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§
¶
¶
§
From the Departments of Pathology, Brigham and Women's
Hospital*
and Children's Hospital,¶
and the Division of Pediatric Oncology,
Dana-Farber Cancer Institute and Children's Hospital, and the
Departments of Pathology
and
Pediatrics,§
Harvard Medical School, Boston,
Massachusetts
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Congenital (infantile) fibrosarcomas (CFSs) are uncommon soft tissue tumors, principally arising in the extremities, which are also diagnosed generally in the first year of life.11,12 CFSs have broad histological overlap with CMNs, and their clinical course is relatively benign, especially in comparison with the aggressive clinical behavior of histologically similar fibrosarcomas in adult patients.13
Cytogenetic studies have demonstrated a strikingly similar profile, consisting of multiple polysomies, in CMN14,15 and CFS.16-23 The more cellular tumors, whether CMN or CFS, often have clonal polysomies of chromosomes 8, 11, 17, and/or 20. On the other hand, these polysomies have not been demonstrated in less cellular CMNs and CFSs, and acquisition of polysomies is associated with progression from classic to cellular histology in mixed histology CMN.15,24 Hence, it is likely that the chromosomal polysomies are secondary oncogenic events, responsible in part for histological progression within these tumors. Presumably, other genomic aberrations are responsible for initial transformation of CMN nonneoplastic progenitor cells. Inasmuch as CMNs and CFSs share histological, clinical, and cytogenetic features, it is reasonable to hypothesize a common pathogenesis in these tumors.15 Recently, CFSs were shown to contain a novel t(12;15)(p13;q25) translocation, resulting in ETV6-NTRK3 gene fusion.25 To date, the t(12;15) translocation has not been reported in CMN. However, this translocation could have been overlooked when evaluated by conventional chromosome banding methods. This is because the regions exchanged between chromosomes 12 and 15 are similar in size and banding characteristics. Given the above mentioned evidence for common pathogenetic pathways in CMN and CFS, we evaluated whether the t(12;15) translocation and ETV6-NTRK3 fusion are present in CMN. Furthermore, we evaluated whether the translocation is present, and therefore a potential initial transforming event, in CMNs and CFSs lacking chromosomal trisomies.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. Histological material was
reviewed in all cases. The CMNs included one case with classic
histology, two cases with cellular histology, and three cases with
mixed histology. Fresh material was available from four CMNs and five
CFSs for cell culture and cytogenetic analysis; the remaining two CMNs
were available only as paraffin blocks. Frozen tumor material for RNA
isolation and reverse transcription polymerase chain reaction (RT-PCR)
was available from the same four CMNs that were karyotyped and from
three CFSs. One CFS was analyzed both at time of original biopsy (CFS
5a) and at definitive resection 1 month later (CFS 5b).
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CMN and CFS specimens were processed for cytogenetic analysis immediately after biopsy. A 2- to 3-mm3 portion of each specimen was minced with scalpels, disaggregated with collagenase, and cultured as described previously.26 Metaphase harvesting, fixation in 3:1 methanol:acetic acid, slide making, and trypsin-Giemsa staining were also performed as described previously.26 Metaphase cells were harvested within 3 to 7 days after establishing the primary cultures.
FISH
Four-micron-thick, paraffin-embedded sections were prepared on
silane-coated slides and baked overnight at 65°C. Tissue section
pretreatment and proteinase K digestion were accomplished using the
Oncor Tissue Kit (Oncor, Gaithersburg, MD), according to the
manufacturer's recommendations. Cytogenetic preparations were
dehydrated and denatured according to standard protocols.27
Hybridization and washing steps, for both tissue sections and
cytogenetic preparations, were also performed according to standard
protocols.27
Rearrangements of the ETV6 region
were evaluated by dual-color fluorescence in situ
hybridization (FISH) using flanking yeast artificial chromosome (YAC)
clones 788_g_5 (telomeric) and 916_d_8 (centromeric). YACs
788_g_5 and 916_d_8 were digoxigenin and biotin labeled, respectively.
Numerical aberrations of chromosomes 8 and 11 were evaluated using
D8Z2 and D11Z1 pericentromeric 
-satellite
probes, which were biotin and digoxigenin labeled, respectively.
