Type II Transmembrane Serine Protease Gene Variants Associate with Breast Cancer

Luostari, Kaisa; Hartikainen, Jaana M.; Tengström, Maria; Palvimo, Jorma J.; Kataja, Vesa; Mannermaa, Arto; Kosma, Veli‐Matti

doi:10.1371/journal.pone.0102519

Cited by 26 publications

(26 citation statements)

References 47 publications

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“…For example, genetic polymorphisms exist in the ACE2 gene [2], which encodes the cellular receptor for SARS-CoV-2; allelic variants of the ACE2 may influence the protein's binding with the virus [3] and subsequent invasion of the cell. In addition, polymorphisms of cellular proteases-believed to facilitate the entry of SARS-CoV-2 into the cell, along with furin [4] and TMPRSS2 [5]-have been shown to exist [6,7]. Indeed, a recent preprint suggests that TMPRSS2 variants and resulting expression may influence COVID-19 severity [8].…”

Section: Genomics Of Susceptibility and Resistancementioning

confidence: 99%

COVID-19 vulnerability: the potential impact of genetic susceptibility and airborne transmission

et al. 2020

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The recent coronavirus disease , caused by SARS-CoV-2, is inarguably the most challenging coronavirus outbreak relative to the previous outbreaks involving SARS-CoV and MERS-CoV. With the number of COVID-19 cases now exceeding 2 million worldwide, it is apparent that (i) transmission of SARS-CoV-2 is very high and (ii) there are large variations in disease severity, one component of which may be genetic variability in the response to the virus. Controlling current rates of infection and combating future waves require a better understanding of the routes of exposure to SARS-CoV-2 and the underlying genomic susceptibility to this disease. In this mini-review, we highlight possible genetic determinants of COVID-19 and the contribution of aerosol exposure as a potentially important transmission route of SARS-CoV-2.

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Section: Genomics Of Susceptibility and Resistancementioning

confidence: 99%

COVID-19 vulnerability: the potential impact of genetic susceptibility and airborne transmission

et al. 2020

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“…Studies into TMPRSS2 single‐nucleotide polymorphisms (SNPs) have been conducted in various diseases. In breast cancer, the minor allele for rs2276205 (A>G) was associated with increased survival, potentially due to sensitization to tamoxifen 12 . In prostate cancer, the most studied disease in relation to TMPRSS2 , rs12329760 (C>T) was associated with cancer in men with a family history of prostate cancer, multiple copies of the ERG gene fusion, and in whites with a doubled time to cancer diagnosis 13,14 .…”

Section: Tmprss2 Single‐nucleotide Polymorphisms As Biomarkers Of Dismentioning

confidence: 99%

TMPRSS2: Potential Biomarker for COVID‐19 Outcomes

Strope

Chau

Figg

2020

The Journal of Clinical Pharma

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Coronavirus disease 2019 (COVID-19) clinical data has so far shown that the mortality rate for men is higher than for women. This disparity is observed worldwide and across different ethnic/racial groups (Table 1). Early reports from Italy and Germany show that while infection rates are similar between sexes, nearly 70% and 65%, respectively, of deaths are males. In New York City, an epicenter of the US outbreak, 54% of those infected are men, yet men account for 63% of deaths. Epidemiologic data from the previous coronavirus infections, severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS), also indicated sex-based differences in disease susceptibility and outcomes. This discrepancy was attributed to many factors, including smoking, immune differences, and other comorbidities. An initial report released by the Centers for Disease Control and Prevention (CDC) on population-based surveillance sampled across 14 states, representing 10% of the US population, has indicated that age and comorbidities are associated with increased hospitalization rates of patients with COVID-19. 1 The data on sex also suggest sexual dimorphism consistent with reports from other countries (Table 1). The preliminary data on race suggest that minority populations may be disproportionately impacted by the coronavirus, where blacks contributed to 33% of the hospitalizations despite representing only 18% of the sampled population. As more data become available, correlations between race and disease severity can be interrogated more thoroughly, including the role of socioeconomic factors on influencing this disparity. Investigations into the genetic and molecular differences between women and men are warranted to identify relevant biomarkers for disease susceptibility and outcomes. Based on data from literature, we propose a novel mechanism of the observed sex differences in clinical outcomes in patients and identify a role for the transmembrane protease serine 2 (TMPRSS2) as a contributing factor to the more severe outcomes noted for COVID-19. TMPRSS2 Expression as a Biomarker of Clinical OutcomesThe angiotensin I-converting enzyme 2 (ACE2) and TMPRSS2 have been implicated in influenza and SARS-corona virus (CoV) infection as well as for SARS-CoV-2 in mediating viral entry into the host cell. 2 Both genes mediate sex-specific effects with ACE2, located on the X chromosome and TMPRSS2 regulated by androgen (located on 21q22.3). While ACE2 is the main receptor for the spike protein for both viruses, its expression and gene polymorphisms did not influence sex-specific effects or outcomes for SARS 3 or COVID-19 (based on 2 recent preprint studies published on medRxiv that have yet to be peerreviewed at the time of writing). 4,5 TMPRSS2 is an androgen-responsive serine protease that cleaves SARS-CoV-2 spike protein, facili-

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“…In some instances, a common enhancer spatially co-regulates multiple genes through looping interactions with the promoters of each gene 57,[64][65][66][67][68] . In MB157 and HCC1599 TNBC cells, Notch activation promotes looping interactions involved in spatial co-regulation of the kinase RIPK4 and the serine protease TMPRSS2 ( Figures 3J and S3H), both of which are implicated in breast cancer pathogenicity [69][70][71][72][73] . Based on normalized contact tracks ( Figures 3J and S3H), Notch activation significantly increased transcript abundance and contact frequency of RIPK4 and TMPRSS2 promoters to common Notch-bound and -activated enhancers, located 155 and 150 Kb away, respectively.…”

Section: Notch-promoted and Preformed Enhancer-promoter Contacts Regumentioning

confidence: 99%

Oncogenic Notch promotes long-range regulatory interactions within hyperconnected 3D cliques

Petrovix

Zhou

Fasolino

et al. 2019

Preprint

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Chromatin loops enable transcription factor-bound distal enhancers to interact with their target promoters to regulate transcriptional programs. Although developmental transcription factors, such as active forms of Notch, can directly stimulate transcription by activating enhancers, the effect of their oncogenic subversion on the 3-dimensional (3D) organization of the cancer genome is largely undetermined. By mapping chromatin looping genome-wide in Notch-dependent triplenegative breast cancer and B-cell lymphoma, we show that far beyond the well-characterized role of Notch as an activator of distal enhancers, Notch regulates its direct target genes through establishing new long-range regulatory interactions. Moreover, a large fraction of Notch-promoted regulatory loops forms highly interacting enhancer and promoter spatial clusters, termed "3D cliques". Loss-and gain-of-function experiments show that Notch preferentially targets hyperconnected 3D cliques that regulate the expression of crucial proto-oncogenes. Our observations suggest that oncogenic hijacking of developmental transcription factors can dysregulate transcription through widespread effects on the spatial organization of cancer genomes.

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Type II Transmembrane Serine Protease Gene Variants Associate with Breast Cancer

Cited by 26 publications

References 47 publications

COVID-19 vulnerability: the potential impact of genetic susceptibility and airborne transmission

COVID-19 vulnerability: the potential impact of genetic susceptibility and airborne transmission

TMPRSS2: Potential Biomarker for COVID‐19 Outcomes

Oncogenic Notch promotes long-range regulatory interactions within hyperconnected 3D cliques

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