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Genetics Causes of LMS
written by Michael
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Introduction
This page attempts to focus on the genetic causes of LMS that have been reported in the literature.  It is by no means an exhaustive study and I look forward to contributions to this page either from LMS patients findings or by published research. Currently the page is made up only of published research.

Special thanks to the editors of "Soft Tissue Sarcomas: Present Achievements and Future Prospects", J Verweij, HM Pinedo and HD Suit. Their book has been the most valuable resource I have found on Soft Tissue Sarcomas.
Chromosome Mutations
Each person has 46 chromosomes which together store 30,000 genes.  Chromosomes can be seen under a microscope when a cell divides.  Cytogenetic aberrations are abnormalities that can be seen in the chromosomes. Most leiomyosarcomas have extremely complex cytogenetic aberrations [1,2,3]. One cytogenetic aberrations found in at least 50% of leiomyosarcomas is deletion of the chromosome 1 short arm [2,3] (Chromosomes have a short and long arm). This deletion is not useful diagnostically, because it is also found, albeit less frequently in leiomyomas [4] and in various other soft tissue tumors.
Gene Mutations
RB1

Loss of a single copy of chromosome 13 in the general region of the RB1 gene was found in around 35% of sarcomas [8]. These abnormalities have been found in many types of sarcomas but were found most commonly in malignant fibrous histiocytoma, leiomyosarcomas, and rhabdomyosarcomas.

CDKN2

Recently homozygous deletion (loss of both gene copies) of the CDKN2 gene, which encodes p16, been reported in malignant peripheral nerve sheath tumors, rhabdomyosarcomas, and leiomyosarcomas [5]. In the same study, amplification and overexpression of the CDK4 and cyclin D1 genes were observed in some sarcomas.

The latter observation agreed with an immunological study showing that the cyclin D1 protein level is elevated in up to 40% of soft tissue sarcomas [6] and with an early report of CDK4 gene amplification in a rhabdomyosarcoma [7].

Direct evidence that cyclin D1 can have a role in cell transformation is provided by experiments showing that overexpression of this gene can (1) confer transformed properties on established fibroblast lines and (2) cooperate with other protooncogenes, including activated RAS and MYC genes, to transform primary cells. The detection of CDK4 amplification and overexpression is of interest because of some cell types it has been proposed that overexpression of CDK4 protein my act by rendering cells insensitive to the CDK inhibitor protein p15 that is induced following exposure to transforming growth factor beta. If removal of the TGF-Beta control pathway acting through p15 is indeed important in sarcoma induction, then it should also be possible to find alterations of the p15 gene, and the results of such studies are awaited with interest.

P53

The p53 gene is located on a region of chromosome 17 that is frequently lost during tumor development, and the p53 allele that remains in these tumors usually contains point mutations. Loss of chromosome 17 and inactivating point mutations have frequently been observed in soft tissue sarcomas, particularly in malignant fibrous histiocytoma, rhabdomyosarcomas, and leiomyosarcomas [10-12]. However, in contrast to the results obtained with most other cancer types but in common with osteosarcoma and blast crisis chronic myeolgenous leukemia, homozygous deletion of the p53 gene was also frequently observed [13,14].

In a study involving 29 leiomyosarcoma revealed p53 overexpression in 17% of tumors and in this study all tumors overexpressing p53 protein were also shown to contain point mutations in the p53 gene [16].

No problem with MDM2

A study [9] showed that 0 of 14 leiomyosarcomas had MDM2 gene amplification.

N-RAS

Activated N-RAS was detected in a leiomyosarcoma [15].
References
[1] Fletcher JA, Kosakewich HP, Hoffer FA, Lage JM, Weidner N, Tepper R, Pinkus GS, Morton CC, Corson JM. Diagnostic relevance of clonal cytogenetic aberrations in malignant soft-tissue tumors. N Engl J Med 324:436-442, 1991.

