2016, Volume 32, Number 2, Page(s) 139-140
Relationship of c-Kit Gene and Microsatellit Instability in the Pathogenesis of Wilms Tumors
Gülden DINIZ1, Yasemin BASKIN2, Gizem ÇALIBAŞI2, Safiye AKTAŞ 2
1Pathology Laboratory, Tepecik Education and Research Hospital, İZMİR, TURKEY
2Department of Basic Oncology, Dokuz Eylul University, Institute of Oncology, İZMİR, TURKEY
Hereditary nonpolyposis colon cancer (HNPCC), known
as Lynch syndrome (LS), is caused by germline mutations
in one of five genes that function in the DNA mismatch
repair (MMR) process involving MLH1, MSH2, MSH6 or
PMS21,2. Patients with mutations in MMR genes exhibit
microsatellite instability (MSI), a phenomenon in which
errors in replication of highly repetitive sequences cannot
be repaired, resulting in alteration of the length of repeat
sequences and eventually genomic integrity2. Mutational
spectra for genes with high MSI frequencies vary between
different cancers. Therefore, only marker genes of MSI
are analyzed for evaluation of MMR genes. It has been
demonstrated that patients with LS almost always exhibit
MSI due to underlying defects in MMR genes and especially
MLH1 and MSH23.
The importance of MSI and MMR has not been fully
established in Wilms tumor (WT). In our earlier study,
we evaluated MSI and MMR in 45 children with WT.
Expressions of MLH1, MSH2, MSH6 and PMS2 were
analyzed by immunohistochemistry of archival tissue
sections. Real-time PCR melting analysis and fluorescence
capillary electrophoresis (FCE) were performed to evaluate
the MSI markers BAT25, BAT26, NR21, NR24, mono27,
pentaD and pentaC genes in DNA extracted from tumor
and normal tissues. MSI was observed in 6 cases but
there was no association of MMR proteins and MSI with
tissue expression. All MSIs were determined in the BAT-
25 sequence of seven microsatellite marker genes3.
Interestingly, this microsatellite marker gene is localized
in the human c-kit gene4. We also found statistical
significance between MSI and the size of the tumors
(p=0.046). These findings were thought to indicate that the
c-kit gene may play an important role in the development of
WT. We therefore analyzed the c-kit gene in these six cases.
Direct sequencing of PCR products for the c-kit gene was
performed using the Beckman Genetic Analysis System. In
three of the six cases, there were several genetic mutations
in exon11 and exon17 of the c-kit gene (Table I, Figüre 1).
The KIT gene belongs to the family of class III receptor
protein tyrosine kinases and KIT mutations have now been
detected in several neoplasms5,6. The use of tyrosine
kinase receptor inhibitor has increasingly become a valuable
therapeutic alternative in some KIT-related neoplasms6.
Hitherto it has been shown that KIT overexpression or
KIT mutations are rare in WT, although they do appear to
confer a worse prognosis6,7. In our study, there were no
statistically significant correlations between MSI positivity,
and clinical prognostic factors such as bilateralism, stage
and survival. However, MSI was correlated with the size
of tumors. The mean diameter was 11.67±2.8cm in tumors
with MSI and 8.92±2.85cm in tumors with microsatellite
In conclusion, the most characteristic features of MSI
tumors associated with the defects of MMR genes in LS
are now becoming clear, but the biological and clinical
implications of MSI and the c-kit gene still remain unclear.
More information related to the Bat25 marker gene of
MSI and its connections to receptor protein tyrosine
kinase pathways are essential to better understand the
fundamental mechanisms of cancer development3. Our
findings suggest that it is important to determine whether
molecular target genes function as a differentially regulated
c-kit gene in the tumorigenesis of WT.
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