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Published in final edited form as: Mol Cell Endocrinol. 2009 Sep 18;321(1):36–43. doi: 10.1016/j.mce.2009.09.013

MECHANISMS OF CHROMOSOMAL REARRANGEMENTS IN SOLID TUMORS: THE MODEL OF PAPILLARY THYROID CARCINOMA

Manoj Gandhi 1, Viktoria Evdokimova 1, Yuri E Nikiforov 1,*
PMCID: PMC2849910  NIHMSID: NIHMS147079  PMID: 19766698

Abstract

Thyroid cancer, and its most common type, papillary carcinoma, frequently have chromosomal rearrangements and therefore represents a good model for the understanding of mechanisms of chromosomal rearrangements in solid tumors. Several types of rearrangement known to occur in thyroid cancer, including RET/PTC, NTRK1 and BRAF/AKAP9, are more common in radiation-associated thyroid tumors and RET/PTC can be induced experimentally by exposing human thyroid cells to ionizing radiation. In this review, the molecular mechanisms of generation of RET/PTC and other chromosomal rearrangements are discussed, with the emphasis on the role of nuclear architecture and interphase gene proximity in the generation of intrachromosomal rearrangements in thyroid cells.

Thyroid cancer and chromosomal rearrangements

Thyroid cancer is the most common malignant tumor of the endocrine system and accounts for approximately 1% of all newly diagnosed cancer cases [1]. Papillary thyroid carcinoma is the most prevalent type of thyroid malignancy and constitutes ~80% of all thyroid cancers. More than 70% of papillary carcinomas have known genetic alterations all of which lead to the activation of the mitogen-activated protein kinase (MAPK) signaling pathway [2–4]. These abnormalities include chromosomal rearrangements (intrachromosomal inversions and interchromosomal translocations) and point mutations. Most common point mutations involve the BRAF gene as well as RAS genes [5,6]. The most common chromosomal rearrangement involves the RET gene and is called RET/PTC [7,8]. In addition to RET/PTC, chromosomal rearrangements involving the NTRK1 and BRAF genes also occur in papillary thyroid carcinomas, although with a significantly lower prevalence [9,10]. As a result, papillary thyroid carcinoma represents a good model to study the mechanisms of chromosomal rearrangements in solid tumors.

Radiation-induced thyroid cancer involves chromosomal rearrangements rather than point mutations

Exposure to ionizing radiation is a well known risk factor for thyroid cancer, especially for papillary carcinoma. An increased incidence of thyroid cancer has been documented after therapeutic use of ionizing radiation during childhood [11,12] as well as after accidental environmental exposure. The latter includes survivors of the atomic bomb explosion in Hiroshima and Nagasaki in 1945 [13,14] and of the nuclear test fallout in the Marshall Islands in 1954 [15,16] and those exposed to radiation after the Chernobyl nuclear disaster in 1986 [17–19]. Studied of thyroid cancer in various populations revealed a sharply different prevalence of chromosomal rearrangements and point mutations in tumors from individuals exposed to ionizing radiation as compared to sporadic tumors, i.e. arising in patients with no radiation history [10,20] (Table 1). Indeed, the prevalence of RET/PTC is very high in individuals with a history of radiation exposure. This includes those subjected to either accidental (mostly radioiodine) irradiation or therapeutic (mostly external beam) irradiation, as 50–80% of those papillary carcinomas harbor RET/PTC [21–23]. In contrast, in the general population clonal RET/PTC rearrangements are seen in 10–40% of papillary carcinomas in most studies, although the reported prevalence varies dramatically [24,25], largely due to different sensitivities of the techniques used for their detection [26,27]. Higher prevalence of RET/PTC is seen in pediatric tumors [23,28,29], a significant portion of which may be associated with radiation exposure. Another chromosomal rearrangement, BRAF/AKAP9 is also found predominantly in papillary carcinomas associated with radiation exposure [10]. The opposite is true for point mutations, such as those involving the BRAF gene. BRAF V600E point mutation represents the most common genetic alteration in sporadic papillary carcinomas, being found in 40–45% of those tumors [30,31], but it is rarely found in radiation-related tumors [32]. Moreover, among papillary carcinomas in atomic bomb survivors in Japan, the presence of RET/PTC directly correlated with the dose of radiation, whereas the inverse correlation was found between the dose and BRAF point mutations [33,34]. These findings provide evidence that generation of chromosomal rearrangements in human thyroid carcinomas is closely linked to radiation exposure.

