2008 Barcelona - European Society of Human Genetics

Cancer genetics
tibility gene will have real utility in case-control mutation screening .
(2) The attributable fraction of rare missense substitutions in ATM for
risk of BC is approximately equivalent to that of truncating and splice
junction variants .
P04.122
Alterations in genes encoding sarcoplasmic-endoplasmic
reticulum ca2+ pumps in association with head and neck
squamous cell carcinoma
M. Ravnik-Glavac, B. Korosec, M. Volavsek, D. Glavac;
University of Ljubljana, Faculty of Medicine, Ljubljana, Slovenia.
Recent studies have suggested that perturbation of intracellular Ca 2+
homeostasis or signalling could contribute to cancer development . The
purpose of this study was to evaluate whether germline variants of the
ATP2A2 and ATP2A3 genes might act as susceptibility alleles in head
and neck squamous cell carcinoma. In both genes, we identified eight
different alterations in 11 patients with head and neck squamous cell
carcinoma (11/79; P = 0.0002, odds ratio = 0.054, 95% confidence interval
= 0 .0069-0 .4236) . We also detected low expression level of both
genes in connection with some of alterations, but could not correlate
low expression level with methylation in the promoter region of either
gene . The results suggest that Ca 2+ pumps of sarcoplasmic-endoplasmic
reticulum are involved in an increased susceptibility to develop
head and neck squamous cell carcinoma in humans .
P04.123
Neuroendocrine carcinoma in Birt-Hogg-Dubé syndrome - do
FLcN mutations contribute to malignancy?
M. A. Van Steensel1 , S. Weppler1 , T. Claessens1 , B. G. Wouters2 ;
1 2 University of Maastricht, Maastricht, The Netherlands, University of Toronto,
Toronto, ON, Canada.
Birt-Hogg-Dubé syndrome (BHD) is a dominantly inherited disorder
characterized by an increased risk of developing kidney cancer, pneumothorax
as a consequence of lung cysts and benign hair follicle tumors
called fibrofolliculomas. It is caused by mutations in the gene
coding for folliculin, a protein involved in mTOR signaling . As the relative
risk of developing renal malignancies is around 5, BHD syndrome
is generally considered to be a relatively benign condition for which
annual follow-up suffices. However, the possibility that the pre-existing
gene defect might act to modify the behavior of other cancers that
arise in patients with BHD syndrome has so far not been considered .
We describe a patient with BHD syndrome who succumbed to an extremely
malignant neuro-endocrine tumor of prostatic or bladder origin
within 6 weeks of its discovery . Tumor tissue showed elevated staining
of phosphorylated mTOR and phosphorylated p70S6K, as did foci in
clinically normal skin and kidney, confirming that folliculin is a negative
regulator of mTOR signaling . We propose that the behavior of this cancer
might have been modulated by the germline FLCN mutation and
propose that patients with BHD syndrome be more closely monitored
than is currently the case .
P04.124
Gene expression in superficial transitional cell carcinoma using
oligonucleotide microarrays
J. Mares 1 , M. Szakacsova 2 , F. Zelezny 3 , J. Klema 3 , V. Soukup 2 , J. Duskova 4 , A.
Sartori 5 , M. Babjuk 2 ;
1 Inst. Biol. and Med. Genet. 2nd Med. Faculty, Prague, Czech Republic, 2 Clin.
of Urol., 1st Med. Faculty, Prague, Czech Republic, 3 Dept. Cybernet., Czech
Tech. University, Prague, Czech Republic, 4 Inst. of Pathol. Anatomy, 1st Med.
Faculty, Prague, Czech Republic, 5 Applied Biosystems, Heidelberg, Germany.
The prediction of tumour recurrence in patients with superficial bladder
tumours presents several challenges in clinical management . For the
improvement of recurrence prognosis in these patients we investigated
gene expression and identified differences between superficial bladder
tumours without recurrence during period of two years (10 patients)
and with early recurrence (12 patients), which might explain differences
in the biology and clinical outcomes High-density oligonucleotide
microarrays (29,019 genes, AB) were used to analyze the transcript
profiles of 22 superficial bladder tumours: 19 pTa and 3 pT1, grading
5 G1 and 17 G2 . Statistical analyses were applied to investigate the
ability of the genes to identify patients without recurrence during period
of two years and with early recurrence . Initial screening using the
GeneSpring and Bioconductor software tools revealed a putative set
of about 120 genes associating with the recurrence class. Significant
differences were observed by HOXA10, GPNMB, TCN1, INA, H19,
AURKC, FABP3 and PLOD2 genes . Besides, we integrated the microarray
dataset with additional background knowledge, in order to
algorithmically mine for differential-expression patterns in terms of the
Gene Ontology functions and processes as well as known regulatory
pathway memberships . Our results indicate that it may be possible to
identify patients with a high risk of disease recurrence at an early stage
using a molecular profile present already in the superficial tumours.
