Biomedical Engineering Reference
In-Depth Information
[49]. Substitutions are the type of mutation usually found and these
tumors (especially with exon 17 mutations) have been recently
reported to be a little more frequent in intestinal GISTs [50]. Exon 17
mutations are concerning for resistance to imatinib, while untreated
exon 13 mutant tumors tend to be responsive [51].
gene mutated;
however, approximately 10% of tumors have alteration of the other
allele, which may result in a malignant clinical course [15, 42, 52].
Parenthetically, it is worth mentioning that the KIT protein can be
detected using immunohistochemistry in greater than 95% GISTs,
and show a less than perfect concordance with the presence of the
mutation [53]. Indeed,
Typically GISTs have one allele of the
KIT
wild-type” tumors, i.e., those tumors that
lack a detectable mutation in one of the kinase genes, often express
the protein.
KIT “
9.2.2
Mutations in RTKs: PDGFRA
While
mutations account for the majority of GISTs, mutually
exclusive mutations occur in the
KIT
which codes for
another type III receptor tyrosine kinase, in 10 - 30% of tumors
PDFGRA
gene
,
lacking the
mutation, i.e., approximately 7% of all GISTs (Fig.
9.1) [54]. The most commonly involved site is exon 18 and rarely
mutations occur in exons 12 and 14 (which correspond to the
kinase II domain, juxtamembrane domain and the kinase I domain
respectively) [1, 8, 11, 12, 16, 43-45, 55]. GISTs with these mutations
preferentially localize to the stomach, contain epithelioid cells that
tend not to express an immunohistochemically detectable KIT
protein and demonstrate more indolent behavior [55]. It should
also be noted that mutations producing the D842V alteration (a
change from aspartic acid to valine at codon 842) in exon 18, occur
most often and characterize GISTs that tend to be non-responsive to
imatinib therapy [16, 42].
KIT
9.2.3
BRAF
Mutation
BRAF,
which codes for a serine/threonine protein kinase, is mutated
in several malignancies particularly melanoma and papillary thyroid
carcinoma, with most mutations involving the V600E amino-acid
substitution in exon 15 [56]. Approximately 4-13% of
KIT/PDGFRA
mutation negative GISTs demonstrate the
BRAF
V600E mutation [18,