Table 1.

Prevalence of chromosomal rearrangements and point mutation in sporadic and radiation-induced papillary thyroid carcinomas

Genetic alteration [ref] Sporadic Tumors
(%)		 Radiation-Induced
Tumors (%)
RET/PTC rearrangement [21–24,26,39] 10–40 50–85
TRK rearrangement [21,96] < 5 6
BRAF rearrangement [10] 1 11
BRAF point mutation [30–32,97–99] 40–45 0–4
RAS point mutation [100–102] 10–15 0
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Types of RET/PTC rearrangement in sporadic and radiation-induced cancers

RET/PTC rearrangement is formed by fusion between the 3’ portion of the RET gene, coding for the receptor tyrosine kinase, and the 5’ portion of various unrelated genes. The two most common rearrangement types, RET/PTC1 and RET/PTC3, are paracentric inversions since both RET and its respective fusion partner, H4 or NCOA4 (ELE1; RFG, ARA70), reside on the long arm of chromosome 10 [8,35,36] RET/PTC2 and nine more recently identified types of RET/PTC are all interchromosomal translocations [37,38].

In most populations, RET/PTC1 is the most common type of RET/PTC as it comprises 60–70% of positive cases, whereas RET/PTC3 accounts for 20–30%, and RET/PTC2 and other novel rearrangement types for less than 5–10% [24,25]. In individuals exposed to accidental or therapeutic radiation, RET/PTC1 remained to be the most common rearrangement type except for the tumors that developed less than 10 years after radiation exposure at Chernobyl, where RET/PTC3 was the predominant rearrangement type [21,22,39,40].

Experimental evidence for the association between RET/PTC rearrangements and radiation exposure

The association between RET/PTC rearrangement and ionizing radiation is supported by several studies demonstrating the induction of RET/PTC by irradiation of cultured human thyroid cells [41,42] and of human fetal thyroid tissue xenografts in SCID mice [43,44]. It has been shown that exposure of HTori-3 human thyroid cells to physiologically relevant doses of gamma-radiation (0.1–10 Gy) resulted in a dose-dependent generation of both RET/PTC1 and RET/PTC3 rearrangements [42]. In this study, RET/PTC1 was more common than RET/PTC3 after each dose, comprising 80% of all rearrangements.

Although the dose of exposure were significantly higher (50–100 Gy) in two studies that employed human fetal thyroid tissue xenografts, they demonstrated that X-ray irradiation led to the generation of both RET/PTC1 and RET/PTC3 rearrangements, with RET/PTC1 type being the most common [43,44]. These studies provide evidence for the direct link between exposure to ionizing radiation and generation of RET/PTC rearrangement in human thyroid cells.

