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1 Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, CMM L8:01, SE-17176 Stockholm, Sweden2 Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital, SE-17176 Stockholm, Sweden3 Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, New South Wales, Australia4 Department of Oncology, Lund University, Lund, Sweden
(Correspondence should be addressed to J-J Lee; Email: jia.jing.lee{at}ki.se; jiajing_lee{at}hms.harvard.edu)
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Abstract |
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 Top Abstract IntroductionMaterials and methodsResultsDiscussionDeclaration of interestReferences |
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionDeclaration of interestReferences |
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Little is presently known about the cellular origin and molecular etiology of ATC. This is partly attributed to the extensive necrosis that is characteristic of the disease and further augmented by the pre-operative treatment. In some patients, a differentiated thyroid cancer is found adjacent to the ATC. Furthermore, in few cases, there is a continuous spectrum from differentiated to poorly differentiated thyroid cancer (PDTC) and ATC in support of a progression model. TP53 mutations that are rare in well-differentiated thyroid cancers, i.e., papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC), are frequent in PDTC and reach up to 68% in ATC (Kondo et al. 2006). PIK3CA mutations have been reported in 12–23% of ATC (Garcia-Rostán et al. 2005, Hou et al. 2007). Activating mutations of RAS (that are mainly seen in FTC) and BRAF (V-raf sarcoma viral oncogene homolog B1), which characterizes aggressive PTC, are also found in a subset of ATCs while RET (rearranged during transfection)/PTC and PAX8 (paired box gene 8)/PPAR
(peroxisome proliferator-activated receptor-) rearrangements have not been determined in ATC (Kondo et al. 2006).
Studies of gene copy number imbalances in ATC using conventional CGH have demonstrated recurrent gains of chromosomal regions 3, 5p, 11q13, and 20q and losses at 5q11–31 and Xp (Wreesmann et al. 2002, Rodrigues et al. 2004). Recently, we characterized karyotypic abnormalities and copy number alterations in ATC cell lines, which revealed gain of 20q as the most common abnormality (Lee et al. 2007). Here, we used bacterial artificial chromosome (BAC) arrays with whole-genome tiling resolution to investigate the DNA copy number alterations in a series of primary ATCs. Subsequently, we investigated the involvement of candidate genes located in areas of recurrent changes.
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Materials and methods |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionDeclaration of interestReferences |
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The human ATC lines (HTh 104, HTh 112, HTh 7, HTh 74, C 643, KAT-4, SW 1736, ARO, and HTh 83) and Nthy-ori 3-1 (SV-40 immortalized normal human thyroid follicular cells; ATCC, Manassas, VA, USA) were cultured under conditions as described previously (Lee et al. 2007).
Patients and tumor tissues
Fresh-frozen primary tumors from 28 cases of ATC (Table 1) were collected at the Karolinska University Hospital, Stockholm, Sweden and the Royal North Shore Hospital, Sydney, Australia. Twenty-three patients had received pre-operative radiotherapy and/or chemotherapy according to standard treatment protocols (Wallin et al. 2004). The histopathological diagnosis was established according to WHO classification (DeLellis et al. 2004), including findings of undifferentiated cells, giant and/or spindle cells, mitosis, and signs of necrosis. Tissue sampling and representativity testing followed established routines for the endocrine biobank. Frozen samples of medullary thyroid cancer and parathyroid adenoma were similarly collected at Karolinska University Hospital, Stockholm, Sweden, and used as references in western blot analyses. Informed consents were obtained from all patients and ethical approvals were granted.
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Tumor DNA was isolated by conventional methodology including phenol purification and ethanol precipitation. Cell line DNA was isolated as described previously (Lee et al. 2007). DNA was quantified using NanoDrop ND1000 (NanoDrop Technologies, Wilmington, NC, USA).
BRAF mutation screening
The mutation hot spot exons 11 and 15 of BRAF were sequenced on both strands in all 28 tumors. The experimental procedure, amplification conditions (35 cycles), primers, and positive control were as previously described (Lee et al. 2007).
