Runs of homozygosity and testicular cancer risk.

Genome Genome-Wide Association Study Genotype Homozygote Humans Male Neoplasms, Germ Cell and Embryonal / genetics Polymorphism, Single Nucleotide Risk Factors Testicular Neoplasms / genetics
cancer genetics genome-wide association studies homozygosity mapping recessive runs of homozygosity testicular germ cell tumour

Journal

Andrology
ISSN: 2047-2927
Titre abrégé: Andrology
Pays: England
ID NLM: 101585129

Informations de publication

Date de publication:
07 2019
Historique:
received: 30 12 2018
revised: 16 05 2019
accepted: 17 05 2019
entrez: 17 7 2019
pubmed: 17 7 2019
medline: 11 7 2020
Statut: ppublish

Résumé

Testicular germ cell tumour (TGCT) is highly heritable but > 50% of the genetic risk remains unexplained. Epidemiological observation of greater relative risk to brothers of men with TGCT compared to sons has long alluded to recessively acting TGCT genetic susceptibility factors, but to date none have been reported. Runs of homozygosity (RoH) are a signature indicating underlying recessively acting alleles and have been associated with increased risk of other cancer types. To examine whether RoH are associated with TGCT risk. We performed a genome-wide RoH analysis using GWAS data from 3206 TGCT cases and 7422 controls uniformly genotyped using the OncoArray platform. Global measures of homozygosity were not significantly different between cases and controls, and the frequency of individual consensus RoH was not significantly different between cases and controls, after correction for multiple testing. RoH at three regions, 11p13-11p14.3, 5q14.1-5q22.3 and 13q14.11-13q.14.13, were, however, nominally statistically significant at p < 0.01. Intriguingly, RoH200 at 11p13-11p14.3 encompasses Wilms tumour 1 (WT1), a recognized cancer susceptibility gene with roles in sex determination and developmental transcriptional regulation, processes repeatedly implicated in TGCT aetiology. Overall, our data do not support a major role in the risk of TGCT for recessively acting alleles acting through homozygosity, as measured by RoH in outbred populations of cases and controls.

Sections du résumé

BACKGROUND
Testicular germ cell tumour (TGCT) is highly heritable but > 50% of the genetic risk remains unexplained. Epidemiological observation of greater relative risk to brothers of men with TGCT compared to sons has long alluded to recessively acting TGCT genetic susceptibility factors, but to date none have been reported. Runs of homozygosity (RoH) are a signature indicating underlying recessively acting alleles and have been associated with increased risk of other cancer types.
OBJECTIVE
To examine whether RoH are associated with TGCT risk.
METHODS
We performed a genome-wide RoH analysis using GWAS data from 3206 TGCT cases and 7422 controls uniformly genotyped using the OncoArray platform.
RESULTS
Global measures of homozygosity were not significantly different between cases and controls, and the frequency of individual consensus RoH was not significantly different between cases and controls, after correction for multiple testing. RoH at three regions, 11p13-11p14.3, 5q14.1-5q22.3 and 13q14.11-13q.14.13, were, however, nominally statistically significant at p < 0.01. Intriguingly, RoH200 at 11p13-11p14.3 encompasses Wilms tumour 1 (WT1), a recognized cancer susceptibility gene with roles in sex determination and developmental transcriptional regulation, processes repeatedly implicated in TGCT aetiology.
DISCUSSION AND CONCLUSION
Overall, our data do not support a major role in the risk of TGCT for recessively acting alleles acting through homozygosity, as measured by RoH in outbred populations of cases and controls.

Identifiants

DOI: 10.1111/andr.12667 PMID: 31310061
pubmed: 31310061
doi: 10.1111/andr.12667
doi:

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

555-564

Subventions

Organisme : Cancer Research UK
ID : C5047/A10692
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C5047/A7357
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C1287/A10118
Pays : United Kingdom
Organisme : NIH HHS
ID : X01HG007492
Pays : United States
Organisme : Cancer Research UK
ID : C16913/A6135
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 10118
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C1287/A16563
Pays : United Kingdom
Organisme : NIH HHS
ID : U19CA148537
Pays : United States
Organisme : Seventh Framework Programme
ID : 223175 (HEALTH-F2-2009-223175)
Pays : International
Organisme : NIH HHS
ID : U01CA188392
Pays : United States
Organisme : The Institute of Cancer Research
Pays : International
Organisme : Movember Foundation
Pays : International
Organisme : Cancer Research UK
ID : C5047/A3354
Pays : United Kingdom

