General

• Cytogenetic analysis of five chordomas revealed normal karyotypes in four patients and an abnormal karyotype in only one tumor cell among 100 cells studied from the fifth patient. [1]
• The most frequently observed imbalances observed in six sacral chordomas by CGH were gains of chromosomal areas 1q23~q24 (3/6), 7p21~p22 (3/6), 7q (4/6), and 19p13 (3/6), as well as loss of chromosomal segment 9p22~p23 (3/6). IP-FISH confirmed the CGH findings and showed that chromosome 7 was polysomic in four of the tumors. Six of six sacral chordomas had trisomic and tetrasomic clones for chromosome 7, and two of them had pentasomic clones as well. [2]
• 27 of 64 (42%) skull base chordomas had clonal chromosome aberrations and 37 (58%) had a normal karyotype. [3]
• A normal karyotype was found in three cases of chordoma of the skull base, whereas a recurrent vertebral chordoma showed 46,XY,t(6;11)(q12;q23). [4]
• 117 chromosomal aberrations (median, six per tumor) were found in 16 chordoma samples. On average, 3.2 losses and 4.2 gains were detected per tumor. [5]
• No statistically significant difference in the number of chromosomal imbalances was detected by CGH between 10 sacrococcygeal chordomas and 5 sphenooccipital chordomas or between primary chordomas and recurrences. FISH experiments confirmed the CGH data . [5]
• DNA sequence copy number gains occurred most frequently at 7q (11/16), 20 (8/16), 5q (6/16), and 12q (6/16). Gains of chromosome 17 and the majority of gains of 5q, 12q, and 20 were found in recurrences. [5]
• The most common chromosome gains included all or part of chromosome 1q and chromosome 7. Three of 11 recurrent tumors shared chromosome aberrations of isochromosome 1q, -3,-4,+7,-10,del13/-13, -18. [6]
• Twenty-seven percent (6/22) of cases showed normal disomy for chromosome 7. Trisomy was seen in 59% (13/22) and polysomy in 14% (3/22) of samples, accounting for almost 73% of aneusomy. [7]
• Case report: A small nuclear family expresses a clustering of malignancy which includes stomach cancer, colorectal cancer and chordoma. Genetic analysis failed to reveal any causative mutation in genes associated with HNPCC or in E-cadherin. Together, the clinical picture in this family may indicate that other genetic factors are behind this family’s clustering of malignancy. [8]
• Polysomy of chromosome 7 was detected in 15 of 33 (45.5%) chordomas . [9]
• Sarcoma-specific gene fusions PAX3-FKHR, ASPL-TFE3, or SYT-SSX were not found in 52 chordomas. [9]
• Twenty-seven percent (6/22) of cases showed normal disomy for chromosome 7. Trisomy was seen in 59% (13/22) and polysomy in 14% (3/22) of samples, accounting for almost 73% of aneusomy. [7]
• Chordoma cells showed a significantly increased telomere length compared with leukocytes from age-matched controls. An average telomere length of 23.1 kb ± 12.6 was found in chordoma cells from the four patients, age-matched controls. [1] compared with 9.6 kb ± 0.8 for the
• Copy number gain of chromosome 6 was found in 92/170 (54%) samples of primary human chordoma by FISH analysis. qPCR on 32 of these samples found concordance in 7/32 (22%) samples. 48/92 (52%) samples with copy number gain by FISH showed polysomy of chromosome 6 with high level copy number gain, whereas 36/92 (39%) displayed polysomy of chromosome 6 with low level copy number gain. qPCR on 18/48 samples with high level copy number gain found concordance in 4/18 (22%) samples, while qPCR on 11/36 samples with low level copy number gain found concordance in 2/11 (18%) samples. 8/92 (9%) revealed minor allelic gain by FISH, and qPCR analysis on 3 of these samples saw concordance in 1/3 (33%) samples. [10]
• Copy number gain of chromosome 6 was found in 50/89 (56%) samples of primary human chordoma from the sacrococcygeal region, 16/31 (51%) samples of primary human chordoma from the mobile spine, and 32/53 (60%) samples of primary human chordoma from the skull base, as shown by FISH analysis. [10]
• One tissue sample from a chordoma patient with recurrent disease demonstrated disomy of chromosome 6 in the primary tumor and polysomy in the recurrent tumor, as shown by FISH analysis. [10]
• FISH analysis on S6 found disomy or low-level polysomy in 14 of 15 (93%) tumor samples from patients with classic, sporadic chordoma. [11]
• Cytogenetic analysis on 2 poorly differentiated chordoma samples from pediatric patients (ages 22 months and 7 years) found a normal karyotype in one sample and a clonally abnormal karyotype in 7 of the 20 (35%) metaphases analyzed in the other sample. [12]
• LOH and microsatellite instability analyses detected no differences between normal and tumor DNA among 8 classic, skull base chordoma samples. [13]
• Genome-wide linkage analysis on 3 families with multiple members affected by chordoma identified chromosome 7q33 as possibly harboring a gene related to chordoma oncogenesis. However, no LOH was detected. [14]
• Microsatellite instability (MIN) was detected at various loci in 6 of 12 (50%) sacral chordoma samples. Specifically, MIN of 7q and 13q were each seen in 3 of 12 (25%) samples, MIN of 17p was seen in 2 of 12 (16.7%) samples, and MIN of 18q was seen in 1 of 12 (8.3%) samples. [15]
• Flow cytometry showed that among 14 samples of classic chordoma, 6 (42.9%) were diploid, 3 (21.4%) were aneuploid, 1 (7.1%) was tetraploid, and the rest were unclassifiable due to insufficient nuclei. [16]
• Flow cytometry showed that among 16 samples of chondroid chordoma, 8 (50%) were diploid, 0 (0%) were aneuploid, 1 (7.1%) was tetraploid, and the rest were unclassifiable due to insufficient nuclei. [16]
• Cytogenetic analysis on 7 sacral chordoma samples found normal karyotypes in 4 (57.1%) cases, only one genetic change in 1 (14.3%) case, and complex karyotypic rearrangements in 2 (28.6%) cases. [17]
• DNA content analyses revealed non-diploid cell populations in 3 of 7 (42.9%) sacral chordoma samples. [17]
• Chromogenic in situ hybridization (CISH) on 22 chordoma samples (19 from primary tumors, 3 from recurrent) at the centromeric region of chromosome 7 detected disomy in 6 of 22 (27.3%) cases, trisomy in 13 of 22 (59.1%) cases, and polysomy in 3 of 22 (13.6%) cases. [7]

