Volume 2, Issue 4, July 2014, Page: 74-81
Correlation of Oncologic Long-Term Results and Genetic Instability in Soft Tissue Sarcomas
Reiner Wirbel, Department of Trauma, hand, and Reconstructive Surgery, Verbundkrankenhaus Bernkastel, Wittlich, Wittlich, Germany
Steffen Weber, Department of Trauma, Hand, and reconstructive Surgery University Hospital Saarland, Homburg, Germany
Joachim Hans, Department of Trauma, Hand, and reconstructive Surgery University Hospital Saarland, Homburg, Germany
Wolf Mutschler, Department of Surgery, Ludwig, Maximilian University, Munich, Germany
Received: Jun. 18, 2014;       Accepted: Jul. 4, 2014;       Published: Jul. 20, 2014
DOI: 10.11648/j.crj.20140204.13       View        Downloads  
Purpose: Soft tissue sarcomas (STS) represent a heterotop group of tumours. Microsatellite instabilities (MSI) and loss of heterozygosity (LOH) as phenomena of a genetic instability should be analysed in STS and correlated with the long-term oncologic outcome. Methods: Patients treated for a STS with a follow-up of at least 10 years were included. Thus, 86 patients (mean age 50.5 years, range 16-86 years) treated for a STS between 1993 and 2000 were routinely controlled every 6 months. Incidence of local recurrences, distant metastases, and overall survival were analysed. Sixty-six tumour samples were available for microsatellite analysis using the former traditional method of PCR amplification at 6 loci in the neighbourhood of hMSH2, hMLH1, p53, p16, rb1, and hTR. Results: There were 30 low-grade and 56 high-grade sarcomas. The mean follow-up was 144 months (120-192 months). Twenty-nine patients died of their disease. Local recurrences were seen in 13 patients, whereas metastases were noticed in 23 patients. The overall survival was dependent on the tumour stage (p<0.05), whereas the local tumour control (incidence of local recurrence) was influenced by the surgical margin achieved (p<0.05). The molecular biologic findings revealed 67% of the investigated loci as informative. MSI was found in 6.8% of the informative loci, whereas LOH in 18.8%, respectively. LOH was present in high-grade tumours in 23.8%, whereas in 1.7% in low-grade tumours. In high-grade sarcomas, the 5-year and 10-year survival probabilities were significantly lower in LOH-positive tumours (48.6% and 38%) than in LOH-negative tumours (72.5% and 62%). Conclusion: The overall survival in soft tissue sarcoma is mainly influenced by the tumour stage. In high-grade sarcomas, the survival rate will drop even after 5 years. The detection of loss of heterozygosity represents a negative prognostic predictor in high-grade sarcomas. Microsatellite instability is a rare phenomenon supposing no relevance in the oncogenesis and tumour progression of soft tissue sarcomas.
Soft Tissue Sarcoma, Oncologic Result, Genetic Instability, Microsatellite Instability
To cite this article
Reiner Wirbel, Steffen Weber, Joachim Hans, Wolf Mutschler, Correlation of Oncologic Long-Term Results and Genetic Instability in Soft Tissue Sarcomas, Cancer Research Journal. Vol. 2, No. 4, 2014, pp. 74-81. doi: 10.11648/j.crj.20140204.13
Fletcher CD, Fletcher JA, Cin PD, Landanyi M, Woodruff JM. Diagnostic gold standard for soft tissue tumours: morphology or molecular genetics? Histopathology 2001; 39: 100-103.
Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature 1998; 396: 643-649.
Suwa K, Ohmori M, Miki H. Microsatellite alterations in various sarcomas in Japanese patients. J Orthop Sci 1999; 4: 223-230.
Tarkannen M, Aaltonen LA, Böhling T, Kivioja A, Karaharju E, Elomaa I, et al. No evidence of microsatellite instability in bone tumours. Br J Cancer 1996; 74: 453-455.
Martin SS, Hurt WG, Hedges LK, Butler MG, Schwartz HS. MIN in sarcomas. Ann Surg Oncol 1998; 5: 356-360.
Alldinger I, Schaefer KL, Goedde D, Ottaviano L, Dirksen U, Ranft A, et al. Microsatellite instability in Ewing tumor is not associated with loss of mismatch repair protein expression. J Cancer Res Clin Oncol 2007; 133: 749-759.
Schneider-Stock R, Szibor R, Walter H, Plate I, Roessner A. No microsatellite instability but frequent LOH in liposarcoma. Int J Oncol 1999; 14: 721-726.
Iyoda A, Hiroshima K, Toyozaki T, Baba M, Fujisawa T, Yusa T, et al. Microsatellite alterations in patients with thoracic sarcomas. Oncol Rep 2001; 8: 917-921.
Verelst S, Hans J, Hanselmann R, Wirbel RJ. Genetic instability in primary leiomyosarcoma of bone. Hum Pathol 2004; 35: 1404-1412.
Maehara Y, Oda S, Sugimachi K. The instability within. Problems in current analyses of microsatellite instability. Mutat Res 2001; 461: 249-263.
Kawaguchi K, Oda Y, Takahira T, Saito T, Yamamoto H, Kobayashi C, et al. Microsatellite instability and hMLH1 and hMSH2 expression analysis in soft tissue sarcomas. Oncol Rep 2005; 13: 241-246.
Sin KH, Park JG. Microsatellite instability is associated with genetic alterations but not with low levels of expression of the human mismatch repair proteins hMSH2 and hMLH1. Eur J Cancer 2000; 36: 925-931.
