Association of imputed prostate cancer transcriptome with disease risk reveals novel mechanisms

Emami, Nima C.; Kachuri, Linda; Meyers, Travis J.; Das, Rajdeep; Hoffman, Joshua; Hoffmann, Thomas J.; Hu, Donglei; Shan, Jun; Feng, Felix Y.; Ziv, Elad; Eeden, Stephen K. Van Den; Witte, John S.

doi:10.1038/s41467-019-10808-7

Cited by 30 publications

(30 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Investigation by CCLE demonstrated higher levels of TMPRSS2 expression in several cell lines such as prostate, colorectal, stomach and bile duct in comparison with other cell lines. These findings were supported by studies conducted on prostate cancer patients that showed higher levels of TMPRSS2 expression in comparison with normal subjects (Emami et al, 2019). Also, results from an investigation of Tmprss2 expression in mice showed that Tmprss2 was considerably expressed in epithelia of the gastrointestinal, urogenital and respiratory tracts (Vaarala et al, 2001).…”

Section: Discussionmentioning

confidence: 66%

First comprehensive computational analysis of functional consequences of TMPRSS2 SNPs in susceptibility to SARS-CoV-2 among different populations

Paniri

Hosseini

Akhavan‐Niaki

2020

Journal of Biomolecular Structure and Dynamics

View full text Add to dashboard Cite

To cite this article: Alireza Paniri, Mohammad Mahdi Hosseini & Haleh Akhavan-Niaki (2020): First comprehensive computational analysis of functional consequences of TMPRSS2 SNPs in susceptibility to SARS-CoV-2 among different populations, Journal of Biomolecular Structure and Dynamics, ABSTRACT Current SARS-CoV-2 pandemy mortality created the hypothesis that some populations may be more susceptible to SARS-CoV-2. TMPRSS2 encodes a transmembrane serine protease which plays a crucial role in SARS-CoV-2 cell entry. Single nucleotide polymorphisms (SNPs) in TMPRSS2 might influence SARS-CoV2 entry into the cell. This study aimed to investigate the impact of SNPs on TMPRSS2 function and structure. In silico tools such as Ensembl, Gtex, ExPASY 2, GEPIA, CCLE, KEGG and GO were engaged to characterize TMPRSS2 and its expression profile. The functional effects of SNPs were analyzed by PolyPhen-2, PROVEN, SNAP2, SIFT and HSF. Also, Phyre2, GOR IV and PSIPRED were used to predict the secondary structure of TMPRSS2. Moreover, post-translational modification (PTM) and secretory properties were analyzed through Modpredand Phobius, respectively. Finally, miRNA profiles were investigated by PolymiRTS and miRSNPs. Out of 11,184 retrieved SNPs from dbSNP, 92 showed a different frequency between Asians and other populations. Only 21 SNPs affected the function and structure of TMPRSS2 by influencing the protein folding, PTM, splicing and miRNA function. Particularly, rs12329760 may create a de novo pocket protein. rs875393 can create a donor site, silencer and broken enhancer motifs. rs12627374 affects a wide spectrum of miRNAs profile. This study highlighted the role of TMPRSS2 SNPs and epigenetic mechanisms especially non-coding RNAs in appearance of different susceptibility to SARS-CoV-2 among different populations. Also, this study could pave the way to potential therapeutic implication of TMPRSS2 in designing antiviral drugs. ARTICLE HISTORY

show abstract

Section: Discussionmentioning

confidence: 66%

First comprehensive computational analysis of functional consequences of TMPRSS2 SNPs in susceptibility to SARS-CoV-2 among different populations

Paniri

Hosseini

Akhavan‐Niaki

2020

Journal of Biomolecular Structure and Dynamics

View full text Add to dashboard Cite

show abstract

“…It is worth noting that based on the predicted DNA methylation-PrCa risk, DNA methylation-gene expression, and predicted gene expression-PrCa risk results, we also observed six CpG sites and four genes (VAMP8, C4B, BAIAP2L1, and NCOA4) with inconsistent directions of association for the DNA methylation-gene expression-PrCa pathway (Supplementary Table 7). Of these genes, NCOA4, BAIAP2L1, and VAMP8 are candidate PrCa susceptibility genes identified in earlier TWAS 27,29,30 . Future work is needed to better understand these associations.…”

Section: Resultsmentioning

confidence: 99%

An integrative multi-omics analysis to identify candidate DNA methylation biomarkers related to prostate cancer risk

Yang

Guo

et al. 2020

Nat Commun

View full text Add to dashboard Cite

It remains elusive whether some of the associations identified in genome-wide association studies of prostate cancer (PrCa) may be due to regulatory effects of genetic variants on CpG sites, which may further influence expression of PrCa target genes. To search for CpG sites associated with PrCa risk, here we establish genetic models to predict methylation (N = 1,595) and conduct association analyses with PrCa risk (79,194 cases and 61,112 controls). We identify 759 CpG sites showing an association, including 15 located at novel loci. Among those 759 CpG sites, methylation of 42 is associated with expression of 28 adjacent genes. Among 22 genes, 18 show an association with PrCa risk. Overall, 25 CpG sites show consistent association directions for the methylation-gene expression-PrCa pathway. We identify DNA methylation biomarkers associated with PrCa, and our findings suggest that specific CpG sites may influence PrCa via regulating expression of candidate PrCa target genes.

show abstract

“…Interestingly, p53 activation induced both FTH and FTL expression in human lung cancer cells [155]. NCOA4, which is responsible for ferritin degradation and cytosolic iron increase, was found overexpressed in transformed endometriotic cells and pancreatic cancer cell lines and correlated to prostate cancer risk [206][207][208]. Furthermore, inactivation of p53 and activation of transforming protein p21 (HRAS) and proto-oncogene MYC led to overexpressed NCOA4 [206].…”

Section: Cellular Iron Dysregulation In Cancermentioning

confidence: 99%

Iron: An Essential Element of Cancer Metabolism

Hsu

Mina

Roetto

et al. 2020

Cells

View full text Add to dashboard Cite

Cancer cells undergo considerable metabolic changes to foster uncontrolled proliferation in a hostile environment characterized by nutrient deprivation, poor vascularization and immune infiltration. While metabolic reprogramming has been recognized as a hallmark of cancer, the role of micronutrients in shaping these adaptations remains scarcely investigated. In particular, the broad electron-transferring abilities of iron make it a versatile cofactor that is involved in a myriad of biochemical reactions vital to cellular homeostasis, including cell respiration and DNA replication. In cancer patients, systemic iron metabolism is commonly altered. Moreover, cancer cells deploy diverse mechanisms to increase iron bioavailability to fuel tumor growth. Although iron itself can readily participate in redox reactions enabling vital processes, its reactivity also gives rise to reactive oxygen species (ROS). Hence, cancer cells further rely on antioxidant mechanisms to withstand such stress. The present review provides an overview of the common alterations of iron metabolism occurring in cancer and the mechanisms through which iron promotes tumor growth.

show abstract

Association of imputed prostate cancer transcriptome with disease risk reveals novel mechanisms

Cited by 30 publications

References 74 publications

First comprehensive computational analysis of functional consequences of TMPRSS2 SNPs in susceptibility to SARS-CoV-2 among different populations

First comprehensive computational analysis of functional consequences of TMPRSS2 SNPs in susceptibility to SARS-CoV-2 among different populations

An integrative multi-omics analysis to identify candidate DNA methylation biomarkers related to prostate cancer risk

Iron: An Essential Element of Cancer Metabolism

Contact Info

Product

Resources

About