Abstract
Little information is available on the molecular mechanisms underlying oncogenesis of dedifferentiated chondrosarcoma. To obtain an overview of the genomic imbalances characterizing this tumor, we analyzed by karyotypes and comparative genomic hybridization (CGH) and reviewed the previous literatures. Cytogenetically, multiple complex abnormalities were observed in each case, but dedifferentiated chondrosarcoma has not shared common abnormal changes in karyotypes. The chondroid portion and anaplastic portion showed similar karyotype suggesting monoclonal origin, not collision tumor. The conspicuous CGH results suggested that chromosome 9 was most critical region in dedifferentiated chondrosarcoma. It may therefore supply a possible data of oncogenic mechanism of this tumor.
Key words : chondrosarcoma, oncogenesis, bone tumor
Department of Orthopedics, University of Toyama,
REVIEW
Toyama Medical Journal Vol. 18 No. 1 2007 34
rarely rhabdomyosarcoma or angiosarcoma (Figure 1).
Metastatic disease is seen more often than in classic chondrosarcoma and its prognosis is poor1-4,11）.
■Conventional karyotype analyses
Cytogenetic studies of dedifferentiated chondrosar-coma are few, because of its rarity. Little is known about the molecular mechanisms involved in the tu-morigenesis of dedifferentiated chondrosarcoma. To date, karyotype analyses of dedifferentiated chondro-sarcoma have been reportedly recognized in only 8 cases from 6 literatures (Table 1)6, 13-17). However, these results were controversial, because the genetic ap-proaches and the samples in these studies were re-stricted. From these studies, it appears that dedifferen-tiated chondrosarcoma is heterogeneous cytogeneti-cally, as well as histologically. A single or characteristic anomaly has not yet emerged from these cytogenetic descriptions.
We analyzed the karyotypes of our cases. Standard cultures and harvesting procedures were used that have been described previously18). The karyotypes were expressed according to the International System for Human Cytogenetic Nomenclature (ISCN) 199519).
In our current study also, there was no common spe-cific abnormality in karyotypes (Table 1). The karyo-types were very complicated by the numerical and structural changes with markers. In cases which sam-ples were taken from several locations or at different times, the clonal karyotypic abnormalities were found in each case, similar to previous reports6,15). We also tried and got several specimens, such as biopsy,
sur-gery or metastasis. All our cases showed similar clonal karyotypic abnormalities in each patient. Of additional interest was the presence of sharing the similar clonal karyotypic abnormalities in both the specimens from chondroid portion and anaplastic portion in our Case 2.
In classical dedifferentiated chondrosarcoma no transi-tional zone is seen between two tumor components, which lead to the idea of a primary separate histogene-sis of two tumor portions9, 20-22). This finding suggests some sort of collision tumor, derived from two com-pletely separate tumor cell clones developed from mul-tipotent mesenchymal stem cells9). However, our kary-otype data from Case 2 suggests the monoclonal origin of oncogenesis of dedifferentiated chondrosarcoma, not collision tumor.
Sawyer23) described the 6q13-21 aberrations in pa-tients with cartilage tumor. The gene for cartilage-spe-cific collagen Type IX (COL9A1) has been mapped to6 q12-14, probably 6q1324). The gene type X collagen (COL10A1) has been mapped to 6q21-2225). In addition, two oncogenes (FYN and ROS1) have been mapped to 6q21. In view point of these findings, involvement of 6q 13-22 aberrations is showed in three cases (No 5, 7 and 8). In our series, Case 2 (b and c) has shared the abnor-malities of 6q22 or 6q23. But it is questionable whether these abnormalities of type X collagen develop the critical gene as a step of oncogenesis.
■Comparative genomic hybridization (CGH) analyses CGH is a molecular cytogenetic technique that al-lows detection of DNA copy number changes26,27). Information on DNA copy number changes, including high-level amplification, can be obtained as a global view of genetic changes. CGH may solve some of the problems of using standard cytogenetics. However limitations and difficulties exist when detecting translo-cations, ploidy changes and analyzing telomeric, and peri- and hetero-chromatic regions by using CGH27).