Array-CGH analysis
Generation, hybridization, and analyses of the 33 K microarrays (resolution of 100 kb) with complete genome coverage produced by the SCIBLU Genomics, Department of Oncology, Lund University, Sweden (http://www.lth.se/sciblu) were essentially as previously reported for 32 K arrays (Barbaro et al. 2007). Genomic DNA of the tumor and commercial reference samples (Promega Corporation, Madison, WI, USA) was labeled as described previously (Jönsson et al. 2007). Arrays were scanned using Axon GenePix 4200A microarray scanner (Molecular Devices, Sunnyvale, CA, USA). Individual spots identified on scanned arrays were collected using GenePix Pro 6.0 (Axon Instruments, Foster City, CA, USA), and the quantified data were loaded into Bio Array Software Environment (BASE; Saal et al. 2002). A BASE implementation of CGH-Plotter was used to identify regions of gains and losses after smoothing with a sliding window over three clones (Autio et al. 2003). Cut-off ratios for gains and losses constant were set at =1.15 and –0.87 respectively, corresponding to log2 (ratio) of ±0.2. A log2 (ratio) below –0.75 was considered as homozygous loss and a ratio above +0.75 as amplification.
Fluorescence in situ hybridization (FISH)
FISH analyses were performed on interphase imprints from frozen ATCs and on metaphase preparations of ATC cells using the BAC clone RP11-344G20 covering UBCH10 at 20q13.12 plus a chromosome 20 centromere probe (CEP20) as described previously (Lee et al. 2007), or pre-labeled probes for CCND1 and the chromosome 11 centromere (LSI CCND1 Spectrum Orange/CEP 11 SpectrumGreen1 Vysis, Inc., Downers Grove, IL, USA). Locus gain in a tumor was considered when a higher number of signals were recurrently observed for the gene-specific probe when compared with the centromere probe. Results for UBCH10 analysis of ATC cell lines have been published in Lee et al. (2007).
Multiplex ligation-dependent probe amplification (MLPA) analysis
Three regions with prominent gains detected from the array, 20q11.2, 20q13.12, and 16p11.2, were selected for verification by MLPA. MLPA reactions were performed as described (Barbaro et al. 2007) using newly designed 5' and 3' half-probes targeting unique exonic or intronic sequences of genes within 20q11.2–q13.2 and 16p11.2 and control genes ALB (4q13.3) and CLDN16 (3q28) according to Barbaro et al. (2007) (Supplementary Table 1, which can be viewed online at http://erc.endocrinology-journals.org/supplemental/). For each sample, the peak areas corresponding to each probe were first normalized to the average of the peak areas of the control probes, and then normalized to the average peak area in eight controls (normal lymphocyte DNA).
Western blot analysis
Total protein extracts from tumor tissues (75 µg) and cultured cell protein were electrophoresed and transferred to nitrocellulose filters (Invitrogen, Carlsbad, CA, USA). For transfected cells, an aliquot was taken from the cell suspension where the starting cell count was 1x106 cells/well plated in a six-well plate. The filters were stained with Ponceau Red (Sigma) as a control for protein presence and incubated overnight at 4 °C with anti-cyclin D1 (1:400; SP4 clones; NeoMarkers, Fremont, CA, USA), anti-p16 (1:100; G175-405; BD PharMingen, San Jose, CA, USA), and anti-
-actinin (1:100; AT6/172 clone; Chemicon International, Temecula, CA, USA) or anti--tubulin (1:2500; Clone DM 1A; Sigma–Aldrich). Anti--actinin and anti--tubulin served as loading controls.