[2] Fletcher JA, Morton CC, Pavelka K, Lage JM. Chromosome aberrations in uterine smooth muscle tumors: Potential diagnostic relevance of cytogenetic instability. Cancer Res 50:4092-4097, 1990.

[3] Sreekantaiah C, Davis JR, Sandberg AA. Chromosomal abnormalities in leiomyosarcomas Am J Pathol 142:293-305, 1993.

[4] Nilbert M, Heim S, Mandahl N, Floderus UM, Willen H, Akerman M, Mitelman F. Ring formation and structural rearrangements of chromosome 1 as secondary changes in uterine leiomyomas with t(12;14)(q14-15;q23-24). Cancer Genet Cytogenet 36:183-190, 1988.

[5] Maelandsmo GM, Berner J-M, Florenos JA, Forus A, Hovig E, Fodstad O, Myklebust O. Homozygous deletion frequency and expression levels of the CDKN2 gene in human sarcomas - relationship to amplification and MRNA levels of CDK4 and CCND1. Br J Cancer 72:393-398, 1995.

[6] Bartkova J, Lukas J, Strauss M, Bartek J. Cyclin D1 oncoprotein aberrantly accumulates in malignancies of diverse histogenesis. Oncogene 10:775-778, 1995.

[7] Khatib ZA, Matsushime H, Valentine M, Shapiro DN , Sherr CJ, Look AT. Coamplification of the CDK4 gene with MDM2 and GL1 in human sarcomas. Cancer Res 53:5535-5541,1993.

[8] Stratton MR, Williams S, Fisher C, Ball A, Westbury G, Gusterson BA, Fletcher CDM, Knight JC, Fung Y-K, Reeves BR, Cooper CS. Structural alterations of the RB1 gene in human soft tissue tumours. Br J Cancer 60:202-205,1989.

[9] Florenes VA, Moelandsmo GM, Fours A, Andreassen A, Myklebost O, Fodstad O. MDM2 gene amplification and transcription levels in human sarcomas: Relationship to TP53 gene status. J Natl Cancer Inst 87:1297-1302, 1994.

[10] Stratton MR, Moss S, Warren W, Patterson H, Clark J, Fisher C, Fletcher CDM, Ball A, Thomas M, Gusterson BA, Cooper CS. Mutation of the p53 gene in human soft tissue sarcomas: Association with abnormalities of the RB1 gene. Oncogene 5:1297-1301, 1990.

[11] Mulligan LM, Matlashewski GJ, Scrable HJ, Cavenee WK. Mechanisms of p53 loss in human sarcomas. Proc Natl Acad Sci USA 87:5863-5867, 1990.

[12] Leach FS, Tokino T, Meltzer P, Burrell M, Oliner JD, Smith S, Hill DE, Sidransky D, Kinzler KW, Vogelstein B. p53 mutation and MDM2 amplification in human soft tissue sarcomas. Cancer Res 52:2231-2234, 1993.

[13] Ahuja H, Bar-Eli M, Advani SH, Benchimol S, Cline M. Alterations in the p53 gene and the clonal evolution of the blast crisis of chronic myelocytic leukemia. Proc Natl Acad Sci USA 86:6783-6787, 1989.

[14] Masuda H, Miller C, Koeffler HP, Battifora H, Cline MJ. Rearrangement of the p53 gene in human osteogenic sarcomas. Proc Natl Acad Sci USA 84:7716-7719, 1987.

[15] Gill S, Stratton MR, Patterson H, Spurr NK, Fisher C, Gusterson B, Cooper CS. Detection of transforming genes by transfection of DNA from primary soft tissue tumours. Oncogene 6: 1651-1656, 1991.

[16] Patterson H, Gill S, Fisher C, Law MG, Jayatilake H, Fletcher CD, Thomas M, Grimer R, Gusterson BA, Cooper CS. Abnormalities of the p53, MDM2 and DCC genes in human leiomyosarcomas. Oncogene 69:1052-1058, 1994.


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