LOH in general regions

• 25 of 27 chordomas (85%) had LOH at 1p36.13. Putative tumor supressor genes at this locus include CASP9, EPHA2, PAX7, DAN and DVL1. 23 of 27 chordomas shared a common LOH interval centered on D1S2697 (1p36.13) and delimited by D1S436 and D1S2826. [18]
• A tumor-suppressor gene involved in familial and sporadic chordoma maps to 1p36: LOH data relating to 6 sporadic chordomas defines a smallest region of overlapping loss of about 25 cM from D1S2845 (1p36.31) to D1S2728 (1p36.13). [19]
• 12 of 16 skull base chordoma patients showed LOH at 1p36, six of whom displayed a wide region of LOH involving all the tested markers. The remaining six patients displayed a variable region of LOH that was different in LOH extent and/or localization. Within the last group, three patients showed segmental LOH. [20]
• The lack of 1p36 LOH or the presence of TNFRSF8 expression might be associated with a better prognosis in patients with SBCs. [20]
• Losses of DNA sequences were most prevalent at 3p (8/16) and 1p (7/16). Losses of 3p were detected in five of seven primary chordomas. Loss of 13q was found in one of 10 sacrococcygeal tumors, in the single spinal tumor, and in 3 of 5 sphenoocciptial tumors. [5]
• Clonal chromosome losses were identified in six of 11 recurrent tumors. In four of these, losses included the deletion or loss of chromosomes 3, 4, 13, and 18, followed by the loss of chromosome 10 in three of the four tumors. [6]
• Microsatellite-based loss of heterozygosity analysis found 9p loss in 3/25 primary clival chordoma specimens. [21]
• FISH analysis found homozygous loss of the 9p21 locus in 5/23 primary clival chordoma specimens. [21]
• Loss of 9p is associated with a 51% decrease in mean patient survival time compared to patients with tumors demonstrating normal 9p. [21]
• Deletion of one copy of chromosome 1p36 was seen in 2 of 7 ( 28.5%) primary and in 3 of 10 ( 30%) recurrent chordoma samples by iFISH. Amplification of this chromosome was detected in 1 of 7 (14.2%) primary and 6 of 10 (60%) recurrent chordoma samples. [22]
• Deletion of one copy of chromosome 7q33 was seen in 1 of 6 (16.6%) primary chordoma samples by iFISH. Amplification of this chromosome was detected in 2 of 6 (33.3%) primary and 3 of 8 (37.5%) recurrent chordoma samples. [22]
• Deletion of one copy of chromosome 3p12-p14 was seen in 1 of 6 (16.6%) primary and in 1 of 10 (10%) recurrent chordoma samples by iFISH. Amplification of this chromosome was detected in 1 of 6 (16.6%) primary and 1 of 10 (10%) recurrent chordoma samples. [22]
• Deletion of one copy of chromosome 1q25 was seen in 3 of 7 (32.7%) primary and in 6 of 9 (66.6%) recurrent chordoma samples by iFISH. Amplification of this chromosome was detected in 2 of 7 (28.5%) primary and 6 of 9 (66.6%) recurrent chordoma samples . [22]
• Overall, iFISH analysis on 7 primary and 11 recurrent tumor samples from 7 patients with chordoma found aberrations in chromosomes 1p36, 1q25, 2p13, and 7q33 in both the primary and recurrent samples. In contrast, chromosome 6p12 was only affected in primary tumor samples. [22]
• LOH was detected in 2 of 12 (16.7%) sacral chordoma samples. Specifically, one sample demonstrated LOH of 17p while the other sample had LOH of 9p and 18q. [15]