Molecular mechanisms of chromosomal aberrations induced by radiation

Ionizing radiation damages DNA in a variety of ways as a result of either direct energy deposition along the radiation track or by secondary reactive oxygen species produced by ionization of water. It is known that 1 Gy of X-ray radiation produces 500–1000 single-strand DNA breaks, 20–40 double-strand breaks (DSBs), >3000 damaged bases, and ~150 DNA-protein crosslinks per cell [45,46]. Of these types of DNA damage, DSBs are considered to be a crucial primary lesion for a variety of biological end points, including cell killing, chromosomal aberrations, and cell transformation [47,48]. However, how exactly radiogenic DSBs lead to chromosomal rearrangements remains not fully understood. Several basic theories have been proposed [49–51]. The most widely accepted is the Breakage-and-Reunion theory. It postulates that chromosomal aberrations arise mainly as a result of rejoining of two DSBs located closely in space and time (two-hit event) [49,50]. Presumably, most rejoining events occur via non-homologous end joining (NHEJ) [52,53]. The initial distribution of primary breaks is assumed to be random, although the rejoining efficiency is expected to be influenced by their proximity. An alternative, one-hit mechanism is suggested by the Molecular theory, which postulates that one radiation-induced DSB is sufficient to initiate an exchange that occurs with an undamaged DNA molecule [54,55]. The only plausible mechanism for such a series of events is homologous recombination initiated by one DSB. The Exchange theory, suggests that the initiation lesions are not DNA breaks induced by radiation but rather “unstable lesions” that do not disrupt the continuity of chromosomes but can initiate exchange between two lesions [56].

Although the Breakage-and-Reunion theory remains most widely accepted, none of the three theories can adequately explain all available experimental data on the dose-effect relationship and complexity of radiation-induced aberrations [57]. Moreover, these theories are based on the assumption that primary DNA lesions, either DSBs or less well-defined “unstable lesions,” are directly induced by radiation (direct mechanism). However, there is at least a theoretical possibility that radiation can lead to chromosomal exchanges entirely by the indirect mechanism, i.e. mediated by radiation-induced genomic instability and not involving the actual breaks induced by radiation. This possibility is supported by studies showing the occurrence of new chromosomal aberrations in subsequent generations of a cell exposed to radiation [58,59], and by a bystander effect, where aberrations are found in cells plated close to, but not in, the field of irradiation or partial irradiation of a cell cytoplasm [60–62].

Interphase gene proximity provides structural basis for the generation of RET/PTC rearrangement

It appears that nuclear architecture contributes to the generation of RET/PTC and other recurrent chromosomal rearrangements found in cancer cells by placing potentially recombinogenic chromosomal loci in close proximity in the interphase nuclei of human cells (Fig 1). For RET/PTC, this was initially demonstrated for the RET and H4 genes in a study that utilized fluorescence in situ hybridization (FISH) and three-dimensional (3D) confocal microscopy and showed that these genes were non-randomly located with respect to each other in the interphase nuclei of human thyroid cells and were much closer than expected based on their genomic separation [63]. In fact, at least one pair of RET and H4 were found juxtaposed in more than one third of adult thyroid cells. This study also showed that the proximity between potentially recombinogenic genes was cell-type specific and was not present in some non-thyroid cells such as mammary epithelial cells. More recently, similar finding were provided for RET and NCOA4, the partners of RET/PTC3 rearrangement [64]. Using FISH and high-resolution 3D confocal microscopy, it was shown that NCOA4 was located closer to RET than expected based on their genomic separation. In addition, spatial proximity was found to exist between the partners of another rearrangement occurring in papillary thyroid cancer, TRK [65]. Utilizing both 2D distance measurements and 3D mathematical projection, NTRK1 was shown to be closer to its translocation partner, TPR, in thyroid cells but not in lymphocytes.

Figure 1.

Figure 1

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Three-color fluorescence in situ hybridization (FISH) showing positioning of RET (green), NCOA4 (orange) and H4 (red) in interphase nuclei of thyroid cells. A. 2D image of a nucleus showing two sets of RET, NCOA4 and H4 with one pair of RET and NCOA4 positioned close to each other. B. 3D image showing that RET and NCOA4 are juxtaposed to each other in the same z plane. C. 2D image of a nucleus showing one pair of RET and H4 positioned close to each other. D. 3D image showing that RET and H4 are juxtaposed to each other in the same z plane.

