.

Grasso Chiara C Popovic Maja M Isaevska Elena E Lazzarato Fulvio F Fiano Valentina V Zugna Daniela D Pluta John J Weathers Benita B D'Andrea Kurt K Almstrup Kristian K Anson-Cartwright Lynn L Bishop D Timothy DT Chanock Stephen J SJ Chen Chu C Cortessis Victoria K VK Dalgaard Marlene D MD Daneshmand Siamak S Ferlin Alberto A Foresta Carlo C Frone Megan N MN Gamulin Marija M Gietema Jourik A JA Greene Mark H MH Grotmol Tom T Hamilton Robert J RJ Haugen Trine B TB Hauser Russ R Karlsson Robert R Kiemeney Lambertus A LA Lessel Davor D Lista Patrizia P Lothe Ragnhild A RA Loveday Chey C Meijer Coby C Nead Kevin T KT Nsengimana Jérémie J Skotheim Rolf I RI Turnbull Clare C Vaughn David J DJ Wiklund Fredrik F Zheng Tongzhang T Zitella Andrea A Schwartz Stephen M SM McGlynn Katherine A KA Kanetsky Peter A PA Nathanson Katherine L KL Richiardi Lorenzo L

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20220901 9

<h4>Background</h4>Testicular germ cell tumors (TGCT), histologically classified as seminomas and nonseminomas, are believed to arise from primordial gonocytes, with the maturation process blocked when they are subjected to DNA methylation reprogramming. SNPs in DNA methylation machinery and folate-dependent one-carbon metabolism genes have been postulated to influence the proper establishment of DNA methylation.<h4>Methods</h4>In this pathway-focused investigation, we evaluated the association ...[more]

PMID: 35700037

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Project description:Cancer-testis (CT) genes are a group of genes restrictedly expressed in testis and multiple cancers and can serve as candidate driver genes participating in the development of cancers. Our previous study identified a number of CT genes in nongerm cell tumors, but their expression pattern in testicular germ cell tumor (TGCT), a cancer type characterized by less genomic alterations, remained largely unknown. In this study, we systematically investigated the expression pattern of CT genes in TGCT samples and evaluated the transcriptome difference between TGCT and normal testis tissues, using datasets from the UCSC Xena platform, The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) project. Pathway enrichment analysis and survival analysis were conducted to evaluate the biological function and prognostic effect of expressed CT genes. We identified that 1036 testis-specific expressed protein-coding genes and 863 testis-specific expressed long noncoding RNAs (lncRNAs) were expressed in TGCT samples, including 883 CT protein-coding genes and 710 CT lncRNAs defined previously. The number of expressed CT genes was significantly higher in seminomas (P = 3.48 × 10-13 ) which were characterized by frequent mutations in driver genes (KIT, KRAS and NRAS). In contrast, the number of expressed CT genes showed a moderate negative correlation with the fraction of copy number altered genomes (cor = -0.28, P = 1.20 × 10-3 ). Unlike other cancers, our analysis revealed that 96.16% of the CT genes were down-regulated in TGCT samples, while CT genes in stem cell maintenance related pathways were up-regulated. Further survival analysis provided evidence that CT genes could also predict the prognosis of TGCT patients with both disease-free interval and progression-free interval as clinical endpoints. Taken together, our study provided a global view of CT genes in TGCT and provided evidence that CT genes played important roles in the progression and maintenance of TGCT.

Project description:Background:Testicular cancer is a very common malignancy in young men. Although testicular cancer has a high cure rate, patients have a high long-term risk of secondary malignant tumors and cardiovascular disease. In addition, for patients resistant to traditional treatment methods, new treatment methods and methods for predicting prognosis are also urgently needed. Methods:Gene expression profiles of 165 normal testicular tissues and 156 testicular germ cell tumor (TGCT) tissues from GTEx database and TCGA database were used to obtain differentially expressed genes (DEGs) in TGCT. Through the ImmPort database, we obtained immune-related genes (IRGs). Univariate Cox regression analysis was used to identify prognostic IRGs. A transcription factor regulatory network was constructed to clarify the possible regulatory mechanism for the differential expression of these IRGs. Multivariate Cox regression analysis was used to establish a prognostic model. Gene expression data and related survival data of 108 TCGT patients from GEO database were used for external validation. Survival analysis, receiver operating characteristic curves (ROC) curve analysis, independent prognostic analysis, principal component analysis (PCA) and clinical correlation analysis were performed to evaluate this model. Results:Three hundred and thirty-three IRGs were differentially expressed between TGCT and normal testicular tissues. We established a prognostic model (riskScore) based on 5 risk genes (SEMA6B, SEMA3G, OBP2B, INSL6 and RETN). Whether in the training cohort, the testing cohort or the entire TCGA cohort, this model could accurately stratify patients with different survival outcomes. The prognostic value of riskScore and 5 risk genes was also confirmed in the GEO database. GSEA analysis showed that DEGs in patients with better prognosis were enriched in immune-related pathways, while DEGs in patients with poorer prognosis were enriched in cancer-related pathways and cardiovascular disease-related pathways. Finally, a new Nomogram with higher prognostic value was constructed to better predict the 1-year PFS, 3-year PFS and 5-year PFS of TCGT patients. Conclusions:We successfully established an immune-related risk model with high prognostic value and created a new Nomogram. We found that different immune status in tumor microenvironment may be responsible for the different survival outcomes among TGCT patients.

Dataset Information

Association Study between Polymorphisms in DNA Methylation-Related Genes and Testicular Germ Cell Tumor Risk.

Background

Methods

Results

Conclusions

Impact

Publications

Association Study between Polymorphisms in DNA Methylation-Related Genes and Testicular Germ Cell Tumor Risk.

Similar Datasets

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