LOH in annotated genes

• 2 of 7 chordomas had Loss of Heterozygosity (LOH) at intron 17 of the retinoblastoma gene [23]
• A minimally deleted region in 1p36 . 31 – p36 . 11 was found in 57 % of chordomas . This region contains the transcription factor RUNX3 . [24]
• Of a total of 26 chordomas investigated by aCGH and FISH, 15 (58%) displayed a heterozygous deletion of the region covering the CDKN2A locus, and 3 (12%) showed a homozygous deletion. Heterogeneous imbalances of large chromosomal regions were common . [24]
• The chromosomal regions containing TP53 and TP53BP1 were lost in 48 % and 29 % of chordomas , respectively. [25]
• 21/49 chordomas showed loss of one copy of RPS6. [26]
• 5/48 chordomas showed no loss of CDKN2A and no loss of RPS6, while 10/48 chordomas showed loss of CDKN2A and no loss of RPS6. [26]
• Unlike normal DNA, chordoma DNA shows no hypermethylation of the RPS6 promoter. [26]
• Metaphase FISH on 2 poorly differentiated chordoma samples from pediatric patients (ages 22 months and 7 years) found heterozygous deletion/loss of the EWSR1 gene in one sample that had been observed with an abnormal karyotype. [12]
• Interphase FISH on 2 poorly differentiated chordoma samples from pediatric patients (ages 22 months and 7 years) found heterozygous deletion of the EWSR1 gene in 96 of 200 (48%) cells in one sample and in 136 of 200 (68%) cells in the other sample. [12]
• Interphase FISH on slides from FFPE sections of 4 poorly differentiated chordoma samples from pediatric patients (age range: 22 months to 11 years) found heterozygous deletion of the BAC RP11-80O7 probe (a surrogate for SMARCB1/INI1) in 169 of 200 (85%) cells in one sample, in 171 of 200 (86%) cells in a second sample, and in 105 of 200 (52.5%) cells in a third sample. Deletion of the probe was not observed in the fourth sample. [12]
• Amplification and sequencing of the SMARCB1/INI1 gene in 4 poorly differentiated chordoma samples from pediatric patients (age range: 22 months to 11 years) detected no point mutations. [12]
• Amplification and sequencing of the SMARCB1/INI1 gene in 4 poorly differentiated chordoma samples from pediatric patients (age range: 22 months to 11 years) detected heterozygosity for common SNPs in exons 6, 7, and 9 in one sample and in exon 6 in another sample. [12]
• Deletion of one copy of chromosome 17p13.1 (p53 gene locus) was seen in 1 of 7 (14.2%) primary and in 2 of 10 (20%) recurrent chordoma samples by iFISH. [22]

Brachyury (T)

