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Absence of structural rearrangements of chromosome 11 in human primary malignant melanoma
SHORT COMMUNICATIONS Absence of Structural Rearrangements of Chromosome 11 in Human Primary Malignant Melanoma Bogus aw Nedoszytko, Krzysztof Mr6zek, and Janusz Limon ABSTRACT: Cytogenetic analysis of 10 primary and 18 metastatic malignant melanomas revealed that structural abnormalities of chromosome 11 were present in 50% of metastatic lesions and were not found in primary tumors. Our findings suggest that chromosome 11 aberrations represent secondary
changes in malignant melanoma tumorigenesis. INTRODUCTION Up to the present day, detailed descriptions of clonal chromosome aberrations have been reported in 100 malignant melanomas [1-4], most of them being highly advanced tumors, often metastases and established cell lines. Primary lesions constitute 20% of all analyzed cases, but primary tissue cultures were cytogenetically analyzed in only seven cases studied [5-9]. Chromosomes 1, 6, and 7 are nonrandomly involved, mainly in structural changes, in malignant melanoma [10]. In a significant subset of metastatic tumors rearrangements of chromosomes 2, 3, 9, and 11 were also described [3, 11-15]. Helm et al. [14] and Trent et al. [11] proposed, on the basis of their observations of frequent translocations and deletions of 11p present in established cell lines and metastatic lesions, respectively, that loss of material from the short arm of this chromosome plays an important role in melanoma tumorigenesis. RESULTS AND DISCUSSION
We have karyotyped melanoma cells obtained from primary, short-term tissue cultures of 10 primary and 18 metastatic tumors. The tumor specimens were processed for cytogenetic analysis as described by Limon et al. [16]. Clonal structural and/or numerical changes were observed in all analyzed tumors. The most frequently rearranged chromosomes are presented in Table 1. Both in primary and metastatic malignant melanomas chromosomes 1, 6, and 7 were most frequently rearranged, which is in accordance with the literature [10-12]. Surpris-
ingly, structural aberrations of chromosome 11, such as deletions and nonreciprocal translocations leading to partial monosomies of both the long and short arms, were present exclusively in metastatic lesions. No chromosome 11 changes were detected in primary tumors. The high frequency of chromosome 11 aberrations in metastatic tumors studied by us (50%} is only slightly lower than that described by Trent et al. [11] and confirms nonrandomness of chromosome 11 abnormalities in metastatic malignant melanoma. The addition of ten new cases of primary malignant melanoma means that altogether 17 primary tumors with clona| aberrations are known. Only three of these tumors display.structural changes of chromosome 11 [5-7]. The low incidence of chromosome 11 aberrations in primary tumors makes it highly unlikely that alterations of 11p play an essential, pathogenetic role in malignant melanoma tumorigenesis, as was proposed by Heim et al. [14] and Trent et al. [11], and should be regarded rather as the secondary changes that characterize tumor progression. This conclusion is further strengthened by the fact that only one of the 46 nevi that have been successfully karyotyped displayed chromosome 11 structural change, namely t(11;11) [1, 7, 17, 18]. Deletions and translocations leading to loss of 11p material have been commonly detected in malignant fibrous histiocytomas and ovarian carcinomas obtained from patients with advanced clffdcal stages of neoplastic diseases [19-21]. In both these Conditions, 11p aberrations were present but always together with numerous other aberrations suggesting that they represent secondary changes.
Table 1
From the Department of Biology and Genetics, Medical Acad-
emy, Gdarisk, Poland. Address reprint requests to: Dr. ]anusz Limon, Department of Biology and Genetics, Medical Academy, 1 Dfbinki St., 80-211 Gdar~sk, Poland. Received April 22, 1991; accepted May 21, 1991.
