2
Basic Cytogenetics and the Role of Genetics in Cancer Development
Table 2.4
Characteristics of different types of RET/PTC rearrangement in papillary thyroid carcinoma
Type of RET/PTC
Gene fused w ith RET
Mechanism of rearrangement
Prevalence among all RET/PTC
RET/PTC 1
H4 (D10S170)
inv(10)(q11.2;q21)
60-70%
RET/PTC2
Ria
t(10;17)(q11.2;q23)
<10%
RET/PTC3
(and
RET/PTC4)
ELE1 (RFG, ARA70)
inv(10)(q11.2)
20-30%
RET/PTC5
GOLGA5
t(10;14)(q11.2;q?)
Rare
RET/PTC6
HTIF1
t(7;10)(q32;q11.2)
Rare
RET/PTC7
RFG7
t(1;10)(p 13;q 11.2)
Rare
RET/ELKS
ELKS
t(10;12)(q11.2;p13)
Rare
RET/KTN1
KTN1
t(10;14)(q11.2;q22.1)
Rare
RET/RFG8
RFG8
t(10;18)(q11.2;q21
-22)
Rare
RET/PC M -1
PCM-1
t(8;10)(p21
-22;q 11.2)
Rare
geographic regions, and sensitivities of the detection methods
used (polymerase chain reaction versus FISH), particularly if the
rearrangement is present only in a small proportion of tumor
cells or if the
RET/PTC
transcripts is expressed at low levels. The
average prevalence is 20-30% in sporadic adult cases and rises
to 45-60% among tumors from children and young adults.
It is higher (50-80% ) in papillary carcinoma associated with
radiation exposure, and it is thought that the close association
between
RET/PTC
translocations and irradiation is due to spatial
proximity of the participating chromosomal loci in the nuclei of
thyroid cells, providing a structural basis for radiation-induced
illegitimate recombination of the genes.14 Most studies con-
cur that
RET/PTC
rearrangements are rare or absent in benign
adenomas, and not observed in other types of thyroid carcino-
mas. They are more frequent in PTC exhibiting a classic architec-
ture and in microcarcinomas.52 Among the different variants of
RET/PTC
translocations,
RET/PTC1
and
3
are the most frequent,
accounting for more than 90% of all rearrangements.53
A small subset of PTC (around 10%) is characterized by
rearrangement of the
NTRK
gene, another receptor tyrosine
kinase, located on chromosome 1q22 and encoding one of the
receptors for the nerve growth factor.
NTRK
gene activation is
due to chromosome 1 inversions or balanced translocations
between chromosome 1 and 10, resulting in fusion of the NTRK
tyrosine kinase domain to 5'-end sequences from at least three
different genes:
tropomyosin (TPM3)
or
TPR
gene, both on chro-
mosome 1, and
TFG
gene located on chromosome 3.51,53
Follicular Thyroid Carcinoma
Follicular thyroid carcinomas
are characterized by
PPARy
(peroxisome proliferator-activated receptor y)
gene rearrangements
in 25-50% of cases, mainly under the form of a distinctive
t(2;3)(q13;p25) chromosomal translocation.53 This transloca-
tion leads to the fusion of the
PAX8
gene
(paired box gene
8) with
PPARy
gene, resulting in a fusion protein designed PPFP. PAX8
is a transcription factor expressed at high levels in thyrocytes
and necessary for normal thyroid development.
PPARy
encodes
a nuclear hormone receptor transcription factor whose activity
is related to adipocyte differentiation, lipid and carbohydrate
metabolism, and cellular proliferation and differentiation. PPFP
is thought to exert its oncogenic properties through a mechanism
in which it acts as a dominant-negative inhibitor of wild-type
PPARy.
This results in inhibition of apoptosis and promotion
of proliferation as well as anchorage-independent growth of
thyroid follicular cells.
PPARy
has mainly been observed in low-
stage follicular carcinomas with vascular invasion and has been
identified at apparent lower frequency in adenomas.
Clinical Applications of Conventional
Cytogenetics and FISH in Cytology
Introduction
Cytological assessment of a fine-needle aspiration (FNA) speci-
men remains the first-line morphological investigation of any
suspected mass but cytomorphology alone—hence, without tis-
sue architecture—is not always sufficient for a definitive diag-
nosis.54,55 For example, small-to-intermediate cell lymphomas
such as MCL, FL, or MZL can show overlapping cytomorpho-
logic features with one another as well as with reactive lymph
node hyperplasia. Limitations of FNA are also encountered in
soft-tissue neoplasms, especially in the diagnostic management
of small round-cell tumors. Most of the diagnostic problems can
be solved with the help of immunocytochemistry but limita-
tions can be encountered mainly due to immunophenotypic
heterogeneity among small B-NHL subtypes.56 For examples,
the intensity of CD10 expression in FL has been shown to be
variable, and even negative in some cases.57 MCL and SLL can
be distinguished by differences in CD23 expression but CD23
can be weakly expressed in both subtypes.58 CD5 expres-
sion may not systematically be used as a diagnostic criterion
between MCL and SLL, and some FL can also exhibit a CD5
positivity.59 It is thus necessary that FNA examination be sup-
plemented with ancillary methods such as karyotype, FISH, or
polymerase chain reaction (PCR). Conventional cytogenetics
allows complete karyotype analysis and, as such, remains the
historic gold standard by which everything is started. However,
it is a cumbersome and time-consuming procedure requiring
adequate fresh tissue and special cell culture techniques. PCR
and interphase FISH (I-FISH) methods are more practical in that
they can bypass the need of cell culture. They have both their
own advantages and disadvantages, and must be considered as
complementary rather than competing with one another. It is
therefore not surprising that both have been included in a com-
bined diagnostic algorithm proposed in the literature.60-62 How-
ever, I-FISH remains a less sophisticated laboratory technique
than PCR and offers a greater qualitative sensitivity in studies
of tumor-associated chromosomal abnormalities as will be
39
previous page 45 ComprehensiveCytopathology 1104p 2008 read online next page 47 ComprehensiveCytopathology 1104p 2008 read online Home Toggle text on/off