<i>HNF1B</i> variants associate with promoter methylation and regulate gene networks activated in prostate and ovarian cancer

Ross-Adams, Helen; Ball, Stephen G.; Lawrenson, Kate; Halim, Silvia; Russell, Roslin; Wells, Claire M.; Strand, Siri H.; Ørntoft, Torben F.; Larson, Melissa C.; Armasu, Sebastian M.; Massie, Charles E.; Asim, Mohammad; Mortensen, Martin M.; Borre, Michael; Woodfine, Kathryn; Warren, Anne Y.; Lamb, Alastair; Kay, Jonathan; Whitaker, Hayley C.; Ramos-Montoya, Antonio; Murrell, Adele; Sørensen, Karina Dalsgaard; Fridley, Brooke L.; Goode, Ellen L.; Gayther, Simon A.; Masters, J; Neal, David E.; Mills, Ian G.

doi:10.18632/oncotarget.12543

Cited by 38 publications

(52 citation statements)

References 46 publications

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“…EMT properties are also seen in cells under stress imbued by tumor microenvironment resulting in methylation dysregulation potentially contributing to a tumor promoting role. Thus, unmethylated HNF1B appears to act as an oncogene in CCOC, but when hypermethylated, acts like a tumor suppressor in the more aggressive HGSOC histotype [75]. This study provides an excellent example the complexity of genomic and epigenetics in EOC.…”

Section: Dna Methylation Analyses In Eocmentioning

confidence: 99%

“…Interestingly, while HNF1B is overexpressed in CCOC, it is methylated in ∼50% of HGSOC [12,19]. A variant in HNF1B was identified as an HGSOC susceptibility locus [74] and recently Ross–Adams et al [75] reported that the susceptibility allele was associated with HNF1B promoter methylation. This methylation, upstream of the transcription start site, also bears hallmarks of poised and active enhancers (H3K27Ac, H3K4me1 and H3K3Me3 histone marks).…”

Section: Dna Methylation Analyses In Eocmentioning

confidence: 99%

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Epigenetics in ovarian cancer

Natanzon

Goode

Cunningham

2018

Seminars in Cancer Biology

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Ovarian cancer is a disease with a poor prognosis and little progress has been made to improve treatment. It is now recognized that there are several histotypes of ovarian cancer, each with distinct epidemiologic and genomic characteristics. Cancer therapy is moving beyond classical chemotherapy to include epigenetic approaches. Epigenetics is the dynamic regulation of gene expression by DNA methylation and histone post translational modification in response to environmental cues. Improvement in technology to study DNA methylation has enabled a more agnostic approach and, with larger samples sets, has begun to unravel how epigenetics contributes to the etiology, response to chemotherapy and prognosis in of ovarian cancer. Investigations into histone modifications in ovarian cancer are more nascent. Much more is needed to be done to fully realize the potential that epigenetics holds for ovarian cancer clinical care.

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Section: Dna Methylation Analyses In Eocmentioning

confidence: 99%

Section: Dna Methylation Analyses In Eocmentioning

confidence: 99%

Epigenetics in ovarian cancer

Natanzon

Goode

Cunningham

2018

Seminars in Cancer Biology

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“…Previous studies suggest that DNA methylation is responsible for modulating gene expression that ultimately affects morphological changes in PCa cells and e pithelial-to- m esenchymal t ransition (EMT) [55–57]. This is especially important in PCa, as PCa cells frequently adopt an EMT phenotype [58–60].…”

Section: A Jack Of All Trades: the Multifaceted Functions Of Kaiso Inmentioning

confidence: 99%

Dancing from bottoms up – Roles of the POZ-ZF transcription factor Kaiso in Cancer