Involvement of selected chromosomes in structural aberrations in malignant melanoma Abnormalities of chromosome
Source
Number of tumors
1
2
3
6
7
9
11
Primary Metastatic
10 18
7 13
2 4
2 9
5 11
5 9
2 5
-9
196 Cancer Genet Cytogenet 58:196-197 (1992}
0165-4608/92/$05.00
1992 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 ©
B. Nedoszytko et al.
197
This study was supported by a grant from the Polish National Cancer Program CPBR 11.5-91. 12. REFERENCES 1. Mitelman F (1991): Catalog of Chromosome Aberrations in Cancer. 4th Ed. Wiley-Liss, New York. 2. Quinn LA, Woods LK, Merrick SB, Arabasz NM, Moore GE (1977): Cytogenetic analysis of twelve human malignant melanoma cell lines. J Natl Cancer Inst 59:301-305. 3. Sozzi G, Miozzo M, Calderone C, Fossati G, Pierotti MA, Cascinelli N, Della Porta G (1990): Chromosome abnormalities and fragile sites in human melanoma. Cancer Genet Cytogenet 44:61-67. 4. Grammatico P, Lo Re ML, Scarpa S, Modesti A, Del Porto G (1990): Human malignant melanoma: Significance of chromosomal abnormalities. Cancer Genet Cytogenet 48:237-242. 5. Kakati S, Song SY, Sandberg AA (1977): Chromosomes and causation of human cancer and leukaemia. XXII. Karyotypic changes in malignant melanoma. Cancer 40:1173-1181. 6. Cowan JM, Halaban R, Lane AT, Francke U (1986): The involvement of 6p in melanoma. Cancer Genet Cytogenet 20:255-261. 7. Cowan JM, Halaban R, Francke U (1988): Cytogenetic analysis of melanocytes from premalignant nevi and melanomas. J Natl Cancer Inst 80:1159-1164. 8. Teyssier JR (1987): Nonrandom chromosomal changes in human solid tumors: Application of an improved culture method. J Natl Cancer Inst 79:1189-1198. 9. Aledo R, Dutrillaux B, Lombard M, Aurias A (1989}: Cytogenetic study on eleven cutaneous neoplasms and two pre-tumoral lesions from xeroderma pigmentosum patients. Int J Cancer 44:79-83. 10. Heim S, Mitelman F (1987): Cancer Cytogenetics. Alan R. Liss Inc., NY. 11. Trent JM, Leong SPL, Meyskens FL (1989): Chromosome alterations in human malignant melanoma. In: Skin Tumors: Exper-
13.
14.
15.
16.
17.
18.
19.
20.
21.
imental and clinical aspects, CJ Conti, TJ Slaga, Klein-Szanto AJP, eds. Raven Press NY, pp. 165-186. Trent JM, Meyskens FL, Salmon SE, Ryschon K, Leong SPL, Davis JR, Mc Gee DL (1990}:Relation of cytogenetic abnormalities and clinical outcome in metastatic melanoma. N Engl J Med 322:1508-1511. Limon J, Dal Cin P, Salt SNJ, Karakousis C, Sandberg AA (1988): Chromosome changes in metastatic human melanoma. Cancer Genet Cytogenet 30:201-211. Helm S, Mandahl N, Arheden K, Giovanella BC, Yim SO, Stehlin JS Jr, Mitelman F (1988): Multiple karyotypic abnormalities, including structural rearrangements of 11p in cell lines from malignant melanomas. Cancer Genet Cytogenet 35:5-20. Priest JH, Philips CN, Wang Y, Richmond A (1988): Chromosome and growth factor abnormalities in melanoma. Cancer Genet Cytogenet 35:253-262. Limon J, Dal Cin P, Sandberg AA (1986): Application of long term collagenase disaggregation for the cytogenetic analysis of human solid tumors. Cancer Genet Cytogenet 23:305-313. Richmond A, Fine R, Murray D, Lawson DH, Priest JH (1986): Growth factor and cytogenetic abnormalities in cultured nevi and malignant melanomas. J Invest Dermatol 86:295-302. Parmitter AH, Balaban G, Clark WH Jr, Nowell PC (1988): Possible involvement of the chromosome region lOq24-q26 in early stages of melanocytic neoplasia. Cancer Genet Cytogenet 30:313-317. Mandahl N, Helm S, Willen H, Rydholm A, Eneroth M, Nilbert M, Kreicbergs A, Mitelman F (1989): Characteristic karyotypic anomalies identify subtypes of malignant fibrous histiocytoma. Genes Chrom Cancer 1:9-14. Mr6zek K, Limon J, Nedoszytko B, Babiriska M, Mr6zek E, Emerich J, Mieszczerski J (1989): Cytogenetical findings in human ovarian tumors. Cancer Genet Cytogenet 38:182. Pejovic T, Helm S, Mandahl N, Elmfors B, Flod~rus U-M, Furgyik S, Helm G, Will6n H, Mitelman F (1989): Consistent occurrence of a 19p + marker chromosome and loss of 11p material in ovarian seropapillary cystadenocarcinoma. Genes Chrom Cancer 1:167-171.
