Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma
Shu-Hong Lin
,
Joshua Sampson
(1)
,
Thomas Grünewald
(2, 3, 4)
,
Didier Surdez
(5)
,
Stephanie Reynaud
(6)
,
Olivier Mirabeau
(5)
,
Eric Karlins
(7, 8)
,
Rebeca Alba Rubio
(9)
,
Sakina Zaidi
(10)
,
Sandrine Grossetête-Lalami
(11)
,
Stelly Ballet
(12)
,
Eve Lapouble
(13, 14)
,
Valérie Laurence
(12, 15)
,
Jean Michon
(13)
,
Gaelle Pierron
(5)
,
Heinrich Kovar
(16)
,
Udo Kontny
(17)
,
Anna González-Neira
(18)
,
Javier Alonso
(19)
,
Ana Patino-Garcia
(20)
,
Nadège Corradini
(21)
,
Perrine Marec Bérard
(22)
,
Jeremy Miller
(23)
,
Neal Freedman
(24)
,
Nathaniel Rothman
(24)
,
Brian Carter
(25)
,
Casey Dagnall
(7, 8)
,
Laurie Burdett
(26, 27)
,
Kristine Jones
(7, 8)
,
Michelle Manning
(7, 8)
,
Kathleen Wyatt
(7, 8)
,
Weiyin Zhou
(26, 27)
,
Meredith Yeager
(26, 27)
,
David Cox
(28)
,
Robert Hoover
(29)
,
Javed Khan
(30)
,
Gregory Armstrong
(31)
,
Wendy Leisenring
(32)
,
Smita Bhatia
(33)
,
Leslie Robison
,
Andreas Kulozik
,
Jennifer Kriebel
,
Thomas Meitinger
,
Markus Metzler
,
Manuela Krumbholz
,
Wolfgang Hartmann
,
Konstantin Strauch
,
Thomas Kirchner
,
Uta Dirksen
,
Lisa Mirabello
,
Margaret Tucker
,
Franck Tirode
(5)
,
Lindsay Morton
,
Stephen Chanock
,
Olivier Delattre
(5)
,
Mitchell Machiela
1
NIH -
National Institutes of Health [Bethesda, MD, USA]
2 KITZ - Hopp Children's Cancer Center Heidelberg [Heidelber, Germany]
3 DKFZ - German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg]
4 Heidelberg University Hospital [Heidelberg]
5 U830 - Unité de génétique et biologie des cancers
6 Institut Curie, PSL Research University, Radiation Oncology Department, Proton Therapy Centre
7 Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics
8 Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics
9 Laboratory for Pediatric Sarcoma Biology [Munich, Germany]
10 ICM - Institut du Cerveau = Paris Brain Institute
11 U830 - Unité de génétique et biologie des cancers
12 Institut Curie [Paris]
13 Département d'Oncologie Médicale [Institut Curie, Paris]
14 Unité de Génétique Somatique [Institut Curie, Paris]
15 PSL - Université Paris Sciences et Lettres
16 Children’s Cancer Research Institute [Vienna, Austria]
17 RWTH - Rheinisch-Westfälische Technische Hochschule Aachen University
18 CNIO - Spanish National Cancer Research Center
19 Unidad de Tumores Sólidos Infantiles – Unidad de Investigación Biomédica [Madrid, Spain]
20 CIMA - Center for Applied Medical Research [Plamplona]
21 CLB - Centre Régional de Lutte Contre le Cancer Lyon Rhône-Alpes
22 IHOPe - Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL]
23 Willamette University
24 Division of Cancer Epidemiology and Genetics [Bethesda, MD, États-Unis]
25 American Cancer Society [Atlanta, GA, USA]
26 FNLCR - Frederick National Laboratory for Cancer Research
27 NCI-NIH - National Cancer Institute [Bethesda]
28 IRFAC - Inserm U1113 - Interface de Recherche Fondamentale et Appliquée en Cancérologie
29 CUMC - Columbia University Medical Center
30 University of Glasgow
31 Department of Epidemiology and Cancer Control [Memphis, TN, USA]
32 Cancer Prevention and Clinical Statistics Program [Seattle, WA, USA]
33 Institute for Cancer Outcomes and Survivorship [Birmingham, AL, USA]
2 KITZ - Hopp Children's Cancer Center Heidelberg [Heidelber, Germany]
3 DKFZ - German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg]
4 Heidelberg University Hospital [Heidelberg]
5 U830 - Unité de génétique et biologie des cancers