It is likely that spatial proximity represent a pre-requisite for most rearrangements in human tumors, including intrachromosomal and interchromosomal exchanges. Thus, BCR and ABL genes, which are located on different chromosomes and frequently rearranged in leukemias, were located close to each other in normal human lymphocytes [66]. Likewise, MYC, BCL and immunoglobulin loci, which are located on different chromosomes and recombined in various types of B-cell lymphoma, were shown to be preferentially positioned in close spatial proximity relative to each other in normal B cells [67].

Irrespective of the specific DNA repair mechanism involved in recombination, spatial proximity is likely to predispose to specific rearrangements by making the neighboring regions prone to simultaneous damage by radiation or other DNA-damaging agents, and/or by facilitating mis-rejoining of free DNA ends located immediately adjacent to each other. Since the nuclear architecture is cell type specific, it may also provide an explanation why, in contrast to point mutations, almost all cancer-related chromosomal rearrangements are specific for particular cell/tumor types.

It remains unclear why specific chromosomal regions are located close to each other. For genetic loci located on the same chromosome, this is likely to involve high order chromosome folding that would allow the genes to be positioned non-randomly with respect to each other. It is known that double stranded DNA is wrapped around histones forming nucleosomes which are then arranged in a 30 nm fiber, solenoid structure [68]. Diverse models varying from irregularly folded chromatin fibers [69], radial loops [70,71], giant loops [72] to the random walk/giant loop model [73] have been proposed for higher order interphase chromatin compaction with the eventual packaging of interphase chromosomes into well defined chromosomal territories (CTs) [74]. With respect to the 18 Mb region on 10q containing RET, NCOA4, and H4, evidence for the large-scale helical folding of this chromosomal region in the interphase nuclei of human thyroid cells was provided [64]. This pattern of chromatin folding can offer the basis for proximity between RET and NCOA4 and H4. Whether or not such folding represents a unique structure of this chromosomal region or is a universal feature of interphase chromosome organization remains unknown.

Location of genes within chromosomal territories may influence the type of recombination

A peculiar feature of rearrangements found in papillary thyroid cancers is that almost all of them are intrachromosomal inversions rather then interchromosomal translocations. Indeed, in addition to RET/PTC1 and RET/PTC3 that involve genes on 10q11.2–q21, the TRK rearrangements most commonly involve the NTRK1 (1q21–q22) fusion to either TPR (1q25) or TPM3 (1q25) [9] and recently indentified BRAF/AKAP9 rearrangement involve two genes located on 7q [10]. A recent study provides experimental evidence suggest that the predominance of intrachromosomal recombination in thyroid cells may also be in part due to the nuclear architecture [75]. In this study, the location of specific chromosomal loci involved in intrachromosomal and interchromosomal exchanges in thyroid cells were analyzed. Simultaneous hybridization with gene-specific probes and their respective whole chromosome paints was used to establish the positioning of specific recombinogenic loci within their chromosome territories (CTs). It was found that genes involved in intrachromosomal rearrangements were positioned at significantly greater distances away from the CT edge and internally within their CTs as compared to genes involved in translocations that were positioned closer to the CT edge [75]. The frequent location of RET and its recombinogenic partners within the interior of the chromosomal territory, surrounded by its own chromosomal material and with limited availability to interact with neighboring chromosomal territories, is likely to predispose it to intrachromosomal exchange, such as seen in most cases of RET/PTC (Fig 2). Similar findings have been obtained in another study that demonstrated a significant correlation between the extent of intermingling between different CTs and frequency of translocation involving specific chromosome pairs [76].

Figure 2.

Figure 2

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Four-color FISH showing chromosome 10 territory (green) and location of RET (blue pseudocolor), NCOA4 (yellow pseudocolor) and H4 (red). A. All three genes, RET, NCOA4 and H4, are positioned within the chromosome 10 territory and away from the CT edge. B. 3D rendered image showing no signals on the surface of the CT due to the gene positioning inside the CT.

