PXD029522 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Lineage factor-dependent signalling by kidney cancer-associated genetic alteration |
Description | As shown by large-scale human genetic data, cancer mutations display strong tissue-selectivity, but how this selectivity arises remains unclear. Here, using experimental models, functional genomics and analysis of patient samples, we demonstrate that the lineage transcription factor paired box 8 (PAX8) is required for oncogenic signalling by two common clear cell renal cell carcinoma (ccRCC)-causing genetic alterations in humans: the germline variant rs7948643 at 11q13.3 and somatic inactivation of the von Hippel-Lindau tumour suppressor (VHL). VHL loss, observed in ~90% of ccRCCs, can lead to hypoxia-inducible factor 2 alpha (HIF2A) stabilization. We show that HIF2A is preferentially recruited to PAX8-bound transcriptional enhancers, including a pro-tumorigenic cyclin D1 (CCND1) enhancer that is controlled by PAX8 and HIF2A. The ccRCC protective allele C at rs7948643 inhibits PAX8 binding at this enhancer and downstream activation of CCND1 expression. Co-option of a PAX8-dependent physiological programme that supports proliferation of normal renal epithelial cells is also required for MYC expression from the ccRCC metastasis-associated amplicons at 8q21.3-q24.3. These results demonstrate that transcriptional lineage factors are essential for the expression of canonical oncogenes and they mediate tissue-specific cancer risk associated with somatic and inherited genetic variants |
HostingRepository | PRIDE |
AnnounceDate | 2022-03-14 |
AnnouncementXML | Submission_2022-03-14_05:04:05.104.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Evangelia Papachristou |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | monohydroxylated residue; deamidated residue |
Instrument | Q Exactive |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2021-11-02 07:24:55 | ID requested | |
⏵ 1 | 2022-03-14 05:04:05 | announced | |
Publication List
Dataset with its publication pending |
Keyword List
submitter keyword: PAX8, renal cell carcinoma, HIF2A, lineage factors |
Contact List
Sakari Vanharanta |
contact affiliation | MRC Cancer Unit, University of Cambridge; Hutchison/MRCResearch Centre, Box 197, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK |
contact email | sv358@cam.ac.uk |
lab head | |
Evangelia Papachristou |
contact affiliation | Senior Scientific Assistant |
contact email | Eva.Papachristou@cruk.cam.ac.uk |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD029522
- Label: PRIDE project
- Name: Lineage factor-dependent signalling by kidney cancer-associated genetic alteration