Germline and Somatic Genetic Variants in the p53 Pathway Interact to Affect Cancer Risk, Progression, and Drug Response

Zhang, Ping; Kitchen-Smith, Isaac; Xiong, Lingyun; Stracquadanio, Giovanni; Brown, Katherine A.; Richter, Philipp; Wallace, Marsha D; Bond, Elisabeth E.; Sahgal, Natasha; Moore, Samantha; Nornes, Svanhild; Val, Sarah De; Surakhy, Mirvat; Sims, David; Wang, Xuting; Bell, Douglas A.; Zerón-Medina, Jorge; Jiang, Yanyan; Ryan, Anderson J.; Selfe, Joanna; Shipley, Janet; Kar, Siddhartha; Pharoah, Paul D.P.; Loveday, Chey; Jansen, Rick; Grochola, Lukasz F.; Palles, Claire; Protheroe, Andrew; Millar, Val; Ebner, Daniel; Pagadala, Meghana; Blagden, Sarah P.; Maughan, Tim; Domingo, Enric; Tomlinson, Ian; Turnbull, Clare; Carter, Hannah; Bond, Gareth L.

doi:10.1158/0008-5472.can-20-0177

Cited by 33 publications

(20 citation statements)

References 68 publications

(63 reference statements)

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“…While germline variants are often found to increase the risk of tumor development, they are typically not sufficient to trigger cancer formation [ 124 , 125 ]. Accumulated somatic mutations on top of these germline variants often have more profound effects, such as conferring growth advantages that drive tumor formation [ 126 , 127 ]. Additional mechanisms to activate oncogenes include chromosomal translocations that place them under the control of previously unassociated enhancers, large deletions or rearrangements that connect them with upregulating elements, amplifications that can convert an individual enhancer into a super-enhancer, and more discreet mutations that constitutively activate regulatory regions [ 33 , 128 , 129 ].…”

Section: Discussionmentioning

confidence: 99%

Enhancer RNA Transcription Is Essential for a Novel CSF1 Enhancer in Triple-Negative Breast Cancer

Lewis

Wiśniewska

King

et al. 2022

Cancers

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Enhancers are critical regulatory elements in the genome that help orchestrate spatiotemporal patterns of gene expression during development and normal physiology. In cancer, enhancers are often rewired by various genetic and epigenetic mechanisms for the activation of oncogenes that lead to initiation and progression. A key feature of active enhancers is the production of non-coding RNA molecules called enhancer RNAs, whose functions remain unknown but can be used to specify active enhancers de novo. Using a combination of eRNA transcription and chromatin modifications, we have identified a novel enhancer located 30 kb upstream of Colony Stimulating Factor 1 (CSF1). Notably, CSF1 is implicated in the progression of breast cancer, is overexpressed in triple-negative breast cancer (TNBC) cell lines, and its enhancer is primarily active in TNBC patient tumors. Genomic deletion of the enhancer (via CRISPR/Cas9) enabled us to validate this regulatory element as a bona fide enhancer of CSF1 and subsequent cell-based assays revealed profound effects on cancer cell proliferation, colony formation, and migration. Epigenetic silencing of the enhancer via CRISPR-interference assays (dCas9-KRAB) coupled to RNA-sequencing, enabled unbiased identification of additional target genes, such as RSAD2, that are predictive of clinical outcome. Additionally, we repurposed the RNA-guided RNA-targeting CRISPR-Cas13 machinery to specifically degrade the eRNAs transcripts produced at this enhancer to determine the consequences on CSF1 mRNA expression, suggesting a post-transcriptional role for these non-coding transcripts. Finally, we test our eRNA-dependent model of CSF1 enhancer function and demonstrate that our results are extensible to other forms of cancer. Collectively, this work describes a novel enhancer that is active in the TNBC subtype, which is associated with cellular growth, and requires eRNA transcripts for proper enhancer function. These results demonstrate the significant impact of enhancers in cancer biology and highlight their potential as tractable targets for therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

Enhancer RNA Transcription Is Essential for a Novel CSF1 Enhancer in Triple-Negative Breast Cancer