Potential DNA repair mechanisms involved in RET/PTC rearrangement

In mammalian cells, DSBs are repaired by two general pathways that are based on homology-dependent or nonhomologous recombination. The homology-dependant mechanism encompasses several pathways such as homologous recombination repair (HRR), single strand annealing (SSA), and non-allelic homologous recombination (NAHR). Nonhomologous mechanism is known as nonhomologous end joining (NHEJ). Another recently described repair pathway, microhomology mediated end joining (MMEJ), combines features of the two major pathways as it joins DNA ends after preliminary aligning them using short homology DNA sequences located distant to the break. These repair pathways utilize common enzymatic factors as well as those distinct to specific repair mechanisms. Usage of ATM/ATR and NBS1 kinases as the primary DSB sensors is common for homology based and non-homologous repair [77]. However, DNA ends are hold together and initially processed by different enzymes, DNA-PKs (Ku70/Ku80) in NHEJ [78] and Rad52 in HHR and SSA [79]. In all pathways, the processing of DNA ends and trimming is carried by conserved multiprotein MRE11/Rad50/NBS1 (MRN) complex, which plays an important role in DSB repair, meiotic recombination and telomere maintenance [80,81]. SSA and MMEJ additionally require the use of ERCC1-XPF (Rad10-Rad1) complex to incise double-stranded DNA at the junction with single-stranded DNA, nicking bubble structures and 3’ single-strand overhangs [82]. After homology search, strand annealing and end processing DNA integrity is restored. NHEJ employs XPCC4 and Lig4 to ligate the DNA ends [78,83,84].

Several mechanisms have been proposed for the formation of RET/PTC rearrangement. They include HRR, NHEJ, SSA, and MMEJ [85–87]. While the genomic sequence of RET/PTC1 fusion point is difficult to obtain due to a very large size of intron 1, which is a breakpoint cluster region of the H4 gene, the genomic sequences of 31 RET/PTC3 fusions from post-Chernobyl thyroid tumors have been reported [85–87] and can be used for the analysis (Table 2).

Table 2.

DNA sequence features of RET/PTC3 breakpoints in post-Chernobyl tumors and their correspondence to specific DNA repair pathways

NHEJ
MMEJ SSA
case
ID* 		microhomology
at breakpoint		 distant
microhomology
(less than 5 nt)		 distant
microhomology
(5 or more nt)		 Deletions
at
breakpoint		 repeats in
both genes		 deleted
repeats
C22 yes yes yes yes yes 2 copies
C82 no yes no yes yes none
C102 yes yes yes yes yes none
C112 no yes yes no yes none
C142 yes yes yes yes yes none
C152 yes yes yes no none none
C172 no yes yes no none none
C202 no yes no yes none none
C242 yes yes no yes none none
C272 yes yes no yes yes 2 copies
C282 yes yes yes yes none none
C302 no yes no yes none none
M2T1 yes yes no yes yes 1 copy
M12T1 yes yes no yes yes 1 copy
M80T1 yes yes yes yes yes 2 copies
M81T1 no yes yes yes yes 3 copies
M89T1 no no no yes yes 3 copies
M122T1 yes yes yes yes yes 1 copy
M129T1 no yes yes yes yes none
M153T1 yes yes yes yes yes 1 copy
M161T1 yes yes yes yes yes 2 copies
M162T1 yes yes yes yes yes 1 copy
M190T1 yes yes yes yes none none
M216T1 no yes yes yes yes 1 copy
M219T1 no yes yes yes none none
M225T1 yes yes yes yes yes 1 copy
M259T1 yes yes yes yes yes 2 copies
M263T1 no yes yes yes yes 1 copy
CH43 no yes yes yes yes 1 copy
CH83 no yes yes yes none none
CH103 no yes yes no yes none
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*

RET/PTC3 sequences reported by

1

Klugbauer et al. [85]

2

Nikiforov et al. [86]

3

Bongarzone et al. [87].