Research is supported by MSM 0021620808 and IGA NR 8934-3 .
P04.125
Gene expression in superficial transitional cell carcinoma using
oligonucleotide microarrays
J. Mares;
Charles University, Prague, Czech Republic.
The prediction of tumour recurrence in patients with superficial bladder
tumours presents several challenges in clinical treatment . For the improvement
of recurrence prognosis in these patients we investigated
gene expression and identified differences between superficial bladder
tumours without recurrence during period of two years (10 patients)
and with early recurrence (12 patients), which might explain differences
in the biology and clinical outcomes High-density oligonucleotide
microarrays (29,019 genes, AB) were used to analyze the transcript
profiles of 22 superficial bladder tumours: 19 pTa and 3 pT1, grading
5 G1 and 17 G2 . Statistical analyses were applied to investigate the
ability of the genes to identify patients without recurrence during period
of two years and with early recurrence . Initial screening using the
GeneSpring and Bioconductor software tools revealed a putative set
of about 120 genes associating with the recurrence class. Significant
differences were observed by HOXA10, GPNMB, TCN1, INA, H19,
AURKC, FABP3 and PLOD2 genes . Besides, we integrated the microarray
dataset with additional background knowledge, in order to
algorithmically mine for differential-expression patterns in terms of the
Gene Ontology functions and processes as well as known regulatory
pathway memberships . Our results indicate that it may be possible to
identify patients with a high risk of disease recurrence at an early stage
using a molecular profile present already in the superficial tumours.
Research is supported by MSM 0021620808 and IGA NR 8934-3 .
P04.126
the Association of CYP A , CYP D , GSTM , GSTP and
GSTT Gene Polymorphisms with Bladder cancer
E. Altaylı 1 , S. Gunes 1 , A. F. Yılmaz 2 , S. Sarıkaya 2 , H. C. Irkılata 3 , C. H. Acikel 4 ,
S. Goktas 3 ;
1 Ondokuz Mayis University, Department of Medical Biology, Samsun, Turkey,
2 Ondokuz Mayis University, Department of Urology, Samsun, Turkey, 3 Gulhane
Military Medical Academy, Department of Urology, Ankara, Turkey, 4 Gulhane
Military Medical Academy, Department of Public Health, Ankara, Turkey.
Bladder cancer is the fourth most common cancer in men and the
eighth in women in the western world . The aim of this study was to
investigate the relationship between bladder tumor and variants of the
cytochrome p450 (CYP), family 1, subfamily A, polipeptide 2 (CYP1A2)
C734A, CYP2D6 G1934A, the glutathione S-transferase (GST), family
M, subfamily 1 (GSTM1 null), GSTT1 null and GSTP1 I105V which
play important roles in xenobiotic metabolism . In this study, we investigated
the distribution of these polymorphisms in 135 bladder cancer
patients and 128 age-matched healthy individuals as controls . The
polymorphisms were analyzed using polymerase chain reaction (PCR)
- restriction fragment length polymorphism (RFLP) assay and multiplex
PCR method . Genotype and allele frequencies were calculated, and
their associations with bladder cancer risk are calculated, and their
association with bladder cancer risk or demographic factors, smoking
status, and tumor stage was investigated . The prevalence of GSTT1
null genotype in cases was 23%, compared with 7% in the control
group (OR, 0 .254, %95 CI, 0 .115-0558, p=0 .001) . No association was
observed between CYP1A2, CYP2D6, GSTM1, and GSTP1 genes
polymorphisms and bladder cancer . There was association between
smoking status and bladder cancer (OR, 1 .914, %95 CI, 1 .055-3 .472,
p=0.033), but there was no statistically significant association between
demographic factors, tumor stage, tumor grade and bladder cancer .
These data seem to indicate that GSTT1 gene polymorphism may be
associated with bladder cancer in this Turkish population .