96. Jahrestagung der Deutschen Gesellschaft für Pathologie e. V ...

Abstracts
tioned above. For patients without lymph node or distant metastases
(UICC stages I/II) and with complete tumor excision, HSP70 expression
was the only independent prognostic factor for survival (p=0.001) and
superior to UICC pT category. In left sided UICC stage I/II carcinomas,
high HSP27 expression also had adverse prognostic impact and was an
independent prognostic factor (p=0.016) besides HSP70 (p=0.002). There
was no correlation between HSP27, HSP60 and HSP70 expression
among each other and with UICC pT category, presence of lymph node,
distant metastases or tumor grading.
Conclusions. High HSP70 and HSP27 expression is associated with worse
clinical outcome. Determination of tumoral HSP70 and HSP27 may be
used as additional biomarker for risk stratification in colon cancer patients
especially in UICC stage I/II patients.
FR-P-082
p.G13D mutations in the KRAS oncogene are associated with
sensitivity of colorectal carcinoma cells to anti-EGFR antibody
treatment
I . Messner1 , S .E . Baldus1 , H .E . Gabbert1 , K .-L . Schäfer1 1Heinrich-Heine-University Düsseldorf, Inst . of Pathology, Düsseldorf
Aims. Targeted therapies with the anti-EGFR antibodies panitumumab
(Pmab) or cetuximab (Cmab) have shown significant benefit for patients
suffering from metastatic colorectal carcinoma (mCRC). According to
the approval by the American Food and Drug Administration and the
European Medicines Agency, application of these antibodies is restricted
to tumors without mutation in the KRAS oncogene. However, a recent
metaanalysis of 579 CRC patients treated with cmab indicated that
patients with p.G13D-mutated tumors (exchange of glycine at codon 13
to aspartic acid) showed a longer overall survival compared to patients
with tumors mutated in KRAS codon 12. In order to study the functional
impact of the subtype of KRAS mutation on the efficiency of EGFR-targeted
therapies in CRC, we have determined the KRAS mutation status
of colorectal carcinoma cell lines and correlated these data to the in vitro
sensitivity of these cells to cmab and Pmab.
Methods. Using a set of 15 colorectal cancer cell lines, the KRAS mutation
status was evaluated by Sanger sequencing. Mutations in the potential
predictive biomarkers BRAF and PIK3CA as well as protein expression
of EGFR and PTEN were also determined. In vitro sensitivity of tumor
cells to anti-EGFR antibodies was measured by standard MTT assays.
Results. Seven of 15 cell lines showed a KRAS mutation including four
cell lines exhibiting the p.G13D mutation. If these cell lines were treated
using panitumumab or cetuximab, a significant growth inhibition was
observed, while cell lines showing a KRAS mutation at codon 12 or 61
were not sensitive to anti-EGFR treatment. Only three of eight cell lines
showing KRAS wild type status were sensitive to Pmab and cmab. Noteworthy,
all of the five resistant KRAS wild type cell lines were either
characterized by BRAF mutation or by absence of EGFR or PTEN protein
expression, respectively. No correlation between PIK3CA mutation
status and sensitivity to anti-EGFR treatment could be demonstrated.
Conclusions. Our in vitro data from colon carcinoma cell lines indicate
that tumor cells showing the KRAS p.G13D mutation may respond to
EGFR-targeted therapy. Therefore, subtype analysis of KRAS mutation
should be included in prospective clinical trials analyzing the responsiveness
of CRC to cmab or Pmab. In KRAS wild type tumor cells, additional
aberrations like BRAF mutation and loss of EGFR or PTEN expression
may lead to resistance to EGFR-targeted therapy and should be
considered as additional negative predictive biomarkers.
110 | Der Pathologe · Supplement 1 · 2012
FR-P-083
UBCH10 overexpression in human colorectal cancers
S . Piscuoglio1 , P . Pallante2 , L . Tornillo3 , A . Fusco2 , L . Terracciano 3
1 2 University of Basel, Department of Biomedicine, basel, Switzerland, University
of Naples, Istituto di Endocrinologia ed Oncologia Sperimentale “G .
Salvatore” (IEOS-CNR) c/o Dipartimento di Biologia e Patologia Cellulare e
Molecolare, naples, Italy, 3University of Basel, Institute of Pathology, Basel,
Switzerland
Aims. Colorectal cancer is the result of the accumulation of different
genetic modifications including critical genes involved in the control of
cell proliferation. In a large number of carcinomas with worst prognosis,
lesions are not diagnosed until the disease is at an advanced stage. To
diagnose cancer at an early stage and to establish more effective therapies
featuring of key molecules in carcinogenesis is a critical step. UBCH10
(also known as E2C or UBE2C) is a cell cycle-related protein involved in
mitosis completion. UbcH10 participates in proper metaphase to anaphase
transition, and abrogation of UbcH10 results in the premature
separation of sister chromatids. Thus, UbcH10 is essential for cell cycle
progression, and his expression is cell-cycle dependent and related to
proliferation. The aim of this study is to investigate the association of
UbcH10 gene expression with clinicopathological features and tumor
progression of colorectal cancer.
Methods. We investigated the expression of the UBCH10 genes in a tissue
microarray platform consisting of normal and neoplastic colorectal
cancers (CRC) tissues by immunohistochemistry. UBCH10 was detectable
in 889 patients. Immunoreactivity was scored semi-quantitatively
by evaluating the number of positive tumor cells over the total number
of tumor cells. Scores were assigned using 5% intervals and ranged from
0% to 100%. Median protein expression levels were used as cut-off scores
to define protein marker positivity and the findings were associated with
clinical-pathological parameters.
Results. Our results demonstrated that UBCH10 is overexpressed in
CRCs tissues compared to normal colon (p