Cell proliferation analysis of cells overexpressing CCND1
Amaxa nucleofection technology (Amaxa Biosystems, Cologne, Germany) was used to transfect cells with siRNA and plasmids for MTS assays. For cell proliferation assays, 1x104 cells/well were plated (96-well plate) and, for western blot analyses, 1x106 cells/well were plated (6-well plate). HTh 7 cells were transfected with 1.5 µg siRNA/1x106 cells using program X-001 with the V solution and Nthy-ori 3-1 cells were transfected with 2 µg plasmid/1x106 cells using program A-020 with the T solution. Cells were incubated for 16 h prior to subsequent analyses at 0, 24, 48, and 72 h after overnight transfection. CCND1 siRNA (#SI02654540, Qiagen GMbH, Valencia, CA, USA) was used in knockdown studies with the All Stars siRNA (#SI1027281, Qiagen) as negative control. The CCND1 plasmid was obtained from Addgene (Rc/CMV-CCND1 #8962, Cambridge, MA, USA) and the control plasmid Rc/CMV was kindly provided by Dr Sue Firth at the Kolling Institute of Medical Research, NSW, Australia. Successful transfection and siRNA were verified by western blot analysis and quantitative real-time PCR (qRT-PCR) as previously described (Lee et al. 2007). TaqMan Gene Expression Assays (Applied Biosystems, Foster City, CA, USA) were used to quantitate CCND1 (Hs00277039-m1) and 18S (#4319413E). Cyclin D1 expression from western blot analyses was quantified against -tubulin expression by Multi gauge V3.0 (FujiFilm Global, Valhalla, NY, USA).
Cell proliferation was quantitated by MTS assay (Promega Corporation) as per protocol at 0, 24, 48, and 72 h after overnight transfection. Absorbance readings (OD490–650) were taken 2 h after the addition of the MTS reagent.
Statistical analysis
Potential correlations between the most frequently altered regions (11q13, 20q11.2, 20q13.12, 13q21.2–q21.31, and 16p11.2) and CCND1 copy number detected by FISH, cyclin D1 and p16 expressions, BRAF mutations, and association with PTC were investigated using Fisher's exact test (n<5) or two-tailed 
2-test (n>5), (http://www.graphpad.com/quickcalcs/contingency1.cfm). For the validation of the 20q11.2, 20q13.12, and 16p11.2 regions identified from the array by MLPA, 
-correlation was computed (Statistica version 6; StatSoft Inc., Johannesburg, South Africa). Absorbance values of CCND1 siRNA knockdown or CCND1-transfected cells were compared with reference-treated cells using paired t-test. P values below 0.05 were considered significant.
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Results |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionDeclaration of interestReferences |
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The clinical characteristics of the 28 cases of primary ATCs studied are given in Table 1, and the molecular analyses carried out in individual cases are detailed in Table 2. Nine cases presented an additional thyroid cancer that was either adjacent or growing in continuous spectrum with the ATC. Three of the twenty-eight ATCs exhibited a heterozygous nucleotide alteration GTG
GAG at position 1799 in exon 15 of BRAF that leads to a missense mutation V600E (Table 2). Two of these cases had an additional thyroid cancer; case 6 exhibited a PTC adjacent to the ATC and, in case 21, a continuous tumor spectrum from PDTC to ATC was observed.
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DNA copy number changes were detected in all 27 primary ATCs successfully studied by array-CGH, preferentially involving sub-chromosomal regions and gains (Tables 2 and 3; Fig. 1). Alterations that were commonly observed and further examined in this study include gains at 11q13, 20q, and 16p11.2 (Figs 2, 3 and 4A). Other frequent events observed (>20% of cases) include gains at 6p, 7q, 12q, 17q, 19, and 22q, and losses on 4q and 13q. Gains in telomeres were observed in >20% of the ATC panel for most chromosomes with the exception of chromosomes 2, 3, 6, and 15.
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=0.55), 20q13.12 (=0.51), and 16p11.2 (=0.54).
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Amplifications and prominent losses revealed by array-CGH in primary ATCs
Interestingly, high-level amplifications with log2 (ratio) exceeding +0.75 were identified in chromosomes 11, 18, and 20 for cases 7, 3, and 4 respectively. ATC case 7 exhibited high-level amplification of a 5 Mb region in 11q22.1 (log2 (ratio)=1.5–2.0; Fig. 2A). Similarly, a 6 Mb region in 18q11.2 was highly amplified in ATC case 3 (log2 (ratio)=1.2; Fig. 4B). Finally, in ATC case 4, high-level amplification was observed of the commonly altered 20q13.12 region that includes the UBCH10 candidate gene (Fig. 3A).
A homozygous loss of a 5 Mb region was detected in ATC case 6 encompassing the CDKN2A gene locus in 9p21.3 (Fig. 4D). Furthermore, almost identical small regional deletions within 5q were observed in cases 1 and 11, which included a common 1.9 Mb region in 5q13.2 (Fig. 4C). In these two cases, other regions commonly altered in the ATC panel were largely unaffected (Table 2).
