Journal article
Transcriptome- and proteome-wide association studies identify genes associated with renal cell carcinoma
American journal of human genetics, Vol.111(9), pp.1864-1876
09/05/2024
DOI: 10.1016/j.ajhg.2024.07.012
PMCID: PMC11393681
PMID: 39137781
Abstract
We performed a series of integrative analyses including transcriptome-wide association studies (TWASs) and proteome-wide association studies (PWASs) of renal cell carcinoma (RCC) to nominate and prioritize molecular targets for laboratory investigation. On the basis of a genome-wide association study (GWAS) of 29,020 affected individuals and 835,670 control individuals and prediction models trained in transcriptomic reference models, our TWAS across four kidney transcriptomes (GTEx kidney cortex, kidney tubules, TCGA-KIRC [The Cancer Genome Atlas kidney renal clear-cell carcinoma], and TCGA-KIRP [TCGA kidney renal papillary cell carcinoma]) identified 38 gene associations (false-discovery rate <5%) in at least two of four transcriptomic panels and identified 12 genes that were independent of GWAS susceptibility regions. Analyses combining TWAS associations across 48 tissues from GTEx identified associations that were replicable in tumor transcriptomes for 23 additional genes. Analyses by the two major histologic types (clear-cell RCC and papillary RCC) revealed subtype-specific associations, although at least three gene associations were common to both subtypes. PWAS identified 13 associated proteins, all mapping to GWAS-significant loci. TWAS-identified genes were enriched for active enhancer or promoter regions in RCC tumors and hypoxia-inducible factor binding sites in relevant cell lines. Using gene expression correlation, common cancers (breast and prostate) and RCC risk factors (e.g., hypertension and BMI) display genetic contributions shared with RCC. Our work identifies potential molecular targets for RCC susceptibility for downstream functional investigation.
We conducted a series of integrative analyses, including transcriptome-wide and proteome-wide association studies, to identify and prioritize genes and proteins for renal cell carcinoma (RCC) and its two major histologic subtypes. We establish relevance of the findings in relation to known genomic features, transcription factors, and risk factors for RCC.
Details
- Title: Subtitle
- Transcriptome- and proteome-wide association studies identify genes associated with renal cell carcinoma
- Creators
- Diptavo Dutta - National Cancer InstituteKenneth G. NeppleRenal Cancer Genetics ConsortiumXinyu Guo - University of Southern CaliforniaTimothy D. Winter - National Cancer InstituteOm Jahagirdar - National Cancer InstituteMark P. Purdue - National Cancer InstituteMitchell J. Machiela - National Cancer InstituteBryan R. GormanDayne OkuharaSara ClelandAida Ferreiro-IglesiasPaul ScheetAoxing LiuChao WuSamuel O. AntwiJames LarkinStênio C. ZequiMaxine SunKeiko HikinoAli HajiranKeith A. LawsonFlavio CárcanoOdile BlanchetBrian ShuchGaëlle MargueDebasish SundiW. Ryan DiverMaria A.A.K. FolgueiraAdrie van BokhovenFlorencia NeffaKevin M. BrownJonathan N. HofmannJongeun RheeMeredith YeagerNathan R. ColeBelynda D. HicksMichelle R. ManningAmy A. HutchinsonNathaniel RothmanWen-Yi HuangW. Marston LinehanAdriana LoriMatthieu FerraguMerzouka Zidane-MarinnesSérgio SerranoWesley J. MagnaboscoBioBank Japan Project ConsortiumAna VilasRicardo DeciaFlorencia CarussoLaura S. GrahamKyra AndersonMehmet A. BilenCletus ArcieroIsabelle PellegrinSolène RicardFinnGenGhislaine SceloRosamonde E. BanksNaveen S. VasudevNaeem SoomroGrant D. StewartAdebanji AdeyojuStephen BromageDavid HroudaNorma GibbonsPoulam PatelMark SullivanAndrew ProtheroeFrancesca I. NugentMichelle J. FournierXiaoyu ZhangLisa J. MartinMaria KomisarenkoTimothy EisenSonia A. CunninghamDenise C. ConnollyRobert G. UzzoDavid ZaridzeAnush MukeriaIvana HolcatovaAnna HornakovaLenka ForetovaVladimir JanoutDana MatesViorel JingaStefan RascuMirjana MijuskovicSlavisa SavicSasa MilosavljevicValérie GaborieauBehnoush Abedi-ArdekaniJames McKayMattias JohanssonLarry PhouthavongsyLindsay HaymanJason LiIlinca LunguStephania M. BezerraAline G. de SouzaClaudia T.G. SaresRodolfo B. ReisFabio P. GallucciMauricio D. CordeiroMark PomerantzGwo-Shu M. LeeMatthew L. FreedmanAnhyo JeongSamantha E. GreenbergAlejandro SanchezR. Houston ThompsonVidit SharmaDavid D. ThielColleen T. BallDiego AbreuElaine T. LamWilliam C. NahasViraj A. MasterAlpa V. PatelJean-Christophe BernhardNeal D. FreedmanPierre BigotRui M. ReisLeandro M. ColliAntonio FinelliBrandon J. ManleyChikashi TeraoToni K. ChoueiriDirce M. CarraroRichard HoulstonJeanette E. Eckel-PassowPhilip H. AbboshAndrea GannaPaul BrennanJian GuStephen J. ChanockEunji Ha - University of PennsylvaniaKatalin Susztak - University of PennsylvaniaMitchell J. Machiela - National Cancer Institute
- Resource Type
- Journal article
- Publication Details
- American journal of human genetics, Vol.111(9), pp.1864-1876
- DOI
- 10.1016/j.ajhg.2024.07.012
- PMID
- 39137781
- PMCID
- PMC11393681
- NLM abbreviation
- Am J Hum Genet
- ISSN
- 0002-9297
- eISSN
- 1537-6605
- Publisher
- Elsevier Inc; CAMBRIDGE
- Grant note
- National Institute of Diabetes and Digestive and Kidney Diseases: R01DK087635
The current analysis was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services. "K.S and E.H. were supported by National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK087635."
- Language
- English
- Electronic publication date
- 08/12/2024
- Date published
- 09/05/2024
- Academic Unit
- Urology
- Record Identifier
- 9984696860502771
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