DNA was extracted from freshly frozen tissue and purified by phenol-chloroform. CGH was done almost as described by Kallioniemi27), and evaluated by using Quips software (Vysis, Downers Grove, IL) according to the manufacturer’s instructions.
From our CGH data of dedifferentiated chondrosar-coma, chromosome 9 was most conspicuous imbalance, which was suggested critical region (Figure 2). In two cases there were structural changes, and in another two cases there were obvious deletion of 9q1.
However, there was no report about oncogene on this Figure1 Representative pathology
Histologic interpose of a dedifferentiated chondrosarcoma with rhabdomyosarcomatous elements on the upper left.
KANAMORI : Cytogenetics of dedifferentiated chondrosarcoma 35
Table1 Cytogenetic abnormalities in dedifferentiated chondrosarcoma from the previous literatures and our cases
No.DedifferentiatedComponentsKaryotypeReferences 1spindlecellcomponent(osteoid+)45,XX,1p-(p36.1),1p+,del(9)(p21.2),-10,t(4;5)(p14;q11.2)Zalupskietal 2spindlecellosteosarcoma55/61-63,XX,???(includingduplicationwithin1p36.2,possibly)Zalupskietal 3arhabdomyosarcoma53,XX,+2,+3,+5,+7,+7,+12,add(17)(p13)x2,+20Bridgeetal 3brhabdomyosarcoma55,XX,+2,+3,+5,+7,+7,+12,add(17)(p13)x2,+19,+20,+20 3crhabdomyosarcoma52,XX,der(4)t(4;13)(p16;q14),+5,+7,+7,+12,add(17)(p13)x2,+20,+20 54,XX,der(4)t(4;13)(p16;q14),+5,+7,+7,+8,+12,add(17)(p13)x2,+19,+20,+20 4MFH46,X,-X,t(9;22)(q34;q11-12),+mar/52-61,X?,2-3dmin,incTarkkanenetal 5a?42,XY,add(1)(p31),der(4;12)(q10;q10),add(6)(q22),-9,-13,-18 76,XXY,add(1)(p31)x2,+2,der(4;12)(q10;q10), +5,+6,add(6)(q22)x2,-8,-9,-10,-12,+14,+15,+17,-18,+19,+20,+22Ozisiketal 5b?45,XY,add(1)(p31),der(4;12)(q10;q10),add(6)(q22) 85,XXY,add(1)(p31)x2,-4,der(4;12)(q10;q10),add(6)(q22)x2,-8,-9,-10,-12,-13,-18,-18 6?57,XY,+Y,+2,+7,+7,+8,der(11)t(11;12)(q23;q24),+der(12)inv(12)(q11q23) t(11;12)(q23;q24),+add(17)(p10),+19,+21,+21+22Ozisiketal 7fibrosarcoma47,XX,i(1)(q10),add(6)(q13),+7,+8,t(10;22)(p11.2;q11.2),+14,-15,-17,add(19)(q13.4)Swartetal 8MFH47,XY,del(6)(q13),r(9)(p24q34),+12/49,idem,+7,+15Sawyeretal 9arhabdomyosarcoma46,XY[16]/92,XXYY[2]Ourdata(Case1) 9brhabdomyosarcoma45,X,-Y[9]/46,XY[11] 9crhabdomyosarcoma47,XY,+7[1]/94,idemx2,del(15)(q15q24)x2[7]/188,idemx4,del(15)(q15q24)x4[2]/46,XY[7]/92,XXYY[2]Ourdata(Case2) 10amalignantspindleselltumor63,XXY,-1,-1,i(1)(p10),-2,-2,del(3)(q26.2),-4,-4,-5,-7,-10,-13,-15,-16,-17,-17,-18,-21,-21,+mar1,;mar2,+9mar, +1dmin,inc[cp2]/126,idemx2,+mar3x2,+mar4,+mar5x2,+mar6,+3dmin[cp2]/252,idemx4,+mar3,mar5, +mar7[cp3]/46,XY[6] 10bMFH49-59,XXY,i(1)(p10),t(2;22)(q11.2;q11.2),del(3)(q21),del(6)(q22),?add(11)(p15),+der(?)t(1;?)