Runs of homozygosity and testicular cancer risk

C Loveday; A Sud; K Litchfield; M Levy; A Holroyd; P Broderick; Z Kote-Jarai; A M Dunning; K Muir; J Peto; R Eeles; D F Easton; D Dudakia; N Orr; N Pashayan; UK Testicular Cancer Collaboration; PRACTICAL Consortium; A Reid; R A Huddart; R S Houlston; C Turnbull

doi:10.1111/andr.12667

Runs of homozygosity and testicular cancer risk

Andrology. 2019 Jul;7(4):555-564. doi: 10.1111/andr.12667.

Authors

C Loveday¹, A Sud¹, K Litchfield², M Levy¹, A Holroyd¹, P Broderick¹, Z Kote-Jarai¹, A M Dunning³, K Muir^{4

5}, J Peto⁶, R Eeles^{1

7}, D F Easton^{3

8}, D Dudakia¹, N Orr⁹, N Pashayan¹⁰; UK Testicular Cancer Collaboration; PRACTICAL Consortium; A Reid¹¹, R A Huddart¹², R S Houlston¹, C Turnbull^{1

13

14

15}

Collaborators

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

Affiliations

¹ Division of Genetics & Epidemiology, The Institute of Cancer Research, London, UK.
² Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
³ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
⁴ Division of Health Sciences, Warwick Medical School, Warwick University, Warwick, UK.
⁵ Institute of Population Health, University of Manchester, Manchester, UK.
⁶ Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
⁷ Royal Marsden NHS Foundation Trust, London, UK.
⁸ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁹ The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
¹⁰ Department of Applied Health Research, University College London, London, UK.
¹¹ Academic Uro-oncology Unit, The Royal Marsden NHS Foundation Trust, Sutton, UK.
¹² Academic Radiotherapy Unit, Institute of Cancer Research, Sutton, UK.
¹³ William Harvey Research Institute, Queen Mary University, London, UK.
¹⁴ Guys and St Thomas' NHS Foundation Trust, London, UK.
¹⁵ Public Health England, National Cancer Registration and Analysis Service, London, UK.

PMID: 31310061
DOI: 10.1111/andr.12667

Abstract

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.

Keywords: cancer; genetics; genome-wide association studies; homozygosity mapping; recessive; runs of homozygosity; testicular germ cell tumour.

Publication types

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

MeSH terms

Genome
Genome-Wide Association Study
Genotype
Homozygote*
Humans
Male
Neoplasms, Germ Cell and Embryonal / genetics*
Polymorphism, Single Nucleotide
Risk Factors
Testicular Neoplasms / genetics*

Supplementary concepts

Testicular Germ Cell Tumor

Abstract

Publication types

MeSH terms

Supplementary concepts

Grants and funding