abstract - Single nucleotide polymorphisms of the EpCAM-coding gene TACSTD1 in patients with ovarian cancer and their potential translational aspects
PURPOSE:
EpCAM
is overexpressed in many neoplasms including ovarian cancer. We
screened the EpCAM-coding gene TACSTD1 for single nucleotide
polymorphisms (SNPs), which could alter ovarian cancer risk, impact upon
disease progression,
or alter binding of the therapeutic EpCAM-binding
antibody, catumaxomab.
METHODS:
DNA
fragments of 10 healthy volunteers were analyzed to identify SNPs.
Subsequently, DNA of ovarian cancer patients (n = 117) and age-matched
healthy controls (n = 115) was genotyped by restriction fragment length
polymorphism and pyrosequencing. TACSTD1 genotypes 4461T>C were
cloned into a gene expression vector; Hek293 cells were subsequently
used for stable transfection. FACS analysis of the transfected Hek293
cells was conducted with HO-3-the
EpCAM binding site of catumaxomab-to
determine antibody binding.
RESULTS:
One
SNP was detected in exon 3 (4461T>C; rs1126497), resulting in an
amino acid exchange at position 115 (Met115Thr). Another polymorphism
was found in the 3'UTR (17225A>G; rs1421). Genotyping of patients and
controls for these SNPs did not reveal significant differences in
genotype distribution. Regarding 17225A>G, the homozygous AA-genotype
was associated with diminished progression-free survival (PFS;
p = 0.032). Overall survival, FIGO-stage, grading, and age did not
differ significantly between genotypes. FACS analysis of transfected
Hek293 cells overexpressing EpCAM 115Met/Thr showed binding of HO-3 to
both proteins.
CONCLUSIONS:
The
AA-genotype of 17225A>G seems to be associated with diminished PFS
in ovarian cancer patients. The amino acid exchange resulting from
4461T>C does not appear to alter binding of HO-3,
suggesting that
treatment with catumaxomab can be offered to patients regardless of
their TACSTD1-genotype.
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