Pierre

Hercules

Yates

et al. 2019

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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The POZ-ZF transcription factor Kaiso was discovered two decades ago as a binding partner for p120ctn. Since its discovery, roles for Kaiso in diverse biological processes (epithelial-to-mesenchymal transition, apoptosis, inflammation) and several signalling pathways (Wnt/β-catenin, TGFβ, EGFR, Notch) have emerged. While Kaiso’s biological role in normal tissues has yet to be fully elucidated, Kaiso has been increasingly implicated in multiple human cancers including colon, prostate, ovarian lung, breast and chronic myeloid leukemia. In the majority of human cancers investigated to date, high Kaiso expression correlates with aggressive tumor characteristics including proliferation and metastasis, and/or poor prognosis. More recently, interest in Kaiso stems from its apparent correlation with racial disparities in breast and prostate cancer incidence and survival outcomes in people of African Ancestry. This review discusses Kaiso’s role in various cancers, and Kaiso’s potential for driving racial disparities in incidence and/or outcomes in people of African ancestry.

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“…Next, we performed a transcriptome-wide association study (TWAS) using diverse gene expression models and GWAS statistics from 13,037 HGSOC cases and 40,941 controls estimated by the Ovarian Cancer Association Consortium (OCAC). We first constructed the predictive models of gene expression and splicing using genotypes and expression from the EOC precursor and HGSOC expression data described above, as well as tumor datasets for other hormonally-regulated cancers (breast and prostate cancers) that have recently been shown known to exhibit genetic pleiotropy with EOC: Breast tumors (n = 1,027) with matched normal precursor tissues (n = 80); and prostate tumors (n = 483) (5,12,31). All data sets were assayed by RNA-seq.…”

Section: Resultsmentioning

confidence: 99%

Multi-Tissue Transcriptome-Wide Association Study Identifies 26 Novel Candidate Susceptibility Genes for High Grade Serous Epithelial Ovarian Cancer

Gusev

Lawrenson

Segato

et al. 2018

Preprint

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Genome-wide association studies (GWASs) have identified about 30 different susceptibility loci associated with high grade serous ovarian cancer (HGSOC) risk. We sought to identify potential susceptibility genes by integrating the risk variants at these regions with genetic variants impacting gene expression and splicing of nearby genes. We compiled gene expression and genotyping data from 2,169 samples for 6 different HGSOC-relevant tissue types. We integrated these data with GWAS data from 13,037 HGSOC cases and 40,941 controls, and performed a transcriptome-wide association study (TWAS) across >70,000 significantly heritable gene/exon features. We identified 24 transcriptome-wide significant associations for 14 unique genes, plus 90 significant exon-level associations in 20 unique genes. We implicated multiple novel genes at risk loci, e.g. LRRC46 at 19q21.32 (TWAS P=1×10−9) and a PRC1 splicing event (TWAS P=9×10−8) which was splice-variant specific and exhibited no eQTL signal. Functional analyses in HGSOC cell lines found evidence of essentiality for GOSR2, INTS1, KANSL1 and PRC1; with the latter gene showing levels of essentiality comparable to that of MYC. Overall, gene expression and splicing events explained 41% of SNP-heritability for HGSOC (s.e. 11%, P=2.5×10−4), implicated at least one target gene for 6/13 distinct genome-wide significant regions and revealed 2 known and 26 novel candidate susceptibility genes for HGSOC.STATEMENT OF SIGNIFICANCEFor many ovarian cancer risk regions, the target genes regulated by germline genetic variants are unknown. Using expression data from >2,100 individuals, this study identified novel associations of genes and splicing variants with ovarian cancer risk; with transcriptional variation now explaining over one-third of the SNP-heritability for this disease.

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HNF1B variants associate with promoter methylation and regulate gene networks activated in prostate and ovarian cancer

Cited by 38 publications

References 46 publications

Epigenetics in ovarian cancer

Epigenetics in ovarian cancer

Dancing from bottoms up – Roles of the POZ-ZF transcription factor Kaiso in Cancer

Multi-Tissue Transcriptome-Wide Association Study Identifies 26 Novel Candidate Susceptibility Genes for High Grade Serous Epithelial Ovarian Cancer

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