Loss of Expression of DNA Mismatch Repair Proteins Is Rare in Pancreatic and Small Intestinal Neuroendocrine Tumors

2011 ◽  
Vol 135 (12) ◽  
pp. 1539-1544 ◽  
Author(s):  
Thomas Arnason ◽  
Heidi L Sapp ◽  
Daniel Rayson ◽  
Penelope J Barnes ◽  
Magdalena Drewniak ◽  
...  
Keyword(s):  
Protein Expression ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Neuroendocrine Tumors ◽  
Dna Mismatch Repair ◽  
High Rate ◽  
Dna Mismatch ◽  
Small Intestinal ◽  
Msi Analysis ◽  
Mmr Proteins

Context.—Two recent studies have identified a high rate of microsatellite instability (MSI) in pancreatic neuroendocrine tumors (pNETs). Microsatellite instability is rare in small intestinal neuroendocrine tumors (NETs). It is unclear why there is discordance in the frequency of MSI in the 2 studies of pNETs and why this mechanism is comparatively rare in small intestinal tumors. Loss of expression of DNA mismatch repair (MMR) proteins, which is known to correlate strongly with MSI, is not well studied in pancreatic or small intestinal NETs. Objective.—To determine if there is loss of expression of MMR protein expression in pancreatic or small intestinal NETs. Design.—Sixty-nine patients (31 male, 38 female; mean age, 59.2 years) were identified who had a resection for a primary pancreatic (n  =  35) or primary small intestinal (n  =  34) NET during an 18-year period. Immunohistochemical stains for MLH1, MSH2, MSH6, and PMS2 were applied to archived tissue from all cases. All pNETs with adequate tissue (n  =  32) were also assessed by MSI analysis. Results.—There was preserved expression of MLH1, MSH2, MSH6, and PMS2 in all 35 pNETs. Of 32 pNETs tested by polymerase chain reaction, 28 were microsatellite stable and DNA did not amplify in 4. In 34 small intestinal NETs, 2 cases had indeterminate MLH1 and 1 case had indeterminate PMS2 expression. The remainder had intact MMR protein expression. Conclusion.—Defects in DNA MMR proteins are rare in pancreatic and small intestinal NETs, raising doubt that MSI plays a significant role in the pathogenesis of these tumors.

Microsatellite instability and protein expression of the DNA mismatch repair gene,hMLH1, of lung cancer in chromate-exposed workers

2005 ◽  
Vol 42 (3) ◽  
pp. 150-158 ◽  
Author(s):  
Yuji Takahashi ◽  
Kazuya Kondo ◽  
Toshiyuki Hirose ◽  
Hidewaki Nakagawa ◽  
Masaru Tsuyuguchi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Protein Expression ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Mismatch Repair Gene ◽  
Repair Gene ◽  
Dna Mismatch ◽  
Exposed Workers ◽  
Dna Mismatch Repair Gene

Microsatellite Instability and p53 Mutations Are Associated With Abnormal Expression of the MSH2 Gene in Adult Acute Leukemia

Blood ◽  
1999 ◽  
Vol 94 (2) ◽  
pp. 733-740 ◽  
Author(s):  
Y.-M. Zhu ◽  
E.P. Das-Gupta ◽  
N.H. Russell
Keyword(s):  
Elderly Patients ◽  
Acute Leukemia ◽  
Protein Expression ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
P53 Mutations ◽  
Dna Mismatch ◽  
Abnormal Expression ◽  
Msh2 Protein

Microsatellite instability (MSI) and p53 mutations have been reported to occur in a significant proportion of patients with therapy-related acute myeloid leukemia (AML). MSH2 is one of the genes involved in DNA mismatch repair to maintain fidelity of genomic replication, and defects of MSH2 are directly involved in MSI in hereditary nonpolyposis colorectal tumors and other human tumors. We have examined the expression of MSH2 protein by Western blotting in 43 adult leukemia samples, including 42 AML and 1 acute lymphoblastic leukemia (ALL) using the antibody MSH2 (Ab-1) (Calbiochem, La Jolla, CA). Abnormal expression of MSH2 protein was found in 14 of 43 (32.6%) cases; a control antibody to actin was always positive. Of the 14 patients that had abnormal expression of MSH2, 2 had therapy-related acute leukemia and 9 were elderly patients (>60 years of age). Expression of MSH2 mRNA was further examined by reverse transcriptase-polymerase chain reaction (RT-PCR). Deletion of MSH2 mRNA was found in 1 of 14 cases with deficient MSH2 protein expression. This group of patients was also screened for loss of heterozygosity (LOH) at the MSH2 locus using a panel 4 microsatellite markers (D2S367, D2S288, D2S391, and D2S2294). LOH was found in 5 of 11 cases examined. There was no evidence of LOH in 14 patients with normal MSH2 expression who were examined using the same markers. Functional evidence for defective DNA mismatch repair in leukemic cells lacking MSH2 as manifest by MSI was found in 7 of 11 cases studied. Mutations of the p53 gene in these 43 samples were also investigated by direct sequencing of full-length p53 cDNA. Mutations of p53 were found in 6 of 43 cases, including 5 of the 14 (35.7%) cases that did not express MSH2 protein. In contrast, mutation of p53 was only found in 1 of 29 (3.4%) cases with normal MSH2 protein expression (χ2 = 5.720, P < .02). These results suggest that abnormalities of DNA mismatch repair due to defective MSH2 expression could play a key role in leukemogenesis, in particular in AML arising in elderly patients or secondary to previous chemotherapy.