Frequent lack of p16 expression in ATCs
Since a homozygous loss at the 9p21.3 locus encompassing the CDKN2A gene was detected in case 6, it was of interest to confirm the presence of tumor suppressor p16 encoded by this locus for case 6 as well as to further investigate p16 expression in the entire panel by western blot analysis. The p16 protein expression was detected in positive control cells SAOS-2 osteo sarcoma and in medullary thyroid carcinoma tissue, but was not detectable in normal thyroid or MCF-7 cells (negative control; Fig. 4D). In addition, no p16 expression was observed in 24 out of 27 ATCs analyzed (89%; Table 2), including case 6 with homozygous loss at the CDKN2A locus.
Gains of chromosome 20 and locus gain of UBCH10
Two separate regions of copy number gain were observed for chromosome 20, of which the more distal at 20q13.12 encompasses the UBCH10 gene that has been suggested to be associated with ATC (Pallante et al. 2005, Lee et al. 2007). We therefore performed a dual-color FISH analysis on ATC imprints using a CEP20 and a BAC clone containing UBCH10. Out of 24 samples, 9 (38%) showed an increased copy number for UBCH10 (Table 2; Fig. 3B).
Gain of CCND1 in 11q13 and overexpression of cyclin D1 protein
Amplification of chromosomal region 11q13 is associated with gain for CCND1 in several human cancers (Alao 2007). To determine whether the CCND1 gene is gained in ATC tumors and cell lines, dual-color FISH analysis was performed with a CCND1 clone and centromere 11 (CEP 11) as a control for chromosome copy number. As illustrated in Fig. 2C, locus gain of CCND1 when compared with CEP 11 was recurrently observed in interphase nuclei of 38% of the ATCs (Table 2). The observation of CCND1 locus gain coincides with the presence of 11q13 gain by array-CGH (P=0.0001; two-tailed 2-test). Locus gain of CCND1 was also recurrently observed in interphase and metaphase cells of the ATC line HTh 7 (Fig. 2C).
Western blot analysis showing strong cyclin D1 expression in parathyroid tumor tissue was used as a positive control, while in normal thyroid cyclin D1 expression was not detectable (Fig. 2B). In primary ATCs, varying levels of cyclin D1 expression were observed in 18 out of 27 cases studied (Table 2). Among these 18 ATCs, the protein level was determined as low (six cases), intermediate (five cases), or high (seven cases) as exemplified in Fig. 2B.
Effects of CCND1 on proliferation of thyroid cells
Gain of CCND1 or cyclin D1 overexpression was observed in the majority of ATCs, while its possible influence on thyroid cell proliferation was assessed in ATC cells (HTh 7) and normal human thyroid cells (Nthy-ori 3-1). The HTh 7 cells showed regional gain of the CCND1 locus and overexpression of cyclin D1 protein and were therefore selected for transfection with small interfering RNA (siRNA) oligonucleotides against CCND1. Successful siRNA within 24 h was demonstrated by 20–30% decrease in western blot expression and up to 60% decrease in CCND1 mRNA expression by qRT-PCR (Fig. 5A). Slightly lower proliferation measured by MTS assay absorbance was observed after CCND1 siRNA when compared with All Stars siRNA used as a control (Fig. 5). Transfection of Nthy-ori 3-1 cells with a cyclin D1 expressing construct resulted in stable 3-fold increase in protein expression and 12-fold increase in mRNA levels (Fig. 5B). Only minor increase in proliferation was observed in cyclin D1 expressing cells when compared with control cells transfected with empty vector (Fig. 5). Taken together, CCND1 siRNA and transfection assays had only minor effects on proliferation, which were not statistically significant.
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionDeclaration of interestReferences |
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An average of 44 DNA copy number changes was detected in each tumor, which is considerably higher than the changes found in differentiated thyroid cancer (Hemmer et al. 1999, Kjellman et al. 2001, Wreesmann et al. 2002, 2004, Rodrigues et al. 2004). This was rather expected, as aggressive and advanced cancers are generally genetically unstable. The widespread telomeric gains observed in this study is an uncommon property of differentiated thyroid tumors, further supporting chromosomal instability in ATC. A role for telomere dysfunction in promoting gene amplification and hence chromosome instability, which is the hallmark of human cancer, is supported by tumor-bearing mice model (Albertson 2006).
