Lead article
A genome-wide study of allelic imbalance in human testicular germ
cell tumors using microsatellite markers
Jon Thor Bergthorsson
a,b,
*
, Bjarni Agnar Agnarsson
b
, Tomas Gudbjartsson
c
,
Kjartan Magnusson
d
, Asgeir Thoroddsen
c
, Birgir Palsson
a
, Johannes Bjornsson
b
,
Kari Stefansson
a
, Jeffrey Gulcher
a
, Gudmundur Vikar Einarsson
c
,
Laufey Thora Amundadottir
a
, Rosa Bjork Barkardottir
b
a
deCODE Genetics, Sturlugata 8, 101 Reykjavik, Iceland
b
Department of Pathology, University Hospital, Reykjavik, Iceland
c
Department of Urology, University Hospital, Reykjavik, Iceland
d
Department of Oncology, University Hospital, Reykjavik, Iceland
Received 18 April 2005; received in revised form 10 June 2005; accepted 13 June 2005
Abstract
Testicular germ cell tumors (TGCT) arise by multistep carcinogenesis pathways involving selective
losses and gains of chromosome material. To locate cancer genes underlying this selection, we per-
formed a genome-wide study of allelic imbalance (AI) in 32 tumors, using 710 microsatellite
markers. The highest prevalence of AI was found at 12p, in line with previous studies finding con-
sistent gain of the region in TGCTs. High frequency of AI was also observed at chromosome arms
4p, 9q, 10p, 11q, 11p, 13q, 16q, 18p, and 22q. Within 39 candidate regions identified by mapping of
smallest regions of overlap (SROs), the highest frequency of AI was at 12p11.21~p11.22 (62%),
12p12.1~p13.1 (53%), 12p13.1~p13.2 (53%), 11q14.1~q14.2 (53%), 11p13~p14.3 (47%),
9q21.13~q21.32 (47%), and 4p15.1~p15.2 (44%). Two genes known to be involved in cancer reside
in these regions, ETV6 at 12p13.2 (TEL oncogene) and WT1 at 11p13. We also found a significant
association (P 5 0.02) between AI at 10q21.1~q22.2 and higher clinical stage. This study contrib-
utes to the ongoing search for genes involved in transformation of germ cells and provides a useful
reference point to previous studies using cytogenetic techniques to map chromosome changes in
TGCTs. Ó 2006 Elsevier Inc. All rights reserved.
1. Introduction
Over the decades, the incidence of testicular cancer has
increased substantially in Western countries [1]. The dis-
ease is typically diagnosed in males between 15 and 35
years old and represents one of the most common malig-
nancies of this age group in Europe, North America, and
Australasia. A small fraction of patients are diagnosed in
childhood, between birth and 6 years of age. The majority
of testicular tumors (95%) derive from primitive germ cells
and are consequently termed testicular germ cell tumors
(TGCT). A small fraction of the tumors may have other ori-
gins (e.g., in specialized stroma, including the Leydig or
Sertoli cells of the testis). Histologically, TGCTs are clas-
sified as either seminomas (50%), or nonseminomas
(50%). The latter group includes various cell types of
embryonic and extraembryonic origin including the tera-
tomas, embryonal carcinoma, choriocarcinoma, and yolk
sac tumors. These different histology types may appear in
pure forms or in various combinations within one and the
same tumor [2]. A benign intermediate stage termed intra-
tubular germ cell neoplasia (ITGCN) is believed to precede
both seminomatous and nonseminomatous TGCTs [3].
Analyses of the DNA content in TGCTs have indicated
that their genome is near triploid; seminomas are hypertri-
ploid and nonseminomas hypotriploid. This may result
from poly- or tetraploidization in early phases of tumor
formation, followed by series of selective losses and gains
of chromosome material [4–6]. Isochromosome formation
involving the short arm of chromosome 12dthat is,
i(12p)dis the most distinctive cytogenetic finding in
TGCTs and overrepresentation of 12p is observed in the
majority of the tumors. In addition, a small fraction of
TGCTs (10%) may display a restricted high-level amplifi-
cations in the region [7–11]. Studies using comparative
* Corresponding author. Tel.: 1354-5702961; fax: 1354-5701903.
E-mail address: jonthor@decode.is (J.T. Bergthorsson).
0165-4608/06/$ – see front matter Ó 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.cancergencyto.2005.06.015
Cancer Genetics and Cytogenetics 164 (2006) 1–9