Pathogenic Germline Variants in 10,389 Adult Cancers

doi:10.1016/j.cell.2018.03.039

Pathogenic Germline Variants in 10,389 Adult Cancers

Producción científica: Article › revisión exhaustiva

688 Citas (Scopus)

Resumen

We 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. A pan-cancer analysis identifies hundreds of predisposing germline variants.

Idioma original	English
Páginas (desde-hasta)	355-370.e14
Publicación	Cell
Volumen	173
N.º	2
DOI	https://doi.org/10.1016/j.cell.2018.03.039
Estado	Published - abr 5 2018

Nota bibliográfica

Publisher Copyright:
© 2018 The Authors

Financiación

Michael Seiler, Peter G. Smith, Ping Zhu, Silvia Buonamici, and Lihua Yu are employees of H3 Biomedicine, Inc. Parts of this work are the subject of a patent application: WO2017040526 titled “Splice variants associated with neomorphic sf3b1 mutants.” Shouyoung Peng, Anant A. Agrawal, James Palacino, and Teng Teng are employees of H3 Biomedicine, Inc. Andrew D. Cherniack, Ashton C. Berger, and Galen F. Gao receive research support from Bayer Pharmaceuticals. Gordon B. Mills serves on the External Scientific Review Board of Astrazeneca. Anil Sood is on the Scientific Advisory Board for Kiyatec and is a shareholder in BioPath. Jonathan S. Serody receives funding from Merck, Inc. Kyle R. Covington is an employee of Castle Biosciences, Inc. Preethi H. Gunaratne is founder, CSO, and shareholder of NextmiRNA Therapeutics. Christina Yau is a part-time employee/consultant at NantOmics. Franz X. Schaub is an employee and shareholder of SEngine Precision Medicine, Inc. Carla Grandori is an employee, founder, and shareholder of SEngine Precision Medicine, Inc. Robert N. Eisenman is a member of the Scientific Advisory Boards and shareholder of Shenogen Pharma and Kronos Bio. Daniel J. Weisenberger is a consultant for Zymo Research Corporation. Joshua M. Stuart is the founder of Five3 Genomics and shareholder of NantOmics. Marc T. Goodman receives research support from Merck, Inc. Andrew J. Gentles is a consultant for Cibermed. Charles M. Perou is an equity stock holder, consultant, and Board of Directors member of BioClassifier and GeneCentric Diagnostics and is also listed as an inventor on patent applications on the Breast PAM50 and Lung Cancer Subtyping assays. Matthew Meyerson receives research support from Bayer Pharmaceuticals; is an equity holder in, consultant for, and Scientific Advisory Board chair for OrigiMed; and is an inventor of a patent for EGFR mutation diagnosis in lung cancer, licensed to LabCorp. Eduard Porta-Pardo is an inventor of a patent for domainXplorer. Han Liang is a shareholder and scientific advisor of Precision Scientific and Eagle Nebula. Da Yang is an inventor on a pending patent application describing the use of antisense oligonucleotides against specific lncRNA sequence as diagnostic and therapeutic tools. Yonghong Xiao was an employee and shareholder of TESARO, Inc. Bin Feng is an employee and shareholder of TESARO, Inc. Carter Van Waes received research funding for the study of IAP inhibitor ASTX660 through a Cooperative Agreement between NIDCD, NIH, and Astex Pharmaceuticals. Raunaq Malhotra is an employee and shareholder of Seven Bridges, Inc. Peter W. Laird serves on the Scientific Advisory Board for AnchorDx. Joel Tepper is a consultant at EMD Serono. Kenneth Wang serves on the Advisory Board for Boston Scientific, Microtech, and Olympus. Andrea Califano is a founder, shareholder, and advisory board member of DarwinHealth, Inc. and a shareholder and advisory board member of Tempus, Inc. Toni K. Choueiri serves as needed on advisory boards for Bristol-Myers Squibb, Merck, and Roche. Lawrence Kwong receives research support from Array BioPharma. Sharon E. Plon is a member of the Scientific Advisory Board for Baylor Genetics Laboratory. Beth Y. Karlan serves on the Advisory Board of Invitae.