It could be argued that the observed copy number alterations are a result of the pre-operative treatment administered to the patients. However, the number and patterns of changes in the three patients, which were operated primarily without pre-treatment did not differ from the rest. Furthermore, many of the alterations were detected recurrently across the different tumors, while alterations resulting from pre-operative radio-chemotherapy are expected to be more random.
Gain of 11q13 was found by array-CGH and FISH analysis for the CCND1 locus in 
50% of ATCs. This finding is in agreement with previous reports of 11q13 gain in ATC lines (Lee et al. 2007) and ATC primary tumors (Wreesmann et al. 2002), and motivated further investigation of the known oncogene CCND1 encoding cyclin D1.
In protein studies, 67% of ATCs were shown to express cyclin D1 while no expression was observed in normal thyroid tissue. Cyclin D1 expression has been reported to be especially prevalent in aggressive forms of thyroid cancers (Wang et al. 2000, Khoo et al. 2002). Gain of 11q13 and/or CCND1 is also frequent in other tumor types of relatively advanced stage, including breast, head, and neck as well as esophagus carcinomas, sometimes as part of homogenously staining regions (Arnold & Papanikolaou 2005). Notably, cyclin D1 overexpression in this study occurred both in presence or absence of 11q13 gain, suggesting alternative mechanisms of activation. Similar observation has been previously reported in breast cancers (Arnold & Papanikolaou 2005), keratoacanthoma (Burnworth et al. 2006), and squamous cell carcinoma of the skin (Utikal et al. 2005). It has also been proposed that in most cancer types, pathogenic activation of cyclin D1 can occur via additional mechanisms, including transcriptional and post-transcriptional dysregulation by oncogenic signals (Arnold & Papanikolaou 2005). Consistent with this possibility, in vitro experiments have shown direct or indirect activation of the CCND1 promoter or cyclin D1 expression by several molecules such as β-catenin, c-Jun, PPAR, calveolin-1, Ras signaling, and others (Arnold & Papanikolaou 2005). Intriguingly, three putative microRNAs (miR-1, miR-206, and miR-613) were predicted to target the 3' UTR of CCND1 (TargetScan 4.0), pointing to additional mechanisms for regulation of cyclin D1 expression.
While cyclin D1 has been shown to promote cell proliferation and drive tumorigenesis in several human cancer models (Ewen & Lamb 2004), little is known about its role in thyroid cancer. In this study, introduction of cyclin D1 to normal thyroid cells (Nthy-ori 3-1) resulted in an increased cell population when compared with control cells. However, the difference in growth rate did not reach statistical significance. Unexpectedly, the population in HTh 7 cells transfected against CCND1 siRNA was only marginally reduced when compared with cells without CCND1 knockdown. This may be attributed to the swift restoration of CCND1 within 24 h of transfection against CCND1 siRNA. The rate of transcription and translation of CCND1 within the cells of both in vitro systems could vary, explaining the discrepancies between cyclin D1 protein and CCND1 mRNA expressions. The results from siRNA and overexpression of CCND1 suggest that cyclin D1 can stimulate thyroid cell proliferation, but is in itself neither a sufficient nor a necessary factor.