Microsatellite Instability and p53 Mutations Are Associated With Abnormal Expression of the MSH2 Gene in Adult Acute Leukemia

Blood ◽  
1999 ◽  
Vol 94 (2) ◽  
pp. 733-740 ◽  
Author(s):  
Y.-M. Zhu ◽  
E.P. Das-Gupta ◽  
N.H. Russell
Keyword(s):  
Elderly Patients ◽  
Acute Leukemia ◽  
Protein Expression ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
P53 Mutations ◽  
Dna Mismatch ◽  
Abnormal Expression ◽  
Msh2 Protein

Abstract Microsatellite instability (MSI) and p53 mutations have been reported to occur in a significant proportion of patients with therapy-related acute myeloid leukemia (AML). MSH2 is one of the genes involved in DNA mismatch repair to maintain fidelity of genomic replication, and defects of MSH2 are directly involved in MSI in hereditary nonpolyposis colorectal tumors and other human tumors. We have examined the expression of MSH2 protein by Western blotting in 43 adult leukemia samples, including 42 AML and 1 acute lymphoblastic leukemia (ALL) using the antibody MSH2 (Ab-1) (Calbiochem, La Jolla, CA). Abnormal expression of MSH2 protein was found in 14 of 43 (32.6%) cases; a control antibody to actin was always positive. Of the 14 patients that had abnormal expression of MSH2, 2 had therapy-related acute leukemia and 9 were elderly patients (&gt;60 years of age). Expression of MSH2 mRNA was further examined by reverse transcriptase-polymerase chain reaction (RT-PCR). Deletion of MSH2 mRNA was found in 1 of 14 cases with deficient MSH2 protein expression. This group of patients was also screened for loss of heterozygosity (LOH) at the MSH2 locus using a panel 4 microsatellite markers (D2S367, D2S288, D2S391, and D2S2294). LOH was found in 5 of 11 cases examined. There was no evidence of LOH in 14 patients with normal MSH2 expression who were examined using the same markers. Functional evidence for defective DNA mismatch repair in leukemic cells lacking MSH2 as manifest by MSI was found in 7 of 11 cases studied. Mutations of the p53 gene in these 43 samples were also investigated by direct sequencing of full-length p53 cDNA. Mutations of p53 were found in 6 of 43 cases, including 5 of the 14 (35.7%) cases that did not express MSH2 protein. In contrast, mutation of p53 was only found in 1 of 29 (3.4%) cases with normal MSH2 protein expression (χ2 = 5.720, P &lt; .02). These results suggest that abnormalities of DNA mismatch repair due to defective MSH2 expression could play a key role in leukemogenesis, in particular in AML arising in elderly patients or secondary to previous chemotherapy.

scholarly journals The Frequency of DNA Mismatch Repair Deficiency Is Very Low in Surgically Resected Lung Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Naoki Yanagawa ◽  
Noriyuki Yamada ◽  
Ryo Sugimoto ◽  
Mitsumasa Osakabe ◽  
Noriyuki Uesugi ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Protein Expression ◽  
Microsatellite Instability ◽  
Cell Carcinoma ◽  
Mismatch Repair ◽  
Squamous Cell ◽  
Lung Carcinoma ◽  
The Other ◽  
Dna Mismatch ◽  
Mmr Deficiency

IntroductionDNA mismatch repair (MMR) deficiency leads to changes in the length of nucleotide repeat sequences of tumor DNA. In that situation, DNA replicational errors occur and accumulate during DNA replication. As a result, this mechanism frequently affects the coding regions of oncogenes and tumor suppressor genes and causes carcinogenesis. Recently, DNA MMR deficiency has been recognized as a predictive biomarker for immunotherapy. The aim of this study is to examine the frequency of DNA MMR deficiency and clinicopathological characteristics in surgically resected lung carcinoma (LC) and their correlation.MethodsA total of 1153 LCs were examined. Tissue microarrays were constructed. The status of MMR deficiency was evaluated by immunohistochemical analysis of MMR protein expression (hMLH1, hMSH2, hMSH6, and hPMS2). Microsatellite instability analysis, BRAF mutation, and MLH1 methylation analysis were performed for cases that showed MMR deficiency.ResultsOnly 2 of the 1153 cases (0.17%) showed a loss of hMLH1/hPMS2 protein expression. They also had high levels of microsatellite instability (MSI-H), had neither MLH1 promoter methylation nor BRAF mutation, and were male smokers. Histopathologically, one was a squamous cell carcinoma, and the other was combined small cell carcinoma with squamous cell carcinoma. Regarding PD-L1 protein expression, one had high expression, and the other had none.ConclusionThe frequency of MMR deficiency was very low in LC. However, our two cases were non-adenocarcinoma and differed from previous studies. Because of its very low frequency, MMR deficiency is not a practical biomarker to predict the effect of immune checkpoint inhibitors in LC.

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