• The chromosomal region on 6q27 containing the T (brachyury) gene was gained in 6 of 21 chordomas (29%). None of the 21 chordomas analyzed showed deletions that could have affected this gene. [24]
• 3 of 39 (8%) chordomas had a minor (3:1) allelic gain of brachyury. [25]
• Duplication of brachyury confers major susceptibility to familial chordoma.[27]
• Aneuploidy of brachyury was seen in 23/47 skull-based chordomas and 17/48 non-skull-based chordomas. [26]
• Imbalance of brachyury with chromosome 6 chromosome enumeration probe was seen 5/47 skull-based chordomas and 4/48 non-skull-based chordomas. [26]
• Normal brachyury was seen in 18/47 skull-based chordomas and 25/48 non-skull-based chordomas. [26]
• Direct DNA sequencing of the promoter region and coding exons of brachyury showed that its expression in 23 chordomas is not the result of somatic mutations. [26]

Receptor Tyrosine Kinase

• Fluorescent in situ hybridisation analysis failed to show amplification of FGFR4 in 50 chordomas. [25]
• 6 of 21 (27%) chordomas had EGFR amplification (4 or more copies) [28]
• 0 of 35 chordomas had amplification of EGFR [29]
• Positive expression of c-MET correlated with increased copy number of chromosome 7, being significantly correlated with aneusomic (trisomy or polysomy) samples. [7]
• FISH analysis of 33 tumors revealed no MET gene amplification. [9]
• Polysomy 7 showed an increasing incidence with escalating MET immunoreactivity , but this finding was not statistically significant. [9]
• FISH revealed that the EGFR gene was disomic in 11, low polysomic in 4, and high polysomic in 3 chordomas. [11]
• FISH revealed that the HER2 / neu gene was disomic in 10, low polysomic in 4 and high polysomic in 3 chordomas. [11]
• No mutations were found in EGFR in 22 chordomas. [11]
• Positive expression of c-MET correlated with increased copy number of chromosome 7, being significantly correlated with aneusomic (trisomy or polysomy) samples. [7]
• No previously reported mutations in FGFR1, FGFR2, FGFR3,and FGFR4; in the brachyury exons and promoter region; in KRAS (codons 12,13,51,61); and in BRAF (exons 11 and 15) were identified in 23 chordomas. [25]
• No mutations were detected in chordoma samples by direct sequencing in exons 3, 6, 11, 12, and 14 of FGFR1 ; exons 5, 7, 11, and 12 of FGFR2 ; exons 2, 4, 5, 6, 8, 9, and 15 of FGFR3 ; and exons 7, 9, and 16 of FGFR4. [26]
• FGFR4 showed a normal disomic pattern upon FISH analysis of human chordoma samples. [26]
• High level polysomy of EGFR was seen in 16/50 non-skull-based and 21/46 skull-based chordoma samples positive for EGFR by FISH. [26]
• Low level polysomy of EGFR was seen in 10/50 non-skull-based and 7/46 skull-based chordoma samples negative for EGFR by FISH. [26]
• Disomy of EGFR was seen in 19/50 non-skull-based and 17/46 skull-based chordoma samples negative for EGFR by FISH. [26]
• No mutations were detected in the exons 18 – 21 of the tyrosine kinase domain of EGFR through direct sequencing of genomic DNA among 23 chordoma samples. [26]
• 15/23 chordoma samples demonstrated a SNP (ID: rs1050171) in exon 20 of the tyrosine kinase domain of EGFR that involved a silent mutation of G to A in glutamine (number 787, cDNA position 2607). [26]
• Direct sequencing found no mutations in the EGFR gene among 22 of 22 (100%) tumor samples from patients with classic, sporadic chordoma. [11]
• FISH analysis on the EGFR gene from tumor samples from patients with classic, sporadic chordoma found disomy in 11 of 18 (61%) samples, low polysomy in 4 of 18 (22%) samples, and high polysomy in 3 of 18 (17%) samples. [11]
• FISH analysis on the HER2/neu gene from tumor samples from patients with classic, sporadic chordoma found disomy in 10 of 18 (56%) samples, low polysomy in 4 of 18 (22%) samples, high polysomy in 3 of 18 (17%) samples, and amplification in 1 of 18 (6%) samples. [11]
• Deletion of one copy of chromosome 6p12 (VEGF locus) was seen in 3 of 6 (50%) primary chordoma samples by iFISH. Amplification of this chromosome was detected in 1 of 8 (12.5%) primary chordoma samples. [22]
• Deletion of one copy of chromosome 2p13 (TGF-alpha locus) was seen in 5 of 6 (83.3%) primary chordoma samples by iFISH. Amplification of this chromosome was detected in 5 of 9 (55.5%) primary chordoma samples. [22]
• Amplification of chromosome 4q26-q27 (bFGF/FGF2 locus) was detected in 1 of 8 (12.5%) recurrent chordoma samples by iFISH. [22]
• Immunohistochemistry and CISH on 22 chordoma samples (19 from primary tumors, 3 from recurrent) found that 5 of 6 (83.3%) cases with diploid chromosome 7 were not immunoreactive for c-MET. In contrast, all 16 (100%) cases with aneusomic chromosome 7 were immunoreactive for c-MET. [7]
• Immunohistochemistry on 22 chordoma samples (19 from primary tumors, 3 from recurrent) found lack of staining for EGFR in 15 of 22 (68.2%) cases. CISH on 13 chordoma samples revealed that 8 of the 15 (53.3%) samples negative for EGFR also lacked amplification of the EGFR gene. [7]
• Direct DNA sequencing of the coding portion for the tyrosine kinase domain of EGFR found no mutations among 62 chordoma samples. However, several SNPs that give rise to synonymous amino acid changes were found. [30]