changes in malignant melanoma tumorigenesis. INTRODUCTION Up to the present day, detailed descriptions of clonal chromosome aberrations have been reported in 100 malignant melanomas [1-4], most of them being highly advanced tumors, often metastases and established cell lines. Primary lesions constitute 20% of all analyzed cases, but primary tissue cultures were cytogenetically analyzed in only seven cases studied [5-9]. Chromosomes 1, 6, and 7 are nonrandomly involved, mainly in structural changes, in malignant melanoma [10]. In a significant subset of metastatic tumors rearrangements of chromosomes 2, 3, 9, and 11 were also described [3, 11-15]. Helm et al. [14] and Trent et al. [11] proposed, on the basis of their observations of frequent translocations and deletions of 11p present in established cell lines and metastatic lesions, respectively, that loss of material from the short arm of this chromosome plays an important role in melanoma tumorigenesis. RESULTS AND DISCUSSION
We have karyotyped melanoma cells obtained from primary, short-term tissue cultures of 10 primary and 18 metastatic tumors. The tumor specimens were processed for cytogenetic analysis as described by Limon et al. [16]. Clonal structural and/or numerical changes were observed in all analyzed tumors. The most frequently rearranged chromosomes are presented in Table 1. Both in primary and metastatic malignant melanomas chromosomes 1, 6, and 7 were most frequently rearranged, which is in accordance with the literature [10-12]. Surpris-
ingly, structural aberrations of chromosome 11, such as deletions and nonreciprocal translocations leading to partial monosomies of both the long and short arms, were present exclusively in metastatic lesions. No chromosome 11 changes were detected in primary tumors. The high frequency of chromosome 11 aberrations in metastatic tumors studied by us (50%} is only slightly lower than that described by Trent et al. [11] and confirms nonrandomness of chromosome 11 abnormalities in metastatic malignant melanoma. The addition of ten new cases of primary malignant melanoma means that altogether 17 primary tumors with clona| aberrations are known. Only three of these tumors display.structural changes of chromosome 11 [5-7]. The low incidence of chromosome 11 aberrations in primary tumors makes it highly unlikely that alterations of 11p play an essential, pathogenetic role in malignant melanoma tumorigenesis, as was proposed by Heim et al. [14] and Trent et al. [11], and should be regarded rather as the secondary changes that characterize tumor progression. This conclusion is further strengthened by the fact that only one of the 46 nevi that have been successfully karyotyped displayed chromosome 11 structural change, namely t(11;11) [1, 7, 17, 18]. Deletions and translocations leading to loss of 11p material have been commonly detected in malignant fibrous histiocytomas and ovarian carcinomas obtained from patients with advanced clffdcal stages of neoplastic diseases [19-21]. In both these Conditions, 11p aberrations were present but always together with numerous other aberrations suggesting that they represent secondary changes.
Table 1
From the Department of Biology and Genetics, Medical Acad-
emy, Gdarisk, Poland. Address reprint requests to: Dr. ]anusz Limon, Department of Biology and Genetics, Medical Academy, 1 Dfbinki St., 80-211 Gdar~sk, Poland. Received April 22, 1991; accepted May 21, 1991.
Involvement of selected chromosomes in structural aberrations in malignant melanoma Abnormalities of chromosome
