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. 2000 Dec;83(12):1707–1714. doi: 10.1054/bjoc.2000.1513

Definition of the role of chromosome 9p21 in sporadic melanoma through genetic analysis of primary tumours and their metastases

G Palmieri 1, A Cossu 2, P A Ascierto 3, G Botti 3, M Strazzullo 3, A Lissia 2, M Colombino 1, M Casula 1, C Floris 4, F Tanda 2, M Pirastu 1, G Castello 3, for the Melanoma Cooperative Group
PMCID: PMC2363459  PMID: 11104570

Abstract

Malignant melanoma (MM) is thought to arise by sequential accumulation of genetic alterations in normal melanocytes. Previous cytogenetic and molecular studies indicated the 9p21 as the chromosomal region involved in MM pathogenesis. In addition to the CDKN genes (p16/CDKN2A, p15/CDKN2B and p19ARF, frequently inactivated in familial MM), widely reported data suggested the presence within this region of other melanoma susceptibility gene(s). To clearly assess the role of the 9p21 region in sporadic melanoma, we evaluated the presence of microsatellite instability (MSI) and loss of heterozygosity (LOH) in primary tumours as well as in synchronous or asynchronous metastases obtained from the same MM patients, using 9 polymorphic markers from a 17-cM region at 9p21. LOH and MSI were found in 27 (41%) and 11 (17%), respectively, out of 66 primary tumours analysed. In corresponding 58 metastases, MSI was found at higher rate (22; 38%), whereas a quite identical pattern of allelic deletions with 27 (47%) LOH+ cases were observed. Although the CDKN locus was mostly affected by LOH, an additional region of common allelic deletion corresponding to marker D9S171 was also identified. No significant statistical correlation between any 9p21 genetic alteration (LOH, MSI or both) and clinicopathological parameters was observed. © 2000 Cancer Research Campaign http://www.bjcancer.com

Keywords: malignant melanoma; chromosome 9p21, polymerase chain reaction; microsatellite analysis; tumour progression