Investigateurs

Gordon Rustin (G)
Narayanan N Srihari (NN)
David Cole (D)
Colin Askill (C)
Gianfilippo Bertelli (G)
James Barber (J)
Ed Gilby (E)
Jeff White (J)
Jeremy Baybrooke (J)
Michael Leahy (M)
Richard Welch (R)
Prabir Chakraborti (P)
Johnathan Joffe (J)
Richard Brown (R)
Guy Faust (G)
Peter Simmonds (P)
Danish Mazhar (D)
Andrew Stockdale (A)
David Hrounda (D)
Caroline Humber (C)
Wiebke Appel (W)
Anne Hong (A)
Grahame Howard (G)
Fiona Douglas (F)
David Bloomfield (D)
Mohammad Butt (M)
Kay Kelly (K)
Rakesh Mehra (R)
Richard Brown (R)
Paul Rogers (P)
Prabir Chakraborti (P)
Matthew Hatton (M)
Ivo Hennig (I)
John McAteer (J)
Philip Savage (P)
Michael Seckl (M)
Joanna Gale (J)
Gordon Rustin (G)
Peter Clark (P)
Steve Woby (S)
Adrian Rathmell (A)
Alan Lamont (A)
Naveed Sarwar (N)
Nick Stuart (N)
Simon Chowdhury (S)
Sharon Beesley (S)
Mathius Winkler (M)
Abdel Hamid (A)
Sanjeev Pathak (S)
Krishnaswamy Madhavan (K)
Martin Highley (M)
Julian Money-Kryle (J)
Cathryn Brock (C)
Thiagarajan Sreenivasan (T)
Karina Dalsgaard Sorensen (K)
Lovise Maehle (L)
David E Neal (DE)
Freddie C Hamdy (FC)
Jenny L Donovan (JL)
Ruth C Travis (RC)
Robert J Hamilton (RJ)
Sue Ann Ingles (S)
Barry S Rosenstein (BS)
Yong-Jie Lu (YJ)
Graham G Giles (GG)
Adam S Kibel (AS)
Ana Vega (A)
Manolis Kogevinas (M)
Jong Y Park (JY)
Janet L Stanford (JL)
Cezary Cybulski (C)
Børge G Nordestgaard (BG)
Hermann Brenner (H)
Christiane Maier (C)
Jeri Kim (J)
Esther M John (EM)
Manuel R Teixeira (MR)
Susan L Neuhausen (SL)
Kim De Ruyck (K)
Azad Razack (A)
Lisa F Newcomb (LF)
Davor Lessel (D)
Radka Kaneva (R)
Nawaid Usmani (N)
Frank Claessens (F)
Paul A Townsend (PA)
Manuela Gago Dominguez (M)
Monique J Roobol (MJ)
Florence Menegaux (F)
Kay-Tee Khaw (KT)
Lisa Cannon-Albrigh (L)
Hardev Pandha (H)
Stephen N Thibodeau (SN)

Informations de copyright

© 2019 American Society of Andrology and European Academy of Andrology.

Auteurs

C Loveday (C)

Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK.
ORCID: 0000-0002-2291-372X

A Sud (A)

Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK.

K Litchfield (K)

Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.

M Levy (M)

Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK.
ORCID: 0000-0001-5078-1747

A Holroyd (A)

Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK.

P Broderick (P)

Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK.

Z Kote-Jarai (Z)

Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK.

A M Dunning (AM)

Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.

K Muir (K)

Division of Health Sciences, Warwick Medical School, Warwick University, Warwick, UK.
Institute of Population Health, University of Manchester, Manchester, UK.

J Peto (J)

Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.

R Eeles (R)

Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK.
Royal Marsden NHS Foundation Trust, London, UK.

D F Easton (DF)

Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

D Dudakia (D)

Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK.

N Orr (N)

The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.

N Pashayan (N)

Department of Applied Health Research, University College London, London, UK.

A Reid (A)

Academic Uro-oncology Unit, The Royal Marsden NHS Foundation Trust, Sutton, UK.

R A Huddart (RA)

Academic Radiotherapy Unit, Institute of Cancer Research, Sutton, UK.

R S Houlston (RS)

Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK.

C Turnbull (C)

Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK.
William Harvey Research Institute, Queen Mary University, London, UK.
Guys and St Thomas' NHS Foundation Trust, London, UK.
Public Health England, National Cancer Registration and Analysis Service, London, UK.

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Classifications MeSH

questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Runs of homozygosity and testicular cancer risk.
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › Runs of homozygosity and testicular cancer risk.
questionsmedicales.fr › Phénomènes génétiques › Génotype › Runs of homozygosity and testicular cancer risk.
questionsmedicales.fr › Phénomènes génétiques › Génotype › Homozygote › Runs of homozygosity and testicular cancer risk.
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Runs of homozygosity and testicular cancer risk.
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs embryonnaires et germinales › Runs of homozygosity and testicular cancer risk.
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Polymorphisme de nucléotide simple › Runs of homozygosity and testicular cancer risk.
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Probabilité › Risque › Facteurs de risque › Runs of homozygosity and testicular cancer risk.
questionsmedicales.fr › Maladies endocriniennes › Troubles gonadiques › Maladies testiculaires › Tumeurs du testicule › Runs of homozygosity and testicular cancer risk.