Source
Number of tumors
1
2
3
6
7
9
11
Primary Metastatic
10 18
7 13
2 4
2 9
5 11
5 9
2 5
-9
196 Cancer Genet Cytogenet 58:196-197 (1992}
0165-4608/92/$05.00
1992 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 ©
B. Nedoszytko et al.
197
This study was supported by a grant from the Polish National Cancer Program CPBR 11.5-91. 12. REFERENCES 1. Mitelman F (1991): Catalog of Chromosome Aberrations in Cancer. 4th Ed. Wiley-Liss, New York. 2. Quinn LA, Woods LK, Merrick SB, Arabasz NM, Moore GE (1977): Cytogenetic analysis of twelve human malignant melanoma cell lines. J Natl Cancer Inst 59:301-305. 3. Sozzi G, Miozzo M, Calderone C, Fossati G, Pierotti MA, Cascinelli N, Della Porta G (1990): Chromosome abnormalities and fragile sites in human melanoma. Cancer Genet Cytogenet 44:61-67. 4. Grammatico P, Lo Re ML, Scarpa S, Modesti A, Del Porto G (1990): Human malignant melanoma: Significance of chromosomal abnormalities. Cancer Genet Cytogenet 48:237-242. 5. Kakati S, Song SY, Sandberg AA (1977): Chromosomes and causation of human cancer and leukaemia. XXII. Karyotypic changes in malignant melanoma. Cancer 40:1173-1181. 6. Cowan JM, Halaban R, Lane AT, Francke U (1986): The involvement of 6p in melanoma. Cancer Genet Cytogenet 20:255-261. 7. Cowan JM, Halaban R, Francke U (1988): Cytogenetic analysis of melanocytes from premalignant nevi and melanomas. J Natl Cancer Inst 80:1159-1164. 8. Teyssier JR (1987): Nonrandom chromosomal changes in human solid tumors: Application of an improved culture method. J Natl Cancer Inst 79:1189-1198. 9. Aledo R, Dutrillaux B, Lombard M, Aurias A (1989}: Cytogenetic study on eleven cutaneous neoplasms and two pre-tumoral lesions from xeroderma pigmentosum patients. Int J Cancer 44:79-83. 10. Heim S, Mitelman F (1987): Cancer Cytogenetics. Alan R. Liss Inc., NY. 11. Trent JM, Leong SPL, Meyskens FL (1989): Chromosome alterations in human malignant melanoma. In: Skin Tumors: Exper-
13.
14.
15.
16.
17.
18.
19.
20.
21.
imental and clinical aspects, CJ Conti, TJ Slaga, Klein-Szanto AJP, eds. Raven Press NY, pp. 165-186. Trent JM, Meyskens FL, Salmon SE, Ryschon K, Leong SPL, Davis JR, Mc Gee DL (1990}:Relation of cytogenetic abnormalities and clinical outcome in metastatic melanoma. N Engl J Med 322:1508-1511. Limon J, Dal Cin P, Salt SNJ, Karakousis C, Sandberg AA (1988): Chromosome changes in metastatic human melanoma. Cancer Genet Cytogenet 30:201-211. Helm S, Mandahl N, Arheden K, Giovanella BC, Yim SO, Stehlin JS Jr, Mitelman F (1988): Multiple karyotypic abnormalities, including structural rearrangements of 11p in cell lines from malignant melanomas. Cancer Genet Cytogenet 35:5-20. Priest JH, Philips CN, Wang Y, Richmond A (1988): Chromosome and growth factor abnormalities in melanoma. Cancer Genet Cytogenet 35:253-262. Limon J, Dal Cin P, Sandberg AA (1986): Application of long term collagenase disaggregation for the cytogenetic analysis of human solid tumors. Cancer Genet Cytogenet 23:305-313. Richmond A, Fine R, Murray D, Lawson DH, Priest JH (1986): Growth factor and cytogenetic abnormalities in cultured nevi and malignant melanomas. J Invest Dermatol 86:295-302. Parmitter AH, Balaban G, Clark WH Jr, Nowell PC (1988): Possible involvement of the chromosome region lOq24-q26 in early stages of melanocytic neoplasia. Cancer Genet Cytogenet 30:313-317. Mandahl N, Helm S, Willen H, Rydholm A, Eneroth M, Nilbert M, Kreicbergs A, Mitelman F (1989): Characteristic karyotypic anomalies identify subtypes of malignant fibrous histiocytoma. Genes Chrom Cancer 1:9-14. Mr6zek K, Limon J, Nedoszytko B, Babiriska M, Mr6zek E, Emerich J, Mieszczerski J (1989): Cytogenetical findings in human ovarian tumors. Cancer Genet Cytogenet 38:182. Pejovic T, Helm S, Mandahl N, Elmfors B, Flod~rus U-M, Furgyik S, Helm G, Will6n H, Mitelman F (1989): Consistent occurrence of a 19p + marker chromosome and loss of 11p material in ovarian seropapillary cystadenocarcinoma. Genes Chrom Cancer 1:167-171.