6 Institut Curie, PSL Research University, Radiation Oncology Department, Proton Therapy Centre
7 Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics
8 Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics
9 Laboratory for Pediatric Sarcoma Biology [Munich, Germany]
10 ICM - Institut du Cerveau = Paris Brain Institute
11 U830 - Unité de génétique et biologie des cancers
12 Institut Curie [Paris]
13 Département d'Oncologie Médicale [Institut Curie, Paris]
14 Unité de Génétique Somatique [Institut Curie, Paris]
15 PSL - Université Paris Sciences et Lettres
16 Children’s Cancer Research Institute [Vienna, Austria]
17 RWTH - Rheinisch-Westfälische Technische Hochschule Aachen University
18 CNIO - Spanish National Cancer Research Center
19 Unidad de Tumores Sólidos Infantiles – Unidad de Investigación Biomédica [Madrid, Spain]
20 CIMA - Center for Applied Medical Research [Plamplona]
21 CLB - Centre Régional de Lutte Contre le Cancer Lyon Rhône-Alpes
22 IHOPe - Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL]
23 Willamette University
24 Division of Cancer Epidemiology and Genetics [Bethesda, MD, États-Unis]
25 American Cancer Society [Atlanta, GA, USA]
26 FNLCR - Frederick National Laboratory for Cancer Research
27 NCI-NIH - National Cancer Institute [Bethesda]
28 IRFAC - Inserm U1113 - Interface de Recherche Fondamentale et Appliquée en Cancérologie
29 CUMC - Columbia University Medical Center
30 University of Glasgow
31 Department of Epidemiology and Cancer Control [Memphis, TN, USA]
32 Cancer Prevention and Clinical Statistics Program [Seattle, WA, USA]
33 Institute for Cancer Outcomes and Survivorship [Birmingham, AL, USA]
Shu-Hong Lin
- Fonction : Auteur
- PersonId : 1401744
- ORCID : 0000-0002-4020-7714
Jeremy Miller
- Fonction : Auteur
- PersonId : 1401745
- ORCID : 0000-0002-3068-5990
Leslie Robison
- Fonction : Auteur
Andreas Kulozik
- Fonction : Auteur
Jennifer Kriebel
- Fonction : Auteur
Thomas Meitinger
- Fonction : Auteur
Markus Metzler
- Fonction : Auteur
Manuela Krumbholz
- Fonction : Auteur
Wolfgang Hartmann
- Fonction : Auteur
Konstantin Strauch
- Fonction : Auteur
Thomas Kirchner
- Fonction : Auteur
Uta Dirksen
- Fonction : Auteur
Lisa Mirabello
- Fonction : Auteur
Margaret Tucker
- Fonction : Auteur
Lindsay Morton
- Fonction : Auteur
Stephen Chanock
- Fonction : Auteur
Mitchell Machiela
- Fonction : Auteur
Résumé
Background: Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherited variants with minor allele frequencies below 5% due to limited genotyped cases of this rare tumor.
Methods: We investigated the contribution of rare and low-frequency variation to EwS susceptibility in the largest EwS genome-wide association study to date (733 EwS cases and 1,346 unaffected controls of European ancestry).
Results: We identified two low-frequency variants, rs112837127 and rs2296730, on chromosome 20 that were associated with EwS risk (OR = 0.186 and 2.038, respectively; P-value < 5×10-8) and located near previously reported common susceptibility loci. After adjusting for the most associated common variant at the locus, only rs112837127 remained a statistically significant independent signal (OR = 0.200, P-value = 5.84×10-8).
Conclusions: These findings suggest rare variation residing on common haplotypes are important contributors to EwS risk.
Impact: Motivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci.
Domaines
Sciences du Vivant [q-bio]| Origine | Fichiers éditeurs autorisés sur une archive ouverte |
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