Pathogenic Germline Variants in 10,389 Adult Cancers

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dc.contributorSistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.authorHUANG, Kuan-lin
dc.contributor.authorMASHL, R. Jay
dc.contributor.authorWU, Yige
dc.contributor.authorRITTER, Deborah I.
dc.contributor.authorWANG, Jiayin
dc.contributor.authorOH, Clara
dc.contributor.authorPACZKOWSKA, Marta
dc.contributor.authorREYNOLDS, Sheila
dc.contributor.authorWYCZALKOWSKI, Matthew A.
dc.contributor.authorOAK, Ninad
dc.contributor.authorSCOTT, Adam D.
dc.contributor.authorKRASSOWSKI, Michal
dc.contributor.authorCHERNIACK, Andrew D.
dc.contributor.authorHOULAHAN, Kathleen E.
dc.contributor.authorJAYASINGHE, Reyka
dc.contributor.authorWANG, Liang-Bo
dc.contributor.authorZHOU, Daniel Cui
dc.contributor.authorLIU, Di
dc.contributor.authorCAO, Song
dc.contributor.authorKIM, Young Won
dc.contributor.authorKOIRE, Amanda
dc.contributor.authorMCMICHAEL, Joshua F.
dc.contributor.authorHUCTHAGOWDER, Vishwanathan
dc.contributor.authorKIM, Tae-Beom
dc.contributor.authorHAHN, Abigail
dc.contributor.authorWANG, Chen
dc.contributor.authorMCLELLAN, Michael D.
dc.contributor.authorAL-MULLA, Fahd
dc.contributor.authorJOHNSON, Kimberly J.
dc.contributor.authorLICHTARGE, Olivier
dc.contributor.authorBOUTROS, Paul C.
dc.contributor.authorRAPHAEL, Benjamin
dc.contributor.authorLAZAR, Alexander J.
dc.contributor.authorZHANG, Wei
dc.contributor.authorWENDL, Michael C.
dc.contributor.authorGOVINDAN, Ramaswamy
dc.contributor.authorJAIN, Sanjay
dc.contributor.authorWHEELER, David
dc.contributor.authorKULKARNI, Shashikant
dc.contributor.authorDIPERSIO, John F.
dc.contributor.authorREIMAND, Juri
dc.contributor.authorMERIC-BERNSTAM, Funda
dc.contributor.authorCHEN, Ken
dc.contributor.authorSHMULEVICH, Ilya
dc.contributor.authorPLON, Sharon E.
dc.contributor.authorCHEN, Feng
dc.contributor.authorDING, Li
dc.contributor.groupauthorCanc Genome Atlas Res Network
dc.contributor.groupauthorLONGATTO-FILHO, Adhemar
dc.date.accessioned2019-01-17T13:37:10Z
dc.date.available2019-01-17T13:37:10Z
dc.date.issued2018
dc.description.abstractWe conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer.eng
dc.description.indexMEDLINEeng
dc.description.sponsorship[U54 HG003273]
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dc.description.sponsorship[R01 CA180006]
dc.description.sponsorship[R01 HG009711]
dc.identifier.citationCELL, v.173, n.2, p.355-370.e14, 2018
dc.identifier.doi10.1016/j.cell.2018.03.039
dc.identifier.eissn1097-4172
dc.identifier.issn0092-8674
dc.identifier.urihttps://observatorio.fm.usp.br/handle/OPI/30106
dc.language.isoeng
dc.publisherCELL PRESSeng
dc.relation.ispartofCell
dc.rightsopenAccesseng
dc.rights.holderCopyright CELL PRESSeng
dc.subject.otherpredisposition geneseng
dc.subject.othermutationseng
dc.subject.otherkinaseeng
dc.subject.otherdiscoveryeng
dc.subject.otherbrca1eng
dc.subject.otherprotooncogeneeng
dc.subject.otherguidelineseng
dc.subject.othercarcinomaeng
dc.subject.othergenomicseng
dc.subject.otherexomeseng
dc.subject.wosBiochemistry & Molecular Biologyeng
dc.subject.wosCell Biologyeng
dc.titlePathogenic Germline Variants in 10,389 Adult Cancerseng
dc.typearticleeng
dc.type.categoryoriginal articleeng
dc.type.versionpublishedVersioneng
dspace.entity.typePublication
hcfmusp.affiliation.countryKuwait
hcfmusp.affiliation.countryEstados Unidos
