The Y deletion gr/gr and susceptibility to testicular germ cell tumor.
Testicular germ cell tumor (TGCT) is the most common cancer in young men. Despite a considerable familial component to TGCT risk, no genetic change that confers increased risk has been substantiated to date. The human Y chromosome carries a number of genes specifically involved in male germ cell development, and deletion of the AZFc region at Yq11 is the most common known genetic cause of infertility. Recently, a 1.6-Mb deletion of the Y chromosome that removes part of the AZFc region--known as the "gr/gr" deletion--has been associated with infertility. In epidemiological studies, male infertility has shown an association with TGCT that is out of proportion with what can be explained by tumor effects. Thus, we hypothesized that the gr/gr deletion may be associated with TGCT. Using logistic modeling, we analyzed this deletion in a large series of TGCT cases with and without a family history of TGCT. The gr/gr deletion was present in 3.0% (13/431) of TGCT cases with a family history, 2% (28/1,376) of TGCT cases without a family history, and 1.3% (33/2,599) of unaffected males. Presence of the gr/gr deletion was associated with a twofold increased risk of TGCT (adjusted odds ratio [aOR] 2.1; 95% confidence interval [CI] 1.3-3.6; P = .005) and a threefold increased risk of TGCT among patients with a positive family history (aOR 3.2; 95% CI 1.5-6.7; P = .0027). The gr/gr deletion was more strongly associated with seminoma (aOR 3.0; 95% CI 1.6-5.4; P = .0004) than with nonseminoma TGCT (aOR 1.5; 95% CI 0.72-3.0; P = .29). These data indicate that the Y microdeletion gr/gr is a rare, low-penetrance allele that confers susceptibility to TGCT.
Nathanson
Katherine L
KL
Department of Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA. knathans@mail.med.upenn.edu
Kanetsky
Peter A
PA
Hawes
Rachel
R
Vaughn
David J
DJ
Letrero
Richard
R
Tucker
Kathy
K
Friedlander
Michael
M
Phillips
Kelly-Anne
KA
Hogg
David
D
Jewett
Michael A S
MA
Lohynska
Radka
R
Daugaard
Gedske
G
Richard
Stéphane
S
Chompret
Agnés
A
Bonaïti-Pellié
Catherine
C
Heidenreich
Axel
A
Olah
Edith
E
Geczi
Lajos
L
Bodrogi
Istvan
I
Ormiston
Wilma J
WJ
Daly
Peter A
PA
Oosterhuis
J Wolter
JW
Gillis
Ad J M
AJ
Looijenga
Leendert H J
LH
Guilford
Parry
P
Fosså
Sophie D
SD
Heimdal
Ketil
K
Tjulandin
Sergei A
SA
Liubchenko
Ludmila
L
Stoll
Hans
H
Weber
Walter
W
Rudd
Matthew
M
Huddart
Robert
R
Crockford
Gillian P
GP
Forman
David
D
Oliver
D Timothy
DT
Einhorn
Lawrence
L
Weber
Barbara L
BL
Kramer
Joan
J
McMaster
Mary
M
Greene
Mark H
MH
Pike
Malcolm
M
Cortessis
Victoria
V
Chen
Chu
C
Schwartz
Stephen M
SM
Bishop
D Timothy
DT
Easton
Douglas F
DF
Stratton
Michael R
MR
Rapley
Elizabeth A
EA
D000483:Alleles; D041322:Chromosomes, Human, Y / Q000737:chemistry / Q000235:genetics*; D016001:Confidence Intervals; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D006801:Humans; D007248:Infertility, Male; D016014:Linear Models; D008297:Male; D016017:Odds Ratio; D010375:Pedigree; D019683:Penetrance; D012306:Risk; D018239:Seminoma / Q000235:genetics* / Q000473:pathology; D013736:Testicular Neoplasms / Q000235:genetics* / Q000473:pathology