Possible association between tumor-suppressor gene mutations and hMSH2/hMLH1 inactivation in alveolar soft part sarcoma

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"Possible association between tumor-suppressor gene mutations and hMSH2/hMLH1 inactivation in alveolar soft part sarcoma.
Saito T, et al. Hum Pathol. 2003.
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Abstract
Alveolar soft part sarcoma (ASPS) is a rare soft tissue tumor of unknown origin and pathogenesis. We clinicopathologically analyzed 16 cases of ASPS and screened for the genetic alterations of various tumor-suppressor genes and oncogenes, including p53, adenomatous polyposis coli (APC), E-cadherin, and beta-catenin, in 11 cases of ASPS. We also examined the expression of hMSH2/hMLH1 of DNA mismatch repair genes by immunohistochemistry, and promoter hypermethylation of these DNA mismatch repair genes by methylation-specific polymerase chain reaction (MS-PCR) to elucidate any possible association between mutation status of these genes and inactivation of the hMSH2/hMLH1 genes. Furthermore, microsatellite instability (MSI) analysis and loss of heterozygosity (LOH) on chromosome 5q analysis were used for some cases of ASPS where DNA derived from normal tissue was available. The 5-year overall survival rate for all of the patients in this study was 68.6%. The 5-year overall survival rates for patients presenting with localized ASPS and for patients with distant metastases were 83.3% and 47.6%, respectively. The high nuclear grade of tumor cells was a significantly adverse prognostic factor (P = 0.0085). Single-strand conformation polymorphism analysis followed by DNA direct sequencing revealed 4 point mutations of the p53 gene in 3 of 11 cases (27.3%), composed of 3 missense mutations and 1 silent mutation. In addition, 1 case with the E-cadherin missense mutation and 1 case with the APC missense mutations were observed, respectively. None of the cases harbored mutation of exon 3 of the beta-catenin gene. Loss of expression of the hMSH2 and hMLH1 genes was observed in 2 (18.2%) and 3 (27.3%) of 11 cases, respectively. All 3 cases with loss of hMLH1 gene expression harbored mutations of the p53 gene. There was a statistically significant correlation between the genetic alteration positive in these tumor-suppressor genes and loss of hMLH1 gene expression (P = 0.024). Methylation-specific PCR did not reveal hypermethylation of the hMSH2/hMLH1 promoter region in any of the cases examined. Three of 8 (37.5%) ASPS cases showed low MSI, and 2 of these 3 cases showed immunohistochemical lack of expression for either hMSH2 or hMLH1. LOH on 5q was present in 2 of 6 (33.3%) informative cases, and both cases showed LOH on the D5S346 marker, a microsatellite marker near the APC locus. Thus, inactivation of hMSH2/hMLH1 of DNA mismatch repair genes seems to have an important role to play in the mutagenesis of the tumor-suppressor genes in ASPS.






https://www.ncbi.nlm.nih.gov/m/pubmed/14562278/

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LOH on 5q was present in 2 of 6 (33.3%) informative cases, and both cases showed LOH on the D5S346 marker, a microsatellite marker near the APC locus. Thus, inactivation of hMSH2/hMLH1 of DNA mismatch repair genes seems to have an important role to play in the mutagenesis of the tumor-suppressor genes in ASPS.

*LOH on 5q

https://www.researchgate.net/publicatio ... Carcinomas

*Mutagenesis

Mutagenesis /mjuːtəˈdʒɛnɪsɪs/ is a process by which the genetic information of an organism is changed in a stable manner, resulting in a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using laboratory procedures.

Mutagenesis - Wikipedia

https://en.wikipedia.org/wiki/Mutagenesis

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Although the frequency of MSI (25%) or a loss of hMLH1 a

Abstract
Alterations of the size of microsatellite DNA sequences, namely microsatellite instability (MSI), have been demonstrated in some types of malignancies. We analyzed the MSI of five microsatellite markers in 40 cases of soft tissue sarcoma (STS) using high resolution fluorescent microsatellite analysis. In addition, we examined the expression of hMLH1 and hMSH2 proteins of DNA mismatch repair (MMR) genes by immunohistochemistry, and promoter methylation of the hMLH1 gene by methylation-specific PCR (MSP). MSI was recognized in 10 of 40 STS cases (25%), which consisted of 2 MSH-high (MSI-H) tumors and 8 MSI-low (MSI-L) tumors. A loss of hMLH1 expression was recognized in 7 of 40 STS cases (18%), and loss of hMSH2 expression was recognized in 3 of 40 STS cases (8%). One case showed a loss of both hMLH1 and hMSH2 expression. Promoter hypermethylation of the hMLH1 gene was detected in only 3 of 40 STS cases (8%). Of 10 cases with MSI, 5 (50%) showed a loss of hMLH1 and/or hMSH2 expression. There was a statistically significant correlation between MSI-positive tumors and the loss of hMLH1 and/or hMSH2 expression (p=0.0286). Although the frequency of MSI (25%) or a loss of hMLH1 and/or hMSH2 expression (23%) was relatively low in STS cases, a loss of hMLH1 and/or hMSH2 was recognized in 5 out of 10 MSI-positive cases (50%). These findings suggest that the inactivation of MMR gene expression might be the cause of MSI in STS cases.


https://www.ncbi.nlm.nih.gov/m/pubmed/1 ... 78/related

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Absence of Microsatellite Instability In Soft Tissue Sarcomas

https://www.karger.com/Article/Pdf/369906

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Know that it was one study so going back to the drawing board
Congenital sarcomas not included as they are a separate group I believe.

Note that 1 of 71 people , was an ASPS patient and was included with paper .

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Mitotic values in primary path report important , with STS?
A thought
My understanding it's a piece of the puzzel , however it's a indolent SLOW presentation of lots of percolated mitosis?

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Affiliations: Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan



Abstract
Objective: Here, we analyze a series of soft tissue sarcomas (STS), which are a heterogeneous group of mesenchymal neoplasms, for the presence and frequency of microsatellite instability (MSI). MSI has been proposed to be clinically relevant for colorectal cancer, yet on STS its role is not consensual, partly due to the limited number of cases analyzed and methodology issues. Methods: The detailed evaluation of MSI in tumor samples from 71 STS patients was performed by pentaplex PCR of the MSI markers NR-27, NR-21, NR-24, BAT-25, and BAT-26, followed by capillary electrophoresis. The expression of DNA mismatch repair (MMR) proteins (MLH1, MSH2, MSH6, and PMS2) was also evaluated in suspected MSI-positive cases by immunohistochemistry. Results: The MSI analysis showed instability of one MSI marker in a total of 3 cases (4.2%). However, MMR protein expression was not affected, demonstrating that all cases were microsatellite stable. Conclusion: Our results suggest that MSI does not play a role in STS tumorigenesis.




http://www.karger.com/Article/FullText/369906

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Absence of Microsatellite Instability In Soft Tissue Sarcomas

Micro instability stable considered absent??

https://www.karger.com/Article/Pdf/369906

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Clinical Significance and Prognostic Relevance of Microsatellite Instability in Sporadic Colorectal Cancer Patients

We are trying to reconcile MSI from a prevalent colon cancer standard , to a sarcoma ASPS rare poorly understood sarcoma .
Trying to understand


Microsatellite Instability-high, in Sporadic Colon Cancer Is Associated with an Improved Prognosis at the Population Level. As well as other factors of tumor location, etc.

http://cebp.aacrjournals.org/content/10/9/917.short

Clinical Significance and Prognostic Relevance of Microsatellite Instability in Sporadic Colorectal Cancer Patients

http://www.mdpi.com/1422-0067/18/1/107/pdf