tumors and respective normal colon tissues from 50 patients with
colorectal cancer, and identified an intron 8 alteration in a single
tumor sample, which results in a nonsense mutation. However, it is
unclear if this is a somatic mutation, as there is no indication
whether this genetic change was also observed in the paired
normal colon sample . This investigation also identified 15
cases with LOH involving the EPHB2 gene and screened for
mutations in the remaining EPHB2 allele. Since mutations in the
remaining allele were not identified, Oba et al. suggested that
EPHB2 is not a classical tumor suppressor gene. However, since
only 50 samples of likely sporadic cases of colorectal cancer were
analyzed, a tumor suppressor role for EPHB2 cannot be excluded.
In a more recent study, Kokko et al. reported an association of
three novel variants with colorectal cancer . Germline
missense changes resulting in I361V, R568W, and D861N were
observed in colorectal cancer patients, but not in healthy controls.
However, it is possible that these three variants are rare neutral
polymorphisms since the biological significance of the variants was
not evaluated using direct functional assays. The patients screened
in these latter two studies did not necessarily have significant
family histories of colorectal cancer. In contrast to these two earlier
reports, our study was designed to specifically evaluate the role of
germline EPHB2 mutations in patients with familial colorectal
cancer, and not in sporadic cases. Despite study design differences,
together these three investigations suggest that EPHB2 germline
mutations are not common occurrences in colorectal cancer.
Further investigations of larger sample sizes are needed to confirm
In summary, we identified a germline EPHB2 variant (G787R)
with diminished biological activity in a colorectal cancer patient,
and suggest that EPHB2 mutations contribute to a small fraction of
hereditary colorectal cancer. The rarity of germline EPHB2
mutations supports a more significant role for EPHB2 in colorectal
tumor progression rather than in tumor initiation. Since the EPHB
receptors (EPHB2, EPHB3 and EPHB4) follow a similar pattern of
transcriptional silencing in colorectal cancers, all EPHB receptor
family members probably play a similar role in this disease.
Therefore, the EPHB family likely accounts for a minor
proportion of genetic predisposition to colorectal cancer but has
an important role in tumor progression. Although our findings
suggest that the EPHB gene family should not be routinely
screened for germline mutations in familial cases, the EPHB genes
are candidate tumor suppressors, likely accounting for rare cases of
familial colorectal cancer.
Found at: doi:10.1371/journal.pone.0002885.s001 (0.06 MB
Found at: doi:10.1371/journal.pone.0002885.s002 (0.05 MB
The authors thank Dr. D. Daftary, Ms. S. Holter, Ms. A. Janson for their
assistance with data collection, and Ms. Joelle Fontaine, Ms. T. Selander
and the Mount Sinai Hospital Biospecimen Repository for technical
Conceived and designed the experiments: GZ BZ TJH TP SG. Performed
the experiments: GZ CJ JB AM PL VF LC SS. Analyzed the data: GZ CJ
JB. Contributed reagents/materials/analysis tools: GZ SG. Wrote the
paper: GZ SG.
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EPHB2 in Colorectal Cancer
PLoS ONE | www.plosone.org 6 August 2008 | Volume 3 | Issue 8 | e2885