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Selected References

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  1. Bahuau M., Vidaud D., Jenkins R. B., Bièche I., Kimmel D. W., Assouline B., Smith J. S., Alderete B., Cayuela J. M., Harpey J. P. Germ-line deletion involving the INK4 locus in familial proneness to melanoma and nervous system tumors. Cancer Res. 1998 Jun 1;58(11):2298–2303. [PubMed] [Google Scholar]
  2. Batova A., Diccianni M. B., Yu J. C., Nobori T., Link M. P., Pullen J., Yu A. L. Frequent and selective methylation of p15 and deletion of both p15 and p16 in T-cell acute lymphoblastic leukemia. Cancer Res. 1997 Mar 1;57(5):832–836. [PubMed] [Google Scholar]
  3. Berwick M., Halpern A. Melanoma epidemiology. Curr Opin Oncol. 1997 Mar;9(2):178–182. doi: 10.1097/00001622-199703000-00013. [DOI] [PubMed] [Google Scholar]
  4. Birindelli S., Tragni G., Bartoli C., Ranzani G. N., Rilke F., Pierotti M. A., Pilotti S. Detection of microsatellite alterations in the spectrum of melanocytic nevi in patients with or without individual or family history of melanoma. Int J Cancer. 2000 Apr 15;86(2):255–261. doi: 10.1002/(sici)1097-0215(20000415)86:2<255::aid-ijc16>3.0.co;2-l. [DOI] [PubMed] [Google Scholar]
  5. Borg A., Johannsson U., Johannsson O., Häkansson S., Westerdahl J., Mäsbäck A., Olsson H., Ingvar C. Novel germline p16 mutation in familial malignant melanoma in southern Sweden. Cancer Res. 1996 Jun 1;56(11):2497–2500. [PubMed] [Google Scholar]
  6. Cairns P., Polascik T. J., Eby Y., Tokino K., Califano J., Merlo A., Mao L., Herath J., Jenkins R., Westra W. Frequency of homozygous deletion at p16/CDKN2 in primary human tumours. Nat Genet. 1995 Oct;11(2):210–212. doi: 10.1038/ng1095-210. [DOI] [PubMed] [Google Scholar]
  7. Costello J. F., Berger M. S., Huang H. S., Cavenee W. K. Silencing of p16/CDKN2 expression in human gliomas by methylation and chromatin condensation. Cancer Res. 1996 May 15;56(10):2405–2410. [PubMed] [Google Scholar]
  8. FitzGerald M. G., Harkin D. P., Silva-Arrieta S., MacDonald D. J., Lucchina L. C., Unsal H., O'Neill E., Koh J., Finkelstein D. M., Isselbacher K. J. Prevalence of germ-line mutations in p16, p19ARF, and CDK4 in familial melanoma: analysis of a clinic-based population. Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8541–8545. doi: 10.1073/pnas.93.16.8541. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Flores J. F., Walker G. J., Glendening J. M., Haluska F. G., Castresana J. S., Rubio M. P., Pastorfide G. C., Boyer L. A., Kao W. H., Bulyk M. L. Loss of the p16INK4a and p15INK4b genes, as well as neighboring 9p21 markers, in sporadic melanoma. Cancer Res. 1996 Nov 1;56(21):5023–5032. [PubMed] [Google Scholar]
  10. Foulkes W. D., Flanders T. Y., Pollock P. M., Hayward N. K. The CDKN2A (p16) gene and human cancer. Mol Med. 1997 Jan;3(1):5–20. [PMC free article] [PubMed] [Google Scholar]
  11. Fountain J. W., Karayiorgou M., Ernstoff M. S., Kirkwood J. M., Vlock D. R., Titus-Ernstoff L., Bouchard B., Vijayasaradhi S., Houghton A. N., Lahti J. Homozygous deletions within human chromosome band 9p21 in melanoma. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10557–10561. doi: 10.1073/pnas.89.21.10557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fujimoto A., Morita R., Hatta N., Takehara K., Takata M. p16INK4a inactivation is not frequent in uncultured sporadic primary cutaneous melanoma. Oncogene. 1999 Apr 15;18(15):2527–2532. doi: 10.1038/sj.onc.1202803. [DOI] [PubMed] [Google Scholar]
  13. Gonzalgo M. L., Bender C. M., You E. H., Glendening J. M., Flores J. F., Walker G. J., Hayward N. K., Jones P. A., Fountain J. W. Low frequency of p16/CDKN2A methylation in sporadic melanoma: comparative approaches for methylation analysis of primary tumors. Cancer Res. 1997 Dec 1;57(23):5336–5347. [PubMed] [Google Scholar]
  14. Haluska F. G., Hodi F. S. Molecular genetics of familial cutaneous melanoma. J Clin Oncol. 1998 Feb;16(2):670–682. doi: 10.1200/JCO.1998.16.2.670. [DOI] [PubMed] [Google Scholar]
  15. Healy E., Belgaid C., Takata M., Harrison D., Zhu N. W., Burd D. A., Rigby H. S., Matthews J. N., Rees J. L. Prognostic significance of allelic losses in primary melanoma. Oncogene. 1998 Apr 30;16(17):2213–2218. doi: 10.1038/sj.onc.1200203. [DOI] [PubMed] [Google Scholar]
