PXD029522

PXD029522 is an original dataset announced via ProteomeXchange.

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

Revision	Datetime	Status	ChangeLog Entry
0	2021-11-02 07:24:55	ID requested
⏵ 1	2022-03-14 05:04:05	announced

Dataset with its publication pending

submitter keyword: PAX8, renal cell carcinoma, HIF2A, lineage factors

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

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2022/03/PXD029522

PRIDE project URI

• PRIDE
  1. PXD029522
     1. Label: PRIDE project
     2. Name: Lineage factor-dependent signalling by kidney cancer-associated genetic alteration