Chromosomes 17 and 20 were not evaluated by FISH, although these
chromosomes are also involved frequently in CMN and CFS polysomies;
very few CMNs or CFSs have chromosome 17 or 20 polysomies in the
absence of chromosome 8 or 11 polysomies. FISH probes were detected
using avidin-Texas Red (Vector, Burlingame, CA) and FITC
anti-digoxigenin (Boehringer, Indianopolis, IN), respectively, and all
slides were counterstained with 0.1 to 1.0 mg/ml
4,6-diamidino-2-phenylindole-dihydrochloride (DAPI). One hundred
nonoverlapping interphase nuclei were scored for each paraffin section,
and images were captured using a charge-coupled device camera
(Photometrics, Tucson, AZ). The criteria used in scoring FISH signals
were as recommend by Hopman et al.28
Tumors were classified
as trisomic or tetrasomic if more than 5% of nuclei had three or four
pericentromeric -satellite signals, respectively. Tumors were
classified as ETV6-region rearranged if more than 20% of
nuclei contained wide splits between the centromeric and telomeric
ETV6-region YAC clones.
RT-PCR and DNA Sequencing
Total RNA was extracted from 20 to 30 mg of frozen tissue using Trizol (Gibco, Gaithersburg, MD), according to the manufacturer's protocol. The resultant RNA pellets were dissolved in 25 µl of dH2O, and 1 µl of the RNA solution was reverse transcribed using random primers (GeneAmp Kit, Perkin Elmer, Norwalk, CT). Semi-nested PCR was performed using two ETV6 forward primers (F/ETV6/541, 5'-CCTCCCACCATTGAACTGTT-3'29 and F/ETV6/701, 5'-AGAACAACCACCAGGAGTCC-3')29 and a NTRK3 reverse primer (R/NTRK3/1838, 5'-CCGCACACTCCATAGAACTTGAC-3').25 First-round PCR was with F/ETV6/541 and R/NTRK3/1838 at 95°C for 15 seconds and 60°C for 2 minutes for 30 cycles. Second-round PCR was with F/ETV6/701 and R/NTRK3/1838 at 94°C for 2 minutes, then 94°C for 30 seconds, 60 to 55°C (touchdown) for 30 seconds, and 72°C for 1 minute for 10 cycles, and then 94°C for 30 seconds, 55°C for 30 seconds, and 72°C for 1 minute for 25 cycles. Five microliters of the second-round PCR product was electrophoresed on a 0.9% agarose gel containing ethidium bromide, and DNA fragments were purified using the Qiaquick gel extraction kit (Qiagen, Valencia, CA). All fragments were sequenced in forward and reverse directions using the F/ETV6/701 and R/NTRK3/1838 primers, respectively, by cycle sequencing with ABI BigDye terminators. Sequences were analyzed using an ABI Prism 377 sequencer.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The clinicopathological data are summarized in Table 1
. One CMN
exhibited the classic histological pattern with thick interlacing
bundles of elongate eosinophilic spindle cells with delicate cytoplasm
(Figure 1A)
. The neoplastic cells
entrapped normal renal structures, and mitoses were rare. The cellular
variants were composed of more polygonal or short spindle cells (Figure 1C)
. They were diffusely cellular, contained focal necrosis, had
numerous mitoses, and had pushing borders. The mixed variants consisted
of an admixture of discrete areas characteristic of both the classic
and cellular variants (Figure 1B)
. The CFSs were composed of a
monomorphic population of densely packed polygonal or short spindle
cells with minimal pleomorphism and a fascicular growth pattern (Figure 1D)
. There were numerous mitoses, and some cases contained focal areas
of necrosis. The CFSs bore a striking resemblance to the cellular
variants of CMN (Figure 1, C and D)
.
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The t(12;15) translocation was subtle cytogenetically (Figure 2, A and B)
and was manifested primarily by
loss of the normal terminal dark band from the long arm of chromosome
15. This translocation was overlooked at the time of original
cytogenetic analysis in most cases. However, review of all karyotypes,
prompted by description of CFS t(12;15) translocations by Knezevich et
al,25
suggested similar t(12;15) translocations in two CMNs
and three CFSs (Table 1)
. Another case, CFS 2, had a rearrangement of
the NTRK3 region (chromosome band 15q26) that could not be
ascribed to t(12;15) based on the banding study. Additional chromosome
aberrations were found in most tumors. Two cellular CMNs contained
trisomy 11, whereas two mixed histology CMNs lacked apparent chromosome
aberrations (Table 1)
. Each of five CFSs contained polysomies of
chromosomes 8, 11, 17, and/or 20 (Table 1)
.
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FISH analyses revealed rearrangement of the ETV6 gene
region in five of six CMNs and five of five CFSs (Table 1
; Figure 2, C–F
). Correlations with chromosome 8 and 11 polysomies were determined
both by Giemsa emulation in DAPI-stained FISH metaphase cell
preparations (Figure 2, A and B)
and by sequential FISH analyses using
chromosome 8 and 11 pericentromeric -satellite probes (Figure 2F)
.