hcfmusp.affiliation.countryChina
hcfmusp.affiliation.countryCanadá
hcfmusp.affiliation.countryisous
hcfmusp.affiliation.countryisocn
hcfmusp.affiliation.countryisoca
hcfmusp.affiliation.countryisokw
hcfmusp.author.externalHUANG, Kuan-lin:Washington Univ, Dept Med, St Louis, MO 63108 USA; Washington Univ, McDonnell Genome Inst, St Louis, MO 63108 USA
hcfmusp.author.externalMASHL, R. Jay:Washington Univ, Dept Med, St Louis, MO 63108 USA; Washington Univ, McDonnell Genome Inst, St Louis, MO 63108 USA
hcfmusp.author.externalWU, Yige:Washington Univ, Dept Med, St Louis, MO 63108 USA; Washington Univ, McDonnell Genome Inst, St Louis, MO 63108 USA
hcfmusp.author.externalRITTER, Deborah I.:Baylor Coll Med, Houston, TX 77030 USA; Texas Childrens Hosp, Houston, TX 77030 USA
hcfmusp.author.externalWANG, Jiayin:Xi An Jiao Tong Univ, Sch Management, Xian, Shanxi, Peoples R China
hcfmusp.author.externalOH, Clara:Washington Univ, Dept Med, St Louis, MO 63108 USA
hcfmusp.author.externalPACZKOWSKA, Marta:Ontario Inst Canc Res, Computat Biol Program, Toronto, ON, Canada
hcfmusp.author.externalREYNOLDS, Sheila:Inst Syst Biol, Seattle, WA 98109 USA
hcfmusp.author.externalWYCZALKOWSKI, Matthew A.:Washington Univ, Dept Med, St Louis, MO 63108 USA; Washington Univ, McDonnell Genome Inst, St Louis, MO 63108 USA
hcfmusp.author.externalOAK, Ninad:Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA
hcfmusp.author.externalSCOTT, Adam D.:Washington Univ, Dept Med, St Louis, MO 63108 USA; Washington Univ, McDonnell Genome Inst, St Louis, MO 63108 USA
hcfmusp.author.externalKRASSOWSKI, Michal:Ontario Inst Canc Res, Computat Biol Program, Toronto, ON, Canada
hcfmusp.author.externalCHERNIACK, Andrew D.:Broad Inst, Cambridge, MA 02142 USA
hcfmusp.author.externalHOULAHAN, Kathleen E.:Ontario Inst Canc Res, Computat Biol Program, Toronto, ON, Canada; Univ Toronto, Dept Med Biophys, Toronto, ON, Canada
hcfmusp.author.externalJAYASINGHE, Reyka:Washington Univ, Dept Med, St Louis, MO 63108 USA; Washington Univ, McDonnell Genome Inst, St Louis, MO 63108 USA
hcfmusp.author.externalWANG, Liang-Bo:Washington Univ, Dept Med, St Louis, MO 63108 USA; Washington Univ, McDonnell Genome Inst, St Louis, MO 63108 USA
hcfmusp.author.externalZHOU, Daniel Cui:Washington Univ, Dept Med, St Louis, MO 63108 USA; Washington Univ, McDonnell Genome Inst, St Louis, MO 63108 USA
hcfmusp.author.externalLIU, Di:Washington Univ, Dept Med, St Louis, MO 63108 USA
hcfmusp.author.externalCAO, Song:Washington Univ, Dept Med, St Louis, MO 63108 USA; Washington Univ, McDonnell Genome Inst, St Louis, MO 63108 USA
hcfmusp.author.externalKIM, Young Won:Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA
hcfmusp.author.externalKOIRE, Amanda:Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA
hcfmusp.author.externalMCMICHAEL, Joshua F.:Washington Univ, McDonnell Genome Inst, St Louis, MO 63108 USA
hcfmusp.author.externalHUCTHAGOWDER, Vishwanathan:Mol Pathology Lab Network Inc, Clin Cytogenet, Maryville, TN 37804 USA
hcfmusp.author.externalKIM, Tae-Beom:Univ Texas MD Anderson Canc Ctr, Dept Bioinformat, Houston, TX 77030 USA; Univ Texas MD Anderson Canc Ctr, Dept Computat Biol, Houston, TX 77030 USA
hcfmusp.author.externalHAHN, Abigail:Inst Syst Biol, Seattle, WA 98109 USA
hcfmusp.author.externalWANG, Chen:Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN 55905 USA; Mayo Clin, Coll Med, Dept Obstet & Gynecol, Rochester, MN 55905 USA