(q11;?)x2,+mar1,+mar2,+1 -3mar,+r,tas,inc[cp6]/98-118,idemx2[cp2]/196-236,idemx4[cp1] 10cMFH48-61,XXY,-1,-1,i(1)(p10),-2,t(2;22)(q11.2;p11.2),-4,-5,del(6)(q23),-7,-8,-9,?add(11)(p15) -13,-13,-14,-15,-15,-17,-17,-17-18,-21,-21,-22, +der(?)t(1;?)(q11;?)x2,+mar1,+mar2,+mar3,+7-11mar,+1-2r,inc[cp5]/96-122,idemx2[3]/46,XY[2] 11aMFH-like45,XY,add(6)(p25),add(11)(p15),-13,-14,-16,-17,-21,+22, der(22)t(9;22)(q12;q13)x2,mar,+r1,+r2[4]/45,idem,add(1)(q44),0-2dmin[2]/90,idemx2Ourdata(Case3) 11bMFH-like43,XY,,add(6)(p25),add(8)(p12),del(9)(p21),der(11)t(9;11)(q12;p15),-13,t(14;15)(p10;q10),-16,-17,-21, der(22)t(9;22)(q12;q13),+r[6]/88,idemx2[2]/46,XX[6] 12apleomorphicspindlecelltumor47,XX,+15[7]/88-135,XXXXXX,add(4)(q35)x2,+mar1,mar2,+mar3,inc[cp3]/46,XX[10]Ourdata(Case4) 12bmyxoidspindlecelltumor47,XX,+15[10] 12cmyxoidspindlecelltumor50,XX,+7,+8,+9,+14[11] 3a,9a,10a,11a,12a:biopsyspecimen, 3b,9c,11b:surgicalspecimen,10b:surgicalspecimen(chondroidportion),10c:surgicalspecimen(chondroidportion)anaplasticportion 3c,9b:lungmetastasis, 5aandb:incisionalbiopsyfromthedifferentsiteofprimarytumor. 12b,candd:surgicalspecimenfromthedifferentsiteofprimarytumor. MFH:malignantfibroushistiocytoma Toyama Medical Journal Vol. 18 No. 1 2007 36
area.
To our knowledge, only one case of dedifferentiated chondrosarcoma has reportedly demonstrated CGH analysis7) But their report was without karyotyping analysis. The cartilagenous component was character-ized by the deletion of chromosomes 4, 5, 13, 22 and the distal part of chromosome16p. Chromosome 17 revealed deletion: del (17)(pter-q12) and an amplification on long arm. In contrast, the anaplastic component demonstrated amplification on 2p, 8q, 10q, 1q, 12p, 12q, 19p and possibly on1p. Deletion was seen on 2q, 4, 5q, 13, Xp, and Xq. This study illustrated the tremendous genetic variability of dedifferentiated chondrosarcoma and a large number of changes per tumor, supporting the idea that accumulation of genetic changes is impor-tant for the tumor progression, just as occurs in the conventional chondrosarcoma. Larramendy28,29) stated that the gain of 20q (especially q12-qter), 8q24.1-qter, 20p and 14q24-qter is observed mainly. Moreover, re-current and metastatic tumors showed a gain of chro-mosome 7 and 5q14-q32. In 45 cases of conventional chondrosarcoma of his reports28,29), there was no abnor-mality of 9q. The imbalance of 9q might be critical re-gion to change up to the dedifferentiated chondrosar-coma.
