Cancer Research in Switzerland - Krebsliga Schweiz

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(SAKK 35-98) the Swiss Group for Clinical Cancer Research
(SAKK) showed that maintenance treatment with
rituximab four times every two months significantly improved
event-free survival. Rituximab is usually well tolerated
and is well suitable for maintenance treatment. The
optimal duration of maintenance therapy is unknown. The
current study is investigating whether prolongation of the
maintenance therapy leads to improved results.
Patients with newly diagnosed, chemotherapy resistant or
recurrent follicular lymphoma were included in this trial.
After an induction therapy of four weekly infusions of
rituximab, patients with partial or complete remission
were randomised to a short maintenance or a prolonged
maintenance for a maximum of five years or until progression
or unacceptable toxicity. Primary endpoint is eventfree
survival. Secondary endpoints are progression-free
survival, overall survival, response rate, toxicity, molecular
remission, duration of molecular remission and evolution
of immunologic competence. Molecular analyses
were performed by Dr. Francesco Bertoni (Experimental
Oncology, Oncology Institute of Southern Switzerland,
Bellinzona).
From October 2004 to November 2007, 270 patients
from 24 centres in seven countries were included and received
induction treatment with rituximab. Many patients
are still under trial treatment, and therefore an efficacy
analysis has not yet been performed. Two safety analyses
showed that rituximab maintenance therapy beyond two
years is safe.
Project coordinator
Dr. Christian Taverna
Onkologie
Medizinische Klinik
Kantonsspital Münsterlingen
CH-8596 Münsterlingen
Phone +41 (0)71 686 22 02
Fax +41 (0)71 686 26 51
christian.taverna@stgag.ch
Terracciano Luigi M. | HOXA13 hyper-expression
in liver cancer: A potential node toward angiogenesis
(OCS 02005-02-2007)
HOX genes control normal development and primary cellular
processes and are characterized by a unique genomic
network organization. The comparison of the HOX gene
network expression between nontumourous livers and
hepatocellular carcinomas highlights significant differences
in the expression of locus A HOX genes with a consistent
over-expression of HOXA13, thus validating this gene as a
marker of HCCs. HOXA13, a determinant of gut primordia
and posterior body structures, generates a fusion protein
with NUP98 nucleoporin involved in leukaemogenesis.
Transcriptome analysis on HCC/nontumourous liver
mRNAs, selected on the basis of HOXA13 overexpression,
recognizes a set of deregulated genes. The matching of
these genes with reported HCC transcriptome analysis
identifies cell-cycle and nuclear pore related HCC phenotype
displaying poor prognosis. HOXA13 and HOXA7 homeoproteins
share a consensus sequence that physically
links eIF4E nuclear bodies acting on the export of specific
mRNAs (c-myc, FGF-2, VEGF, ODC, cyclin D1).
A series of 47 frozen liver biopsies were collected from 35
patients identified by searching the files of the pathology
institutes at the University of Basel, Switzerland, and at
Federico II Medical School, Naples, Italy. Twelve patients
underwent two liver biopsies, one of HCC and the second
one of adjacent nontumourous liver tissue; 23 patients
underwent a single HCC biopsy. Thirteen single liver biopsies
were obtained during visceral surgery for gallbladder
lithiasis and morbid obesity and were used as normal controls.
A second series of 123 liver samples was used:
1) partially (57 HCC samples), to detect the transcriptome
expression of the 33 out of 39 HOX genes included in the
Affymetrix Chip 133A 2.0 and of the deregulated genes
identified through the Affymetrix analysis of HOXA13 hyper-expressing
HCC/nontumourous liver pairs; 2) in toto,
to detect HOXA13 mRNA real-time expression through
G1-G6 HCC groups in the Zucman-Rossi laboratory.
No substantial differences in the HOX gene expression
were detectable by comparing normal and nontumourous
livers, whereas major differences were found by comparing
the frequency of active locus A HOX genes such as
HOXA5, HOXA7, HOXA10 and HOXA13 in HCCs vs nontumourous
and normal livers. Further, by analyzing the
sequences of HOXA13 and HOXA7 homeoproteins, encoded
by the two most deregulated locus A HOX genes of
our HCC survey, we identified a consensus sequence
(YQPWALP and YYVNALF=YXXXXLF) respectively responsible
for their potential interaction with the rate-limiting
step of eukaryotic cap-dependent translation initiation
factor eIF4E.
In this study the comparison of HOX gene network expression
in hepatocellular carcinomas and nontumourous
liver tissue identified the HOX A locus as the part of the
network more significantly involved in hepatocarcinogenesis.
Among locus A HOX genes, HOXA13 appears to be
a marker of hepatocellular carcinomas as well as an important
transcriptional and post-transcriptional node in
the cancerous liver’s reversion to an embryonal stage
towards gut primordia. The deregulation of genes identified
through transcriptome analysis of highly HOXA13expressing
pairs of HCC/nontumourous liver matched to
the G1-G6 classification of hepatocarcinomas identifies
the poor prognosis HCC G3 group, suggesting the inclusion
of HOX genes transcriptome as a potential prognostic
tool in liver cancer.
Project coordinator
Prof. Dr. Luigi M. Terracciano
Abteilung für Molekularpathologie
Institut für Pathologie
Universitätsspital Basel
Schönbeinstrasse 40
CH-4003 Basel
Phone +41 (0)61 265 28 49
Fax +41 (0)61 265 31 94
lterracciano@uhbs.ch