Prognostic significance of p53 gene mutations and p53 protein expression in synovial sarcomas

Schneider‐Stock, Regine; Onnasch, D.; Haeckel, Carsten; Mellin, W.; Franke, D.-S.; Roessner, Albert

doi:10.1007/s004280050418

Cited by 32 publications

(30 citation statements)

References 24 publications

(33 reference statements)

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“…Therefore, in the present study, we analyzed p53 mutations in STSs. Mutations at this locus were identified in 22 out of 86 STS patients, consistent with studies in the literature where p53 mutations were detected in STS (25,26). Furthermore, we selected 6 cases that were positive for the PAX3/7-FKHR fusion transcripts in alveolar rhabdomyosarcoma by RT-PCR in our previous study (27).…”

Section: Discussionsupporting

confidence: 87%

Mutational analysis of p53 and PTEN in soft tissue sarcoma

2011

Mol Med Report

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Abstract. p53 and PTEN are the two most frequently mutated tumor suppressors in human cancer. However, literature on the effect of the joint inactivation of tumor-suppressor genes in soft tissue sarcoma (STS) is lacking. The purpose of this study was to investigate whether p53 and PTEN mutations play a role in the carcinogenesis of STS, as well as to evaluate their mutual role in STS pathogenesis. We screened mutations of p53 and PTEN in 86 human STSs using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and DNA sequencing, respectively. p53 mutations were detected in 25.6% (22 out of 86) of STSs: 6 cases of p53 mutations were detected in 46 cases of specific reciprocal translocations in STSs (13.0%), 16 cases were detected in 40 cases of nonspecific reciprocal translocations in STSs (40.0%); the majority of the mutations were point mutations in exon 6-7. Furthermore, PTEN mutations were observed in 2 out of 86 STSs (2.3%). Two out of 86 cases revealed a 130th codon G>A missense mutation in exon 8 of PTEN which resulted in an Arg change to Gln in the PTEN protein structure; and a 334th codon A>T missense mutation in exon 8 of PTEN, which resulted in an Asn change to Lys in the PTEN protein structure. All subjects were examined for p53 exon 5-9 mutations and for PTEN exon 5-9 mutations. However, no tumors contained an alteration of the two genes. The findings indicate that p53 mutations may be involved in the oncogenesis of STS and also suggest that p53 may function as a potential molecular marker for distinguishing between STSs with specific reciprocal translocations and nonspecific reciprocal translocations. Although the existence of PTEN mutations in STS was detected, the PTEN mutation frequency was quite low. We conclude that PTEN may have played a less prognostic role than p53 in the development and malignant transformation of STS in the patients examined. IntroductionSomatic mutations of tumor-suppressor genes and oncogenes are the most common genetic alterations found in human malignancies. p53 plays a major role in regulating the response of mammalian cells to stresses and damage, in part, through the transcriptional activation of genes involved in cell cycle control, DNA repair, senescence, angiogenesis and apoptosis (1,2). Deletions or point mutations in p53 are prevalent in the majority of types of human cancer (3,4). Furthermore, mutations in p53 have also been identified as the most common genetic alterations in soft tissue sarcoma (STS) (5).PTEN, a phosphatase with specificity for lipids and proteins, is involved in basic cellular functions including adhesion, migration, proliferation and cell survival (6). PTEN is a tumor-suppressor gene located on chromosome 10q23.3, and somatic mutations in PTEN are now known to cause tumorigenesis in a number of human tissues (7). Germline mutations of PTEN are associated with inherited Cowden and Bannayan-Riley-Ruvalcuba syndromes, which are characterized by multiple benign tumors and with enhanced risk of breast and thyroid cancers...

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Section: Discussionsupporting

confidence: 87%

Mutational analysis of p53 and PTEN in soft tissue sarcoma

2011

Mol Med Report

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“…In sequencing 31 stage III soft tissue sarcoma specimens, we identified 10 (32%) that harbored p53 mutations, consistent with the incidence of p53 mutation in soft tissue sarcoma as described by others. 8,32 Moreover, none of these have been previously defined as a hotspot p53 mutation. Although 2 of the 10 mutations have been previously identified, 1 in liposarcoma 29 and the other in bladder cancer, 30 the other 7 mutations were novel, have not been previously recorded in established p53 mutation databases, and thus merit further investigation for possible relevance in soft tissue sarcoma tumorigenesis and progression.…”