The identification of 20q11.2 and 20q13.12 amplicons in this study corroborated our earlier findings in ATC lines (Lee et al. 2007), as well as those reported in ATC primary tumors (Wreesmann et al. 2002, Rodrigues et al. 2004) and confirmed that the amplicons of 20q are frequent events in ATC. Interestingly, the only patient who was relapse free in this study (case 12) did not exhibit 20q gain by array-CGH. These findings suggest that 20q gain has a role in the dedifferentiation of thyroid tumors. Recently, overexpression of UBCH10, which resides in chromosomal region 20q13.12 and belongs to the E2 gene family, was shown to be involved in thyroid cell proliferation and was therefore suggested as a candidate marker and possible therapy target for ATC (Pallante et al. 2005). We observed locus gain of UBCH10 in 25% of ATC tumors by FISH analysis, which concurs with our previous observations in ATC lines (Lee et al. 2007). Gain in 20q11.2–q21 and 20q13.12–q13.31 are also characteristics of other human cancers (Hodgson et al. 2003, Weiss et al. 2003, Lockwood et al. 2007). Gain of 20q13.12 and 11q13 was recurrently found in the same ATC cases. This could result from an unbalanced translocation followed by an amplification event as observed in lymphomas (Zhu et al. 2002), or reflect tumor evolution with selection of clones amplifying growth-promoting genes in different locations as reported in breast cancers (Al-Kuraya et al. 2004). Translocations in ATC have so far only been reported in ATC cell lines, in particular involving chromosomes 11 (Lee et al. 2007). CCND1 at the 11q13 locus is also known to be frequently co-amplified with several other genes at other chromosomes in breast carcinoma and head neck and oral squamous cell cancers (Schuuring 1995). Furthermore, co-amplification of CCND1 with genes within the 11q13 cluster in oral squamous cancer has been reported (Hsu et al. 2006).
A homozygous loss in the CDKN2 locus encoding CDKN2A (p16INK4A) on chromosome 9p21 was observed in one ATC, which was associated with lack of p16 protein expression. This prompted us to investigate p16 expression in the entire panel, which revealed lack of p16 expression in 89% of the cases. The lack of copy number loss at 9p21.3 in these ATCs suggests other mechanisms for the inactivation of p16 such as methylation (Schagdarsurengin et al. 2006). The normal thyroid tissues examined in our study did not express p16. This observation is concurrent with Ball et al. (2007) where the vast majority of normal thyroid samples lacked p16 immunostaining. However, we and others observed p16 expression in well-differentiated thyroid tumors but not in ATC (Fig. 4C; Ferru et al. 2006, Ball et al. 2007). Taken together, these findings suggest that p16 is induced in differentiated thyroid cancer and suppressed during progression toward the undifferentiated phenotype.
Gain of 16p11.2 was frequently observed in this study although this region encompasses no obvious candidate oncogenes. However, this region was identified as one of the most extensively duplicated regions on chromosome 16 based on chromosome 16 genome sequencing (Martin et al. 2004). Loss of chromosomal region 13q21 was exclusive to PTC-associated ATCs (Table 3). Notably, recurrent loss of 13q21 has been reported in PTC (Kjellman et al. 2001, Wreesmann et al. 2004). Conversely, loss of 4q determined in our study has thus far only been observed in ATC (Rodrigues et al. 2004, Lee et al. 2007). Restricted loss of 5q13.2 was noted in two ATCs with low involvement of other recurrent alterations. Of note, similar finding was previously observed in an ATC line exhibiting concomitant translocation of the 5q13 region (Lee et al. 2007).
Our results are consistent with previous works (Wilkens et al. 2000, Miura et al. 2003, Pallante et al. 2005, Lee et al. 2007) showing marked DNA copy number alterations and frequent gains in ATCs; suggesting high level of chromosomal instability in ATC. Previous studies have shown that well-differentiated tumors harbor fewer alterations (Hemmer et al. 1999, Wreesmann et al. 2002). Three ATC tumors harbored the common BRAF mutation V600E that is frequently observed in PTC (Kondo et al. 2006). The array-CGH profiling and BRAF mutation findings, together with previous works, further support the hypothesis previously suggested by Galera-Davidson et al. (1987), that a subset of ATCs may be derived from dedifferentiation of PTCs.
Taken together, DNA copy number changes were found to be abundant in ATCs. Gains involving 20q (20q11.2 and 20q13.12) and 11q13 represent recurrent findings potentially targeting the candidate genes CCND1/cyclin D1 and UBCH10. Lack of p16 expression and overexpression of cyclin D1 are characteristics of ATCs, and cyclin D1 has a limited effect on thyroid cell proliferation. The study revealed several recurrent copy number alterations as well as several candidate locations for tumor suppressor genes and oncogenes that are potentially involved in molecular pathogenesis of ATC.
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Declaration of interest |
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Funding |
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Acknowledgements |
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References |
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