These analyses demonstrated that all tumors containing chromosome 8 and
11 polysomies also contained ETV6-region rearrangements. By
contrast, ETV6 rearrangements were demonstrable in three
specimens, CMN 2, CMN 5, and CFS 5a, which lacked chromosome
polysomies. CFS 5a was a diagnostic needle biopsy in a 7-day-old girl,
whereas CFS 5b, containing trisomies 8 and 11 along with the
ETV6-region rearrangement, was the subsequent resection
performed 3 weeks later. The CFS 5 data are consistent with intratumor
cytogenetic heterogeneity resulting from acquisition of chromosomal
trisomies in an ETV6-rearranged tumor population.
The rationale in undertaking the FISH chromosome 8 and 11 studies was to determine, particularly in mixed histology CMN, whether chromosome polysomies might be restricted to more cellular regions whereas ETV6-region rearrangements might be found in both less cellular and more cellular regions. However, because of the complex admixture of less cellular and more cellular areas in a given histological section, combined with a relative loss of histological detail after proteinase K treatment, it was difficult to ascertain whether a particular nucleus was in a more cellular or less cellular region within an individual case of mixed histology CMN.
RT-PCR and DNA Sequencing
Nested RT-PCR, using ETV6 forward primers and an
NTRK3 reverse primer, revealed ~550-bp fragments in three
of four CMNs and three of three CFSs (Figure 3)
. Forward and reverse sequencing for
each of these fragments demonstrated ETV6-NTRK3 fusion
transcripts (Figure 4)
, identical to
those reported previously in CFS (GenBank accession number AF041811).
No sequence variations were detected in any of these six fusion
transcripts. The corresponding full-length ETV6-NTRK3 fusion
transcripts, as demonstrated by Knezevich et al,25
encode
ETV6 helix-loop-helix and NTRK3 tyrosine kinase
domains.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Demonstration of a molecular relationship, in and of itself, does not establish a more general relationship between different clinicopathological tumor entities. It is well known, for example, that a wide variety of neoplasms acquire inactivating mutations of the same tumor suppressor genes. However, specific chromosome translocations are typically found only in tumors of related, or identical, histogenesis and pathogenesis. This is because nonrandom chromosome translocations involve juxtaposition, and often fusion, of genes from each of the participating chromosomes. These gene rearrangements are functional only if one of the genes is transcriptionally active in the nonneoplastic progenitor cell and if one or both of the genes, when overexpressed or rearranged, can serve an oncogenic role in that cell. Observations to date suggest that a specific translocation is unlikely to play a transforming role, in vivo, in widely divergent cell lineages.32
Our studies reveal identical chromosome translocations, associated with ETV6-NTRK3 fusion transcripts, in CFS and CMN. CFS and CMN arise in the soft tissues and kidney, respectively, and share many clinicopathological features. CFSs are histologically similar, but clinically distinct, from fibrosarcomas in older children and adults.11-13,16,33-36 Many CFSs follow a benign clinical course despite worrisome histological features, whereas adult fibrosarcomas are often lethal. Likewise, CMNs, which are very similar histologically to CFSs, are generally cured by complete resection or nephrectomy.2,3 Karyotypic and molecular cytogenetic studies also support a pathogenetic relationship between CFS and CMN. Both tumors, particularly in cases with greater degrees of cellularity, are associated with gains of chromosomes 8, 11, 17, and 20.14-23 In the present study, we demonstrate ETV6-NTRK3 fusion transcripts and/or ETV6-region chromosomal rearrangement in five of six CMNs and in five of five CFSs. Notably, Knezevich et al demonstrated that the CFS-associated t(12;15)(p13;q25) translocation is not found in adult fibrosarcomas.25 Therefore, the accumulated evidence indicates that CFSs and CMNs are closely related neoplasms, which are distinct, clinically and pathogenetically, from adult fibrosarcomas. It remains unclear, however, whether CMN and CFS are the same entity, differing only in site of origin. We favor this viewpoint, given that the histological, clinical, cytogenetic, and molecular evidence support a common histogenesis and pathogenesis.
Cytogenetic t(12;15) translocations were not identified in several
cases in this series (CMN4, CFS1, and CFS5), although RT-PCR and FISH
analyses revealed ETV6-region rearrangements in those same
cases (Table 1)
. The chromosome banding was of average quality in these
cases, but cytogenetic recognition of the t(12;15) translocation
requires superior banding quality. Therefore, we view these cytogenetic
analyses as uninformative, rather than negative, for the translocation.