Stahl J. Mismatch repair proteins and microsatellites hit clinical practice. Adv Ant Pathol 2000; 7: 85-93.
Garcia JJ, Kramer MJ, O`Donnell RJ, Horvai AE. Mismatch repair protein expression and microsatellite instability: a comparison of clear cell sarcoma of soft parts and metastatic melanoma. Modern Pathology 2006; 19: 950-957.
Ericson K, Engellau J, Petersson A, Lindblom A, Domanski H, Akerman M, et al. Immunhistochemical loss of DNA mismatch repair proteins MSH2 and MSH6 in malignant fibrous histiocytomas. Sarcoma 2004; 8: 123-127.
Chang SC, Lin JK, Lin TC, Liang WY. Loss of heterozygosity: an independent prognostic factor in colorectal cancer. Word J Gastroenterol 2005; 14: 778-784.
Choi SW, Lee KL, Bae YA, Min KO, Kwon MS, Kim KM, et al. Genetic classification of colorectal cancer based on chromosomal loss and microsatellite instability predicts survival. Clin Cancer Res 2002; 8: 2311-2322.
Adachi JI, Shiseki M, Okazaki T, Ishimaru G, Noguchi M, Hirohani S, et al. Microsatellite instability in primary and metastatic lung carcinomas. Genes Chromosomes Cancer 1996; 14: 301-306.
Saito T, Oda Y, Kawaguchi K, Takahira T, Yamamoto H, Sakamoto A, et al. Possible association between tumor-suppressor gene mutations and hMSH2/hMLH1 inactivation in alveolar soft part sarcoma. Hum Pathol 2003; 34: 841-849.
Sabah M, Cummins R, Leader M, Kay E: Leiomyosarcoma and malignant fibrous histiocytoma share similar allelic imbalance pattern at 9p. Virch Arch 2005; 446: 251-258.
Rucinska M, Kozlowski L, Pepinski W, Shawronska M, Janinca J, Wojtukiewicz MZ. High grade sarcomas are associated with microsatellite instability (chromosome 12) and loss of heterozygosity (chromosome 2). Med Sci Monit 2005; 11: 65-68.
Taubert H, Schuster K, Brinck U, Bartel F, Kappler W, Lautenschlager C, et al. Loss of heterozygosity at 12Q14-15 often occurs in stage I soft tissue sarcomas and is associated with MDM2 amplification in tumors at various stages. Mod Pathol 2003; 16: 1109-1116.
Yoo J, Lee HK, Kang CS, Park WS, Lee JY, Shim SI. P53 gene mutation and p 53 protein expression in human soft tissue sarcomas. Arch Pathol Lab Med 1997; 121: 395-399.
Heinsohn S, Evermann U, Zur Stadt U, Bielack S, Kabisch H. Determination of the prognostic value of loss of hetreozygosity at the Retinoblastoma gene in osteosarcoma. Int J Oncol 2007; 30: 1205-1214.
Würl P, Taubert H, Bache M, Koll J, Meye A, Berger D, et al. Frequent occurrence of p53 mutations in rhabdomyosarcoma and leiomyosarcoma, but not in fibrosarcoma and malignant neural tumors. Int J Cancer 1996; 69: 317-323.
Fuegas O, Guriec N, Babin-Boilletot A, Marcellin L, Simon P, Babin S. Et al. Loss of heterozygosity of the RB gene is a poor prognostic factor in patients with osteosarcoma. J Clin Oncol 1996; 14: 467-472.
Patino-Garcia A, Pineito ES, Diez MZ, Iturriagagoitia LG, Klussmann FA, Ariznabarreta LS. Genetic and epigenetic alterations of the cell cycle regulators and tumor suppressor genes in pediatric osteosarcomas. J Pediatr Hematol Oncol 2003; 25: 362-367.
Enneking W. A system of staging musculoskeletal neoplasms. Clin Orthop 1986; 204: 9-24.
Kaplan E, Meier P. Nonparametric estimation for incomplete observation. Am J Stat Assoc 1952; 52: 457-481.
Bassam B, Caetano-Anolles G, Gresshoff PM. Fast and sensitive silver staining of DNA in polyacylamide gels. Anal Biochem 1991; 16: 80-83.
Pisters PW, Leung DH, Woodruff JM, Shi W, Brennan MF. Analysis of prognostic factors in 1041 patients with localized soft tissue sarcoma on the extremity. J Clin Oncol 1996; 14: 1679-1689.
Chang HR, Gaynor J, Tan C, Hajdu SI, Brennan MF. Multifactorial analysis of survival in primary extremity liposarcoma. Word J Surg 1990; 14: 610-618.
Davidge K, Bell R, Ferguson P, Turcotte R, Wunder J, Davis AM. Patient expectations for surgical outcome in extremity soft tissue sarcoma. J Surg Oncol 2009; 100: 375-381.
Aksnes LH, Bauer HC, Jebsen NL, Folleras G, Allert C, Haugen GS, et al. Limb-sparing surgery preserves more function than amputation: a Scandinavian sarcoma group study of 118 patients. J Bone J Surg 2008; 90B: 786-794.
Lewis JJ, Leung D, Espat J, Woddruff JM, Brennan MF. Effect of resection in extremity soft tissue sarcoma. Ann Surg 2000; 231: 655-663.
Schneider-Stock R, Walter H, Haeckel C, Radig K, Rys J, Roessner A. Gene alterations at the CDKN2A (p16/MTS1) locus in soft tissue tumours. Int J Oncol 1998; 13: 325-329.
Browse journals by subject