Financiadores	Número del financiador
Merck
National Childhood Cancer Registry – National Cancer Institute	U24CA143858, R01CA163722, R01CA178383, U24CA210988, R01CA180006, U24CA143882, U24CA143843, U24CA143866, U24CA143867, U24CA143845, U24CA143883, U24CA143840, P30CA016672, U24CA143848, U24CA210969, U24CA210949, U24CA210957, U24CA144025, U24CA211006, U24CA210972, U24CA210950, U24CA143799, U24CA210990, U24CA143835, U24CA211000
National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences	R01GM079656, K12GM084897
National Human Genome Research Institute	U54HG003273, R01HG009711, U54HG003079, U54HG003067
National Institute of Diabetes and Digestive and Kidney Diseases	R01DK102520

ODS de las Naciones Unidas

Este resultado contribuye a los siguientes Objetivos de Desarrollo Sostenible

Good health and well being

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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@article{bdf6f6e0cb5347e1b4051db57fcfd82e,

title = "Pathogenic Germline Variants in 10,389 Adult Cancers",

abstract = "We 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. A pan-cancer analysis identifies hundreds of predisposing germline variants.",

keywords = "LOH, cancer predisposition, germline and somatic genomes, variant pathogenicity",

author = "Huang, \{Kuan lin\} and Mashl, \{R. Jay\} and Yige Wu and Ritter, \{Deborah I.\} and Jiayin Wang and Clara Oh and Marta Paczkowska and Sheila Reynolds and Wyczalkowski, \{Matthew A.\} and Ninad Oak and Scott, \{Adam D.\} and Michal Krassowski and Cherniack, \{Andrew D.\} and Houlahan, \{Kathleen E.\} and Reyka Jayasinghe and Wang, \{Liang Bo\} and Zhou, \{Daniel Cui\} and Di Liu and Song Cao and Kim, \{Young Won\} and Amanda Koire and McMichael, \{Joshua F.\} and Vishwanathan Hucthagowder and Kim, \{Tae Beom\} and Abigail Hahn and Chen Wang and McLellan, \{Michael D.\} and Fahd Al-Mulla and Johnson, \{Kimberly J.\} and Caesar-Johnson, \{Samantha J.\} and Demchok, \{John A.\} and Ina Felau and Melpomeni Kasapi and Ferguson, \{Martin L.\} and Hutter, \{Carolyn M.\} and Sofia, \{Heidi J.\} and Roy Tarnuzzer and Zhining Wang and Liming Yang and Zenklusen, \{Jean C.\} and Zhang, \{Jiashan (Julia)\} and Sudha Chudamani and Jia Liu and Laxmi Lolla and Rashi Naresh and Todd Pihl and Qiang Sun and Yunhu Wan and Ye Wu and Therese Bocklage",

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doi = "10.1016/j.cell.2018.03.039",

language = "English",

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AU - Huang, Kuan lin

AU - Mashl, R. Jay

AU - Wu, Yige

AU - Ritter, Deborah I.

AU - Wang, Jiayin

AU - Oh, Clara

AU - Paczkowska, Marta

AU - Reynolds, Sheila

AU - Wyczalkowski, Matthew A.

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AU - Liu, Di

AU - Cao, Song

AU - Kim, Young Won

AU - Koire, Amanda

AU - McMichael, Joshua F.

AU - Hucthagowder, Vishwanathan

AU - Kim, Tae Beom

AU - Hahn, Abigail

AU - Wang, Chen

AU - McLellan, Michael D.

AU - Al-Mulla, Fahd

AU - Johnson, Kimberly J.

AU - Caesar-Johnson, Samantha J.

AU - Demchok, John A.

AU - Felau, Ina

AU - Kasapi, Melpomeni

AU - Ferguson, Martin L.

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AU - Wu, Ye

AU - Bocklage, Therese

PY - 2018/4/5

Y1 - 2018/4/5

N2 - We 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. A pan-cancer analysis identifies hundreds of predisposing germline variants.

AB - We 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. A pan-cancer analysis identifies hundreds of predisposing germline variants.

KW - LOH

KW - cancer predisposition

KW - germline and somatic genomes

KW - variant pathogenicity

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DO - 10.1016/j.cell.2018.03.039

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AN - SCOPUS:85044578706

SN - 0092-8674

VL - 173

SP - 355-370.e14

JO - Cell

JF - Cell

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Pathogenic Germline Variants in 10,389 Adult Cancers

Resumen

Nota bibliográfica

Financiación

ODS de las Naciones Unidas

ASJC Scopus subject areas

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