  16. Healy E., Rehman I., Angus B., Rees J. L. Loss of heterozygosity in sporadic primary cutaneous melanoma. Genes Chromosomes Cancer. 1995 Feb;12(2):152–156. doi: 10.1002/gcc.2870120211. [DOI] [PubMed] [Google Scholar]
  17. Healy E., Sikkink S., Rees J. L. Infrequent mutation of p16INK4 in sporadic melanoma. J Invest Dermatol. 1996 Sep;107(3):318–321. doi: 10.1111/1523-1747.ep12363118. [DOI] [PubMed] [Google Scholar]
  18. Kamb A., Gruis N. A., Weaver-Feldhaus J., Liu Q., Harshman K., Tavtigian S. V., Stockert E., Day R. S., 3rd, Johnson B. E., Skolnick M. H. A cell cycle regulator potentially involved in genesis of many tumor types. Science. 1994 Apr 15;264(5157):436–440. doi: 10.1126/science.8153634. [DOI] [PubMed] [Google Scholar]
  19. Kamb A., Shattuck-Eidens D., Eeles R., Liu Q., Gruis N. A., Ding W., Hussey C., Tran T., Miki Y., Weaver-Feldhaus J. Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus. Nat Genet. 1994 Sep;8(1):23–26. doi: 10.1038/ng0994-22. [DOI] [PubMed] [Google Scholar]
  20. Kumar R., Smeds J., Lundh Rozell B., Hemminki K. Loss of heterozygosity at chromosome 9p21 (INK4-p14ARF locus): homozygous deletions and mutations in the p16 and p14ARF genes in sporadic primary melanomas. Melanoma Res. 1999 Apr;9(2):138–147. doi: 10.1097/00008390-199904000-00005. [DOI] [PubMed] [Google Scholar]
  21. Lee J. Y., Dong S. M., Shin M. S., Kim S. Y., Lee S. H., Kang S. J., Lee J. D., Kim C. S., Kim S. H., Yoo N. J. Genetic alterations of p16INK4a and p53 genes in sporadic dysplastic nevus. Biochem Biophys Res Commun. 1997 Aug 28;237(3):667–672. doi: 10.1006/bbrc.1997.7212. [DOI] [PubMed] [Google Scholar]
  22. Little M., Wainwright B. Methylation and p16: suppressing the suppressor. Nat Med. 1995 Jul;1(7):633–634. doi: 10.1038/nm0795-633. [DOI] [PubMed] [Google Scholar]
  23. Liu L., Dilworth D., Gao L., Monzon J., Summers A., Lassam N., Hogg D. Mutation of the CDKN2A 5' UTR creates an aberrant initiation codon and predisposes to melanoma. Nat Genet. 1999 Jan;21(1):128–132. doi: 10.1038/5082. [DOI] [PubMed] [Google Scholar]
  24. Liu L., Goldstein A. M., Tucker M. A., Brill H., Gruis N. A., Hogg D., Lassam N. J. Affected members of melanoma-prone families with linkage to 9p21 but lacking mutations in CDKN2A do not harbor mutations in the coding regions of either CDKN2B or p19ARF. Genes Chromosomes Cancer. 1997 May;19(1):52–54. [PubMed] [Google Scholar]
  25. Merbs S. L., Sidransky D. Analysis of p16 (CDKN2/MTS-1/INK4A) alterations in primary sporadic uveal melanoma. Invest Ophthalmol Vis Sci. 1999 Mar;40(3):779–783. [PubMed] [Google Scholar]
  26. Merlo A., Herman J. G., Mao L., Lee D. J., Gabrielson E., Burger P. C., Baylin S. B., Sidransky D. 5' CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med. 1995 Jul;1(7):686–692. doi: 10.1038/nm0795-686. [DOI] [PubMed] [Google Scholar]
  27. Morita R., Fujimoto A., Hatta N., Takehara K., Takata M. Comparison of genetic profiles between primary melanomas and their metastases reveals genetic alterations and clonal evolution during progression. J Invest Dermatol. 1998 Dec;111(6):919–924. doi: 10.1046/j.1523-1747.1998.00458.x. [DOI] [PubMed] [Google Scholar]
  28. Nobori T., Miura K., Wu D. J., Lois A., Takabayashi K., Carson D. A. Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature. 1994 Apr 21;368(6473):753–756. doi: 10.1038/368753a0. [DOI] [PubMed] [Google Scholar]
  29. Ohgaki K., Minobe K., Kurose K., Iida A., Habuchi T., Ogawa O., Kubota Y., Akimoto M., Emi M. Two target regions of allelic loss on chromosome 9 in urinary-bladder cancer. Jpn J Cancer Res. 1999 Sep;90(9):957–964. doi: 10.1111/j.1349-7006.1999.tb00841.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Ohta M., Berd D., Shimizu M., Nagai H., Cotticelli M-G, Mastrangelo M., Shields J. A., Shields C. L., Croce C. M., Huebner K. Deletion mapping of chromosome region 9p21-p22 surrounding the CDKN2 locus in melanoma. Int J Cancer. 1996 Mar 15;65(6):762–767. doi: 10.1002/(SICI)1097-0215(19960315)65:6<762::AID-IJC9>3.0.CO;2-X. [DOI] [PubMed] [Google Scholar]
  31. Palmieri G., Strazzullo M., Ascierto P. A., Satriano S. M., Daponte A., Castello G. Polymerase chain reaction-based detection of circulating melanoma cells as an effective marker of tumor progression. Melanoma Cooperative Group. J Clin Oncol. 1999 Jan;17(1):304–311. doi: 10.1200/JCO.1999.17.1.304. [DOI] [PubMed] [Google Scholar]