Lewis

Wiśniewska

King

et al. 2022

Cancers

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“…Only an intersection between the LD block defined by our tranSNP rs760077 and association signal with gastric cancer (variant rs760077 and LD variants rs140081212, rs4072037) and breast cancer (LD variants rs2075570, rs2974935) was identified. We further explored the intersection between the tranSNPs and a set of GWAS-implicated cancer risk SNPs identified in 41 genes of the p53 response pathway, of which those mapping at KITLG , CDKN2A , and TEX9 genes were reported to potentially impact drug sensitivity ( Stracquadanio et al., 2016 ; Zhang et al., 2021 ). Given that MCF7 cells express wild-type p53 and that the doxorubicin or Nutlin treatments elicit a p53-dependent response, we were motivated to examine the potential overlap with our tranSNP list.…”

Section: Discussionmentioning

confidence: 99%

“…However, only 13 of those 41 GWAS-implicated cancer risk SNPs could be evaluated in our MCF7 RNA-seq data. They map at six genes ( CERSS , ISYNA1 , CFLAR , SESN1 , AKAP9 , CYP51A1 ) that were not reported to impact drug sensitivity ( Stracquadanio et al., 2016 ; Zhang et al., 2021 ). Finally, we considered the results of a very recent study where over 12,000 3′ UTR variants, including more than 2,000 disease-associated SNPs from the GWAS catalog, were cloned within 100-nt-long fragments and tested in a massively parallel reporter assay measuring relative RNA expression ( Griesemer et al., 2021 ).…”

Section: Discussionmentioning

confidence: 99%

TranSNPs: A class of functional SNPs affecting mRNA translation potential revealed by fraction-based allelic imbalance

et al. 2021

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Summary Few studies have explored the association between SNPs and alterations in mRNA translation potential. We developed an approach to identify SNPs that can mark allele-specific protein expression levels and could represent sources of inter-individual variation in disease risk. Using MCF7 cells under different treatments, we performed polysomal profiling followed by RNA sequencing of total or polysome-associated mRNA fractions and designed a computational approach to identify SNPs showing a significant change in the allelic balance between total and polysomal mRNA fractions. We identified 147 SNPs, 39 of which located in UTRs. Allele-specific differences at the translation level were confirmed in transfected MCF7 cells by reporter assays. Exploiting breast cancer data from TCGA we identified UTR SNPs demonstrating distinct prognosis features and altering binding sites of RNA-binding proteins. Our approach produced a catalog of tranSNPs , a class of functional SNPs associated with allele-specific translation and potentially endowed with prognostic value for disease risk.

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“…She completed her PhD at the University of Nottingham in 2014, with a focus on identifying and characterizing ancient viral elements in the DNA of modern primates and rodents [ 38 , 39 ]. She went on to complete the MRC Computational Genomics Analysis and Training (CGAT) fellowship program [ 40 ] at the University of Oxford, collaborating on a series of projects focused on human disease [ 41 ]. She also has a BSc.…”

Section: Women In the Evbcmentioning

confidence: 99%

Women in the European Virus Bioinformatics Center

Hufsky

Abecasis

Patrícia

et al. 2022

Viruses

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Viruses are the cause of a considerable burden to human, animal and plant health, while on the other hand playing an important role in regulating entire ecosystems. The power of new sequencing technologies combined with new tools for processing “Big Data” offers unprecedented opportunities to answer fundamental questions in virology. Virologists have an urgent need for virus-specific bioinformatics tools. These developments have led to the formation of the European Virus Bioinformatics Center, a network of experts in virology and bioinformatics who are joining forces to enable extensive exchange and collaboration between these research areas. The EVBC strives to provide talented researchers with a supportive environment free of gender bias, but the gender gap in science, especially in math-intensive fields such as computer science, persists. To bring more talented women into research and keep them there, we need to highlight role models to spark their interest, and we need to ensure that female scientists are not kept at lower levels but are given the opportunity to lead the field. Here we showcase the work of the EVBC and highlight the achievements of some outstanding women experts in virology and viral bioinformatics.

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Germline and Somatic Genetic Variants in the p53 Pathway Interact to Affect Cancer Risk, Progression, and Drug Response

Abstract: and somatic genetic variants in the p53 pathway interact to affect cancer risk, progression and drug response', Cancer Research.

Cited by 33 publications

References 68 publications

Enhancer RNA Transcription Is Essential for a Novel CSF1 Enhancer in Triple-Negative Breast Cancer

Enhancer RNA Transcription Is Essential for a Novel CSF1 Enhancer in Triple-Negative Breast Cancer

TranSNPs: A class of functional SNPs affecting mRNA translation potential revealed by fraction-based allelic imbalance

Women in the European Virus Bioinformatics Center

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