Large proportion of low frequency microsatellite-instability and loss of heterozygosity in pheochromocytoma and endocrine tumors detected with an extended marker panel

Kupka, Susan; Haack, Birgit; Zdichavsky, Marty; Mlinar, Tanja; Kienzle, Christine; Bock, C.‐Thomas; Kandolf, Reinhard; Kroeber, Stefan-Martin; Königsrainer, Alfred

doi:10.1007/s00432-007-0307-9

Cited by 6 publications

(5 citation statements)

References 23 publications

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“…Therefore, 77% (10/13) of the dMMR may contain the substitution of MSH6 with MSH3 or the substitution of MLH3/PMS1 with PMS2, which could, at least partially, explain the contradictory results of dMMR and MSI assays. Kupka et al (2008) increased the MSI-L detection rate by 9% using an expanded panel of reference loci including D2S443, Fluorescent PCR-capillary electrophoresis is a gold standard to detect microsatellite instability (Zhang and Li, 2013). Using this method, we found that PPGL is largely in the microsatellite stable state (MSS), which echoes the TMB levels previously reported in PPGL (Fishbein and Wilkerson, 2018).…”

Section: Discussionsupporting

confidence: 62%

“… Kupka et al (2008) increased the MSI-L detection rate by 9% using an expanded panel of reference loci including D2S443, D21S1436, D1S104, D3S1284, D16S752, and D11S1338, suggesting that detection of Bat25, Bat26, D2S123, D5S346, D17S250, and MONO-27 loci may not fully reflect the MSI status of PPGL. Thus, it is worthwhile to expand the microsatellite reference loci to improve the detection accuracy of MSI-H in PPGL.…”

Section: Discussionmentioning

confidence: 96%

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Initial characterization of immune microenvironment in pheochromocytoma and paraganglioma

et al. 2022

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Due to fewer adverse events, faster onset of action, and longer durable responses compared to chemotherapy, immunotherapy has been widely used to treat advanced solid tumors. Moreover, immunotherapy can improve the autoimmune status, thus allowing patients to benefit from the treatment in the long term. The immune microenvironment status is closely associated with the response to chemotherapies. Here, we analyzed the characteristics of the immune microenvironment in pheochromocytoma and paraganglioma (PPGL). Immunohistochemistry showed that PD-L1 is sparely expressed in PPGL with low positive rates and low expression levels, an expression pattern, that is, not correlated with tumor malignancy. Moreover, the level of intratumoral CD4+ and CD8+ lymphocyte infiltration in PPGL is low, suggesting that the immune microenvironment in PPGL may be in “immune desertification” or “immune rejection” states in which CD4+ and CD8+ lymphocyte infiltration is prevented, rendering immunotherapy less effective. In sum, our results indicate that PPGL is a microsatellite-stable tumor with low tumor mutational burden (TMB) levels, weak neoantigen production, and poor tumor antigenicity, hinting at a poor response of PPGL to chemotherapies.

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 96%

Initial characterization of immune microenvironment in pheochromocytoma and paraganglioma

et al. 2022

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“…In a small study of 22 pheochromocytomas (Kupka et al , 2008), 2 patients demonstrated MSI in 1 and 2 of three tetranucleotide repeats (D2S443, D16S752 and D21S1436) investigated; both cancers were defined as MSI-L by the Bethesda panel. None of the endocrine tumours in that study exhibited instability in the tetranucleotide markers used, although 13% were classified as MSI-H (Kupka et al , 2008). …”

Section: Prevalence and Relevance Of Emast In Human Cancersmentioning

confidence: 99%

Prevalence and implications of elevated microsatellite alterations at selected tetranucleotides in cancer

2014

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Elevated microsatellite alterations at selected tetranucleotides (EMAST), a variation of microsatellite instability (MSI), has been reported in a variety of malignancies (e.g., neoplasias of the lung, head and neck, colorectal region, skin, urinary tract and reproductive organs). EMAST is more prominent at organ sites with potential external exposure to carcinogens (e.g., head, neck, lung, urinary bladder and colon), although the specific molecular mechanisms leading to EMAST remain elusive. Because it is often associated with advanced stages of malignancy, EMAST may be a consequence of rapid cell proliferation and increased mutagenesis. Moreover, defects in DNA mismatch repair enzyme complexes, TP53 mutation status and peritumoural inflammation involving T cells have been described in EMAST tumours. At various tumour sites, EMAST and high-frequency MSI share no clinicopathological features or molecular mechanisms, suggesting their existence as separate entities. Thus EMAST should be explored, because its presence in human cells may reflect both increased risk and the potential for early detection. In particular, the potential use of EMAST in prognosis and prediction may yield novel types of therapeutic intervention, particularly those involving the immune system. This review will summarise the current information concerning EMAST in cancer to highlight the knowledge gaps that require further research.

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“…Microsatellite analysis was performed applying an extended marker panel for endocrine tumors which was previously established in our department [9]. In brief, markers BAT25, BAT26, D2S123, and D17S250 were amplified in a multiplex PCR (multiplex 1) using the QIAGEN Multiplex PCR Master Mix (Qiagen) under following conditions: final concentration of each forward primer (dye labeled) was 0.2 μM, of each reverse primer 1 μM, DNA concentration was 100 ng.…”

Section: Methodsmentioning

confidence: 99%

MSH2 and CXCR4 involvement in malignant VIPoma

Müller¹,

Kupka

Königsrainer

et al. 2012

World J Surg Onc

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BackgroundVasoactive intestinal polypeptide secreting tumors(VIPomas) are rare endocrine tumors of the pancreas with an estimated incidence of 0.1 per million per year. The molecular mechanisms that mediate development of VIPomas are poorly investigated and require definition.MethodsA genome- and gene expression analysis of specimens of a primary pancreatic VIPoma with hepatic metastases was performed. The primary tumor, the metastases, the corresponding healthy tissue of the liver, and the pancreas were compared with each other using oligonucleotide microarrays and loss of heterozygosity (LOH).ResultsThe results revealed multiple LOH events and several differentially expressed genes. Our finding of LOH and downregulation was conspicuous in the microarray analysis for the mismatch repair gene MSH2 in the primary pancreatic VIPoma tumor, the hepatic metastasis but not in the corresponding healthy tissue. Further a strong overexpression of the chemokine CXCR4 was detected in the hepatic metastases compared to its pancreatic primary. With a review of the literature we describe the molecular insights of metastatic development in VIPoma.ConclusionIn VIPoma, defects in the mismatch repair system especially in MSH2 may contribute to carcinogenesis, and increased CXCR4 may be associated with liver metastasis.

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Large proportion of low frequency microsatellite-instability and loss of heterozygosity in pheochromocytoma and endocrine tumors detected with an extended marker panel

Abstract: The extended microsatellite panel is qualified to detect MSI in PCC. Nine percent of MSI-positive cases would have not been noticed by the use of the reference panel alone. PCCs are characterized by low frequency MSI pointing to failures in factors involved in DNA replication.

Cited by 6 publications

References 23 publications

Initial characterization of immune microenvironment in pheochromocytoma and paraganglioma

Initial characterization of immune microenvironment in pheochromocytoma and paraganglioma

Prevalence and implications of elevated microsatellite alterations at selected tetranucleotides in cancer

MSH2 and CXCR4 involvement in malignant VIPoma

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