NHEJ utilizes microhomology (2–4 nt) at DNA ends, and frequently produces microdeletions/insertions at the breakpoints, usually joining the corresponding ends by fast end processing [88]. The nucleotide sequence feature of NHEJ is the presence of microhomology regions located immediately at the fusion points. In addition, sequence modifications, including small deletions and insertions, are common at the fusion point. Among 31 post-Chernobyl tumors with reported RET/PTC3 genomic sequence [85–87], 55% of cases had 3–5 nucleotide homology located at the break (Fig. 3A). Modifications at breakpoints, typically small deletions, were present in 26 (84%) of post-Chernobyl tumors with RET/PTC3. In addition to microhomology located immediately at breakpoints, NHEJ may utilize short homology regions located up to 60–300 nt away from the break, as it has been shown in prokaryotic cells [89,90]. In post-Chernobyl tumors with RET/PTC3, microhomology regions located within 50 nt from breakpoint were seen perfectly aligned relatively to the breakpoint in 58% of cases and with 1–2 nucleotide shift in 68% (Fig. 3B). Overall, microhomology regions were present at the breaks or on adjacent to the breaks in 97% of RET/PTC3 fusions, making the NHEJ pathway a strong candidate in the formation of RET/PTC products.

Figure 3.

Figure 3

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Representative examples of sequences at RET/PTC3 breakpoints (//) with DNA-based characteristics for NHEJ (A), MMEJ (B) and SSA (C).

MMEJ is another repair pathway that utilizes short homology sequences. It has been reported that nuclear extracts from urothelial cancers repair DSBs preferentially by MMEJ compared to normal urothelial cell extracts [91]. Characteristic attributes of MMEJ are the utilization of 5–25 nt homology stretches and the presence of deletions flanking the breaks [92]. It has been suggested that high levels of DNA damage can induce MMEJ over typically predominant NHEJ [93]. Among RET/PTC fusions, 19% (6 out of 31) had 5 or more nucleotides in homologous regions, and another 49% (15 from 31) had 5–10 nucleotides imperfect homology regions with inserted base(s) between short homologous sequences (Fig. 3C). Overall, 61% of fusions had 5 nt homology stretches and deletions at the fusion point, suggesting that MMEJ may also serve as a mechanism for RET/PTC rearrangement in many cases.

SSA and NAHR utilize the repeatable DNA elements for alignment of broken DNA strand(s) and in quiescent cells have typically a limited participation in DSB repair. However, the loss of NHEJ due to down-regulation of its key factors leads to higher incidence of SSA and NAHR [79,90]. Of these two repair pathways, NAHR is unlikely to play a significant role in the generation of RET/PTC rearrangements because of the requirement for non-canonical DNA structures (Z-DNA in CG reach DNA regions) at the site of recombination, which are not present in the RET/PTC breakpoint cluster regions [94]. SSA utilizes homology regions larger than 15 nt and induces recombination between direct repeats with concomitant loss of one or more repeat units [95]. In model systems, tandem direct repeats serve the best for SSA, but in living cell SSA may use not only direct tandem repeats but also mirror and inverted repeats and repeats dispersed throughout flanking regions of the breaks [85,95]. The available RET/PTC3 fusion sequences revealed no 15 nt stretches of tandem repeat homology in any of the cases. However, dispersed homologous di-, tri- or tetranucleotide repeats in both fusion partners could be found in 22 (71%) cases. In addition, 16 of those 22 sequences had a deletion involving at least one repeat copy (Fig. 3D). Thus, SSA may be an additional potential repair mechanism for RET/PTC rearrangement.

These data, which are based on the analysis of DNA sequences at the fusion points, suggest that the generation of RET/PTC rearrangement may involve several possible DNA repair mechanisms, particularly NHEJ and MMEJ, and to lesser extent SSA. It remains unknown whether all of these mechanisms contribute to the generation of RET/PTC with similar frequency and if the choice is determined by specific conditions and/or individual genetic background.

Acknowledgments

This work was supported by the NIH grant R01 CA88041 to Y.E.N.

Footnotes

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