Section: Discussionmentioning

confidence: 99%

“…5 Such mutations are found more fre-quently in metastases than in primary tumors and in high-grade versus low-grade sarcomas, and these mutations are thought to have a significant negative impact on both overall as well as sarcoma-specific survival. [6][7][8] Our own investigations of autologous human primary and metastatic sarcoma have demonstrated that clonal expansion of p53-mutated cells in soft tissue sarcoma confers distinct metastatic advantages. 9 Moreover, we have shown that reintroduction of wtp53 into soft tissue sarcoma cells that harbor a p53 mutation inhibits cell proliferation, soft agar colony formation in vitro, and tumorigenesis in severe combined immunodeficient (SCID) mice.…”

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confidence: 99%

High prevalence of p53 exon 4 mutations in soft tissue sarcoma

Das

Kotilingam

Korchin

et al. 2007

Cancer

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Objective The contribution of genetics to osteoarthritis (OA) progression is not known. To gain more insight into whether familial factors play a role in disease progression of OA, we analyzed familial aggregation of radiologic OA progression in a study of sibling pairs (the Genetics, Arthrosis, and Progression [GARP] study). Methods A total of 105 white probands and their 105 siblings with OA at multiple joint sites were included in a prospective cohort study. Radiologic progression of OA was defined as a 1‐point score increase in total scores for severity of joint space narrowing (JSN) or osteophytes on standardized radiographs of the hands, knees, and hips obtained at baseline and after 2 years. Odds ratios were calculated for siblings and probands sharing radiologic disease progression. Results A total of 100 probands and 93 siblings were followed for 2 years (median age 60 years, 80% women). In 92 sibling pairs both the proband and sibling had complete radiographic followup. Radiologic progression of JSN and osteophytes was present in 47% and 42% of the probands and 34% and 37% of the siblings, respectively. The odds ratios (95% confidence intervals), adjusted for age, sex, and body mass index, of a sibling having radiologic progression if the proband had progression were 3.0 (1.2–7.8) for JSN progression and 1.5 (0.6–3.6) for osteophyte progression. A dose‐response relationship was found between the amount of increase in JSN total scores among probands and the progression of JSN in siblings. Conclusion Familial factors played a role in the radiologic progression of JSN over 2 years in patients with OA at multiple sites.

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“…We focused on the role of p53 in p21 expression because synovial sarcoma has been shown to be more aggressive in patients with p53 mutations (Pollock et al, 1996;Schneider-Stock et al, 1999). However, SYT-SSX1 increased the activity of the p21 gene promoter in p53-deficient HCT116 cells as well as in the wild-type cells.…”

Section: Discussionmentioning

confidence: 99%

Induction of p21WAF1/CIP1 by human synovial sarcoma-associated chimeric oncoprotein SYT-SSX1

et al. 2005

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Oncogenic protein provokes cell cycle arrest termed premature senescence. In this process Ras has been known to induce cyclin-dependent kinase inhibitor (CKI) p16 INK4A in primary fibroblasts. Here, we present a novel finding that human chimeric oncoprotein SYT-SSX1 induces CKI p21 WAF1/CIP1 (p21) for suppression of cell growth. In human synovial sarcoma cell lines, the expression levels of p21 were high and the transcriptional activity of the p21 gene promoter was significantly elevated. The transient expression of SYT-SSX1-induced activation of the p21 gene promoter in human diploid fibroblasts. The N-terminus deletion form of SYT-SSX1, which failed to bind to hBRM one of the chromatin remodeling factors, preserved the p21 induction ability. This effect of SYT-SSX1 was similar in extent in both wild-type and p53-deficient HCT116 cell lines. Furthermore, the introduction of mutation in Sp1/Sp3 binding sites of the p21 gene promoter abolished the SYT-SSX1-induced transcriptional activity of its promoter. In SW13 cells, the stable expression of SYT-SSX1 suppressed cell growth in culture. These results suggest that SYT-SSX1 is able to induce p21 in a manner independent on hBRM and p53 but dependent on Sp1/Sp3. Oncogene (2005) 24, 7984-7990.

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Prognostic significance of p53 gene mutations and p53 protein expression in synovial sarcomas

Cited by 32 publications

References 24 publications

Mutational analysis of p53 and PTEN in soft tissue sarcoma

Mutational analysis of p53 and PTEN in soft tissue sarcoma

High prevalence of p53 exon 4 mutations in soft tissue sarcoma

Induction of p21WAF1/CIP1 by human synovial sarcoma-associated chimeric oncoprotein SYT-SSX1

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