hcfmusp.author.externalMCLELLAN, Michael D.:Washington Univ, McDonnell Genome Inst, St Louis, MO 63108 USA
hcfmusp.author.externalAL-MULLA, Fahd:Kuwait Univ, Dasman Diabet Inst, Kuwait, Kuwait; Kuwait Univ, Mol Pathol Lab, Kuwait, Kuwait
hcfmusp.author.externalJOHNSON, Kimberly J.:Washington Univ, Brown Sch Master Publ Hlth Program, St Louis, MO 63108 USA
hcfmusp.author.externalLICHTARGE, Olivier:Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA
hcfmusp.author.externalBOUTROS, Paul C.:Ontario Inst Canc Res, Computat Biol Program, Toronto, ON, Canada; Univ Toronto, Dept Med Biophys, Toronto, ON, Canada
hcfmusp.author.externalRAPHAEL, Benjamin:Princeton Univ, Lewis Sigler Inst, Princeton, NJ 08544 USA
hcfmusp.author.externalLAZAR, Alexander J.:Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA; Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Houston, TX 77030 USA
hcfmusp.author.externalZHANG, Wei:Wake Forest Sch Med, Dept Canc Biol, Winston Salem, NC 27157 USA; Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC 27157 USA
hcfmusp.author.externalWENDL, Michael C.:Washington Univ, McDonnell Genome Inst, St Louis, MO 63108 USA; Washington Univ, Dept Genet, St Louis, MO 63108 USA; Washington Univ, Dept Math, St Louis, MO 63108 USA
hcfmusp.author.externalGOVINDAN, Ramaswamy:Washington Univ, Dept Med, St Louis, MO 63108 USA
hcfmusp.author.externalJAIN, Sanjay:Washington Univ, Dept Med, St Louis, MO 63108 USA
hcfmusp.author.externalWHEELER, David:Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA
hcfmusp.author.externalKULKARNI, Shashikant:Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA; Baylor Genet, Houston, TX 77021 USA
hcfmusp.author.externalDIPERSIO, John F.:Washington Univ, Dept Med, St Louis, MO 63108 USA; Washington Univ, Siteman Canc Ctr, St Louis, MO 63108 USA
hcfmusp.author.externalREIMAND, Juri:Ontario Inst Canc Res, Computat Biol Program, Toronto, ON, Canada; Univ Toronto, Dept Med Biophys, Toronto, ON, Canada
hcfmusp.author.externalMERIC-BERNSTAM, Funda:Univ Texas MD Anderson Canc Ctr, Dept Invest Canc Therapeut, Houston, TX 77030 USA
hcfmusp.author.externalCHEN, Ken:Univ Texas MD Anderson Canc Ctr, Dept Bioinformat, Houston, TX 77030 USA; Univ Texas MD Anderson Canc Ctr, Dept Computat Biol, Houston, TX 77030 USA
hcfmusp.author.externalSHMULEVICH, Ilya:Inst Syst Biol, Seattle, WA 98109 USA
hcfmusp.author.externalPLON, Sharon E.:Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA; Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA
hcfmusp.author.externalCHEN, Feng:Washington Univ, Dept Med, St Louis, MO 63108 USA; Washington Univ, Siteman Canc Ctr, St Louis, MO 63108 USA
hcfmusp.author.externalDING, Li:Washington Univ, Dept Med, St Louis, MO 63108 USA; Washington Univ, McDonnell Genome Inst, St Louis, MO 63108 USA; Washington Univ, Dept Genet, St Louis, MO 63108 USA; Washington Univ, Siteman Canc Ctr, St Louis, MO 63108 USA
hcfmusp.citation.scopus512
hcfmusp.description.articlenumber370.e1
hcfmusp.description.beginpage355
hcfmusp.description.endpage370.e14
hcfmusp.description.issue2
hcfmusp.description.volume173
hcfmusp.origemWOS
hcfmusp.origem.pubmed29625052
hcfmusp.origem.scopus2-s2.0-85044578706
hcfmusp.origem.wosWOS:000429320200011
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hcfmusp.publisher.countryUSAeng
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