Given this experience, we would be reluctant to exclude a t(12;15)
translocation, in CMN or CFS, based solely on chromosome banding
findings.
Acquisition of the above mentioned chromosome polysomies is associated
with histological progression in CMN.15,24
The polysomies
are often acquired only as CMNs become more cellular, and they are
unlikely to be the oncogenetic events responsible for initial
neoplastic transformation of the nonmalignant progenitor cells. Our
present findings suggest that ETV6-NTRK3 fusion might
represent the initial transforming event. This possibility is supported
by demonstration of ETV6-region rearrangement, and/or
ETV6-NTRK3 fusion, in two CMNs (cases CMN 2 and CMN 5) and
one CFS (case CFS 5a) that lacked detectable chromosome polysomies
(Table 1)
. It is also notable that the original diagnostic needle
biopsy, CFS 5a, lacked chromosome polysomies but had
ETV6-region rearrangement, whereas the subsequent resection,
CFS 5b, contained trisomy 8, 11, and 20, in addition to the
ETV6-region rearrangement.
ETV6 (also known as TEL) was originally characterized as an oncogene in several types of leukemias and myeloproliferative syndromes.37,38 ETV6 translocations, in these hematopoietic neoplasms, involve a variety of partner genes. Several of the ETV6 translocation partners, including PDGFRß, ABL, and JAK2,29,37-39 are tyrosine kinase genes; the transcripts associated with these translocations consist of the ETV6 5' end fused to the 3' end of the tyrosine kinase gene. The corresponding oncoproteins include the ETV6 helix-loop-helix (HLH) domain (amino-terminal end) and a tyrosine kinase domain (carboxyl-terminal end). The oncogenic mechanism, in the well characterized ETV6-ABL and ETV6-PDGFRß fusion oncoproteins, involves ETV6 HLH-mediated dimerization, resulting in constitutive tyrosine kinase catalytic activity.29,40,41 Similarly, HLH-mediated ETV6-NTRK3 homodimerization might engender ligand-independent activation of the NTRK3 tyrosine kinase, leading to autophosphorylation of specific tyrosine residues and activation of p21ras-related signal transduction cascades.42 NTRK3 expression has been observed primarily in neuronal cells43,44 and in neuroectodermal tumors, and Knezevich et al did not detect NTRK3 expression in fibroblasts.25 These observations suggest that unscheduled NTRK3 tyrosine kinase domain expression, mediated by the ETV6 promotor, is important in CMN and CFS oncogenic transformation. However, as discussed above, it is also likely that ETV6 performs an oncogenic role above and beyond driving NTRK3 transcription. The critical role of the ETV6 HLH domain is evidenced by the invariant sequence of the ETV6-NTRK3 fusion transcripts in the six CFSs and CMNs reported herein and in the three CFSs reported by Knezevich et al.25
Only one of six CMNs (case CMN 4) in this study lacked the t(12;15)
translocation or ETV6-region rearrangement (Table 1)
. It is
reasonable to question the histological diagnosis in this case, because
low-grade fibrous lesions of infancy represent a difficult area in
pathological diagnosis. The differential diagnosis of CMN is complex,
including such entities as fibromatosis, clear-cell sarcoma,
stroma-predominant Wilms' tumor, and low-grade malignant peripheral
nerve sheath tumor. However, even upon additional review, this tumor
was believed to be a CMN. It is possible that neither ETV6
nor NTRK3 was oncogenically activated in this case, but it
is also possible that NTRK3 was activated by a point
mutation undetected by the cytogenetic and RT-PCR assays. There is
ample precedence for activating point mutations in other receptor
tyrosine kinase (RTK) oncogenes. Oncogene mutations in RTK
extracellular, transmembrane, or juxtamembrane domains can affect
tyrosine kinase activity by promoting dimerization.45
Other
activating mutations modulate tyrosine kinase activity through direct
involvement of the catalytic domain.45
In summary, we have established that CMNs contain the same t(12;15)(p13;q25) translocation described recently in CFS. This translocation is associated with an ETV6-NTRK3 fusion gene, in which the ETV6 HLH domain is coupled with the NTRK3 tyrosine kinase domain. ETV6-NTRK3 fusion appears to be an early event in the oncogenesis of CMN and CFS, antedating the acquisition of several characteristic chromosome polysomies. Clinical behavior, histological features, cytogenetics, and molecular data all suggest a close relationship between CMN and CFS. In fact, the evidence is strong that these are one and the same neoplasm, albeit presenting in different anatomic sites.
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Footnotes |
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Accepted for publication July 31, 1998.
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