■Conclusion
This review aimed to characterize the cytogenetics findings of dedifferentiated chondrosarcoma. But, cyto-genetic anomaly has not emerged from previous de-scription. Our cytogenetic data suggests the monoclo-nal origin of oncogenesis of dedifferentiated
chondro-sarcoma, not collision tumor.
Moreover, we provide the genomic imbalance of 9q might be critical region to dedifferentiate. The rele-vance of the newly identified regions of gains and losses found in this study remains to be determined by future studies, focusing on the identification of critical genes in these regions.
■Acknowledgments
We are grateful to Drs. Julia A. Bridge and Jian Liu of the Department of Pathology and Microbiology, and James R. Neff of the Department of Orthopaedics, Uni-versity of Nebraska Medical Center, Omaha, NE, USA.
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博士論文名 The role of platelet-derived growth factor receptor
β
in the activation of mouse hepatic stellate cell―――――――――――――――――――――
学位記番号 医博甲第４３４号
ヨシ ダ トオル
氏 名 吉田 徹
博士論文名 ドキソルビシンと低強度超音波併用による 抗腫瘍効果の増強―薬剤併用細胞致死効果 における超音波の諸条件の検討とその増強 の機序について―
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学位記番号 医博甲第４３５号
ワタナベ トモ コ
氏 名 渡邊 智子
博士論文名 ヒト胃癌細胞における分化とAquaporin-5
（AQP5）のUpregulationと 生 理 機 能 の 解 明
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学位記番号 医博甲第４３６号
イ クボ マ リ コ
氏 名 井窪 万里子
博士論文名 リピッドホスファ タ ー ゼSHIP2，SKIP，
PTENによるインスリンシグナルの3T3-L1 脂肪細胞での制御特性の解析
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学位記番号 医博甲第４３７号
ホウノキ ヒロユキ
氏 名 朴木 博幸
博士論文名 Activation of peroxisome proliferatiors-activated receptor gamma (PRAR
γ
) inhib-its TNF-αmediated osteoclast differentia-tion in human peripheral blood mono-cytes in part via suppression of MCP-1 expression―――――――――――――――――――――
学位記番号 医博甲第４３８号
カナタニ ユ キ コ
氏 名 金谷 由紀子
博士論文名 チアゾリジン誘導体によるインスリン抵抗 性改善の機序に関する研究―ピオグリタゾ ンはSOCS3の発現抑制を介しアディポネ クチンの発現を促進する
学位記番号 医博甲第４３９号
サ ド ガ ド カ メ ル モ ハ メ ド
氏 名 SAAD GAD KAMEL MOHAMED 博士論文名 Interleukin-10 (IL-10) inhibits
RANKL-mediated expression of NFATc1 in part via suppression of c-Fos and c-Jun in RAW 264.7 cells and mouse bone marrow cells
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学位記番号 医博甲第４４０号
コ リ シン
氏 名 胡 莉珍
博士論文名 Smoking Behavior, Lung Function and Mortality in Japanese Population : A Lon-gitudinal Study
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学位記番号 医博甲第４４１号
ジ ュ ラ イ ラ ッ ト ポ ロ ム ジ ャ イ
氏 名 JURAIRAT PHROMJAI
博士論文名 Infection and Direct Injury in Human Hepatocyte explants and a Hepatoblas-toma Cell Line due to Hepatiticomimetic (Non-hepatitis) Viruses
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学位記番号 医博甲第４４２号
ガ ケンエイ
氏 名 英
博士論文名 Interleukin-1
α
inhibits insulin signaling with phosphorylating insulin receptor substrate-1 on serine residues in 3T3-L1 adipocytes―――――――――――――――――――――
学位記番号 医博甲第４４３号
マツ イ ケンイチ
氏 名 松井 健一
博士論文名 東京都区内で発生した「医療関連死」
〜平成１５年の監察医務院取り扱い例から〜
（平成１８年６月３０日〜平成１９年３月２３日）
学位授与 41