PI3K

• No translocations of ETS2 and ERG were found in 27 chordomas. [25]
• FISH analysis for mTOR and RPS6 loci showed that 11 of 33 and 21 of 44 tumours had loss of one copy of the respective genes, results which correlated with the loss of the relevant total proteins. [31]
• FISH analysis for loci containing TSC1 and TSC2 revealed that all cases analysed harbored two copies of the respective genes. [31]
• Among 22 chordomas no mutations were detected in mutation hotspots in PI3KCA (exons 9 and 20) , PTEN (exons 5,6,7,8, and 9), KRAS (exons 1 and 2) and BRAF (exons 11 and 15). [11]
• Chromosome 7 monosomy was observed in 7 of 19 chordomas, and a high degree of polysomy was observed in 2 of 19 chordomas by FISH. However, western blot evaluating the overall expression of PTEN protein indicated no differences in expression levels among Chromosome 7 monosomic or polysomic cases. These biochemical results were confirmed by real-time PCR. [11]
• FISH analysis for mTOR (FRAP1) locus on chromosome 1 showed loss of one allele in 11/33 tumors. Similarly, loss of one allele for RPS6 was detected in 21/45 of tumors. Two alleles were seen for TSC1 (28/28 cases) and TSC2 (24/24 cases) in all studied tumors. [26]
• No mutations were found in exons 4, 5, 7, 9, and 20 for PI3KCA or in codons 15, 16, and 64 for Rheb. [26]
• ETS2 showed a normal disomic pattern upon FISH analysis of human chordoma samples. No gene rearrangement was detected either. [26]
• Direct sequencing found no mutations in the PI3KCA gene among 22 of 22 (100%) tumor samples from patients with classic, sporadic chordoma. [11]
• Direct sequencing found no mutations in the PTEN gene in tumor samples from patients with classic, sporadic chordoma. [11]
• FISH analysis on tumor samples from patients with classic, sporadic chordoma found chromosome 10 monosomy in 7 of 19 (37%) samples and high level polysomy in 2 of 19 (11%) samples. Western blotting, however, found no differences in PTEN expression levels. Further biochemical analysis with confirmation by RT-PCR found no differences in PTEN mRNA levels between 2 tumor samples from chordoma patients with chromosome 10 disomy and 2 tumor samples from chordoma patients with chromosome 10 monosomy. [11]
• Mutations were not identified in PI3KCA (exons 4, 5, 7, 9 and 20) and RHEB1 (codons 15, 16 and 64) in the 23 cases for which genomic DNA was available. [31]

MAPK

• dHPLC analysis failed to show any abnormalities in the coding sequences of KRAS (exons 2 and 3; codons 12, 13, and 61) and BRAF (exons 11 and 15) from among 23 chordomas. [26]
• RT-PCR failed to detect tandem duplication at the BRAF locus in 23 chordoma samples. [26]
• Direct DNA sequencing found no mutations in KRAS, NRAS, and HRAS among 61, 39, and 49 chordoma samples, respectively. [30]

References