  32. Perinchery G., Bukurov N., Nakajima K., Chang J., Li L. C., Dahiya R. High frequency of deletion on chromosome 9p21 may harbor several tumor-suppressor genes in human prostate cancer. Int J Cancer. 1999 Nov 26;83(5):610–614. doi: 10.1002/(sici)1097-0215(19991126)83:5<610::aid-ijc7>3.0.co;2-2. [DOI] [PubMed] [Google Scholar]
  33. Peris K., Keller G., Chimenti S., Amantea A., Kerl H., Höfler H. Microsatellite instability and loss of heterozygosity in melanoma. J Invest Dermatol. 1995 Oct;105(4):625–628. doi: 10.1111/1523-1747.ep12323809. [DOI] [PubMed] [Google Scholar]
  34. Pisano M., Cossu A., Persico I., Palmieri G., Angius A., Casu G., Palomba G., Sarobba M. G., Rocca P. C., Dedola M. F. Identification of a founder BRCA2 mutation in Sardinia. Br J Cancer. 2000 Feb;82(3):553–559. doi: 10.1054/bjoc.1999.0963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Platz A., Hansson J., Månsson-Brahme E., Lagerlof B., Linder S., Lundqvist E., Sevigny P., Inganäs M., Ringborg U. Screening of germline mutations in the CDKN2A and CDKN2B genes in Swedish families with hereditary cutaneous melanoma. J Natl Cancer Inst. 1997 May 21;89(10):697–702. doi: 10.1093/jnci/89.10.697. [DOI] [PubMed] [Google Scholar]
  36. Pollock P. M., Pearson J. V., Hayward N. K. Compilation of somatic mutations of the CDKN2 gene in human cancers: non-random distribution of base substitutions. Genes Chromosomes Cancer. 1996 Feb;15(2):77–88. doi: 10.1002/(SICI)1098-2264(199602)15:2<77::AID-GCC1>3.0.CO;2-0. [DOI] [PubMed] [Google Scholar]
  37. Reed J. A., Loganzo F., Jr, Shea C. R., Walker G. J., Flores J. F., Glendening J. M., Bogdany J. K., Shiel M. J., Haluska F. G., Fountain J. W. Loss of expression of the p16/cyclin-dependent kinase inhibitor 2 tumor suppressor gene in melanocytic lesions correlates with invasive stage of tumor progression. Cancer Res. 1995 Jul 1;55(13):2713–2718. [PubMed] [Google Scholar]
  38. Ruiz A., Puig S., Lynch M., Castel T., Estivill X. Retention of the CDKN2A locus and low frequency of point mutations in primary and metastatic cutaneous malignant melanoma. Int J Cancer. 1998 May 4;76(3):312–316. doi: 10.1002/(sici)1097-0215(19980504)76:3<312::aid-ijc4>3.0.co;2-y. [DOI] [PubMed] [Google Scholar]
  39. Rübben A., Babilas P., Baron J. M., Hofheinz A., Neis M., Sels F., Sporkert M. Analysis of tumor cell evolution in a melanoma: evidence of mutational and selective pressure for loss of p16ink4 and for microsatellite instability. J Invest Dermatol. 2000 Jan;114(1):14–20. doi: 10.1046/j.1523-1747.2000.00838.x. [DOI] [PubMed] [Google Scholar]
  40. Schuchter L. M. Melanoma and other skin neoplasms. Curr Opin Oncol. 1997 Mar;9(2):175–177. doi: 10.1097/00001622-199703000-00012. [DOI] [PubMed] [Google Scholar]
  41. Smith-Sørensen B., Hovig E. CDKN2A (p16INK4A) somatic and germline mutations. Hum Mutat. 1996;7(4):294–303. doi: 10.1002/(SICI)1098-1004(1996)7:4<294::AID-HUMU2>3.0.CO;2-9. [DOI] [PubMed] [Google Scholar]
  42. Soufir N., Avril M. F., Chompret A., Demenais F., Bombled J., Spatz A., Stoppa-Lyonnet D., Bénard J., Bressac-de Paillerets B. Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone families in France. The French Familial Melanoma Study Group. Hum Mol Genet. 1998 Feb;7(2):209–216. doi: 10.1093/hmg/7.2.209. [DOI] [PubMed] [Google Scholar]
  43. Talwalkar V. R., Scheiner M., Hedges L. K., Butler M. G., Schwartz H. S. Microsatellite instability in malignant melanoma. Cancer Genet Cytogenet. 1998 Jul 15;104(2):111–114. doi: 10.1016/s0165-4608(97)00452-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Wagner S. N., Wagner C., Briedigkeit L., Goos M. Homozygous deletion of the p16INK4a and the p15INK4b tumour suppressor genes in a subset of human sporadic cutaneous malignant melanoma. Br J Dermatol. 1998 Jan;138(1):13–21. doi: 10.1046/j.1365-2133.1998.02020.x. [DOI] [PubMed] [Google Scholar]
  45. Zuo L., Weger J., Yang Q., Goldstein A. M., Tucker M. A., Walker G. J., Hayward N., Dracopoli N. C. Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. Nat Genet. 1996 Jan;12(1):97–99. doi: 10.1038/ng0196-97. [DOI] [PubMed] [Google Scholar]

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