Synchronous and metachronous colorectal cancers: DNA mismatch protein expression and clinicopathological implications of 44 cases

2017 ◽  
Author(s):  
Fatma Yildirim
Keyword(s):  
Protein Expression ◽  
Colorectal Cancers ◽  
Dna Mismatch

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.

Somatic tumor profiling of DNA mismatch repair (MMR) deficient endometrial cancers (EC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e17121-e17121
Author(s):  
Karen Anne Cadoo ◽  
Deborah DeLair ◽  
Diana Mandelker ◽  
Magan Trottier ◽  
Carolyn Stewart ◽  
...  
Keyword(s):  
Protein Expression ◽  
Promoter Hypermethylation ◽  
Protein Loss ◽  
Loss Assessment ◽  
Degree Relative ◽  
Dna Mismatch ◽  
History Of ◽  
Generation Sequencing ◽  
Tumor Profiling ◽  
Rule Out

e17121 Background: Approximately 20% of EC have loss of MMR ( MSH2, MSH6, MLH1, PMS2) protein expression by immunohistochemistry (IHC). The majority have somatic MLH1/PMS2 loss, driven by MLH1 promoter hypermethylation. For the remaining patients (pts), germline testing for Lynch Syndrome (LS) is recommended. However, half do not have a corresponding germline mut. This is considered “Lynch-like syndrome” (LLS) & clinical management is challenging. We sought to determine if tumor profiling could identify somatic mut potentially underpinning loss of protein expression. Methods: Per institutional standard, all EC, regardless of age or family history undergo reflex LS screening with IHC for MMR protein expression. Pts consented to IRB approved protocols. Tumor-normal sequencing was performed via custom next-generation sequencing panel (MSK-IMPACT). Electronic medical records were reviewed. Results: 16 pt have completed tumor sequencing, median age 53 (35-83), 6 (38%) < 50 yrs at diagnosis. 2 had personal history of additional cancer (DCIS, ovary), none had first degree relative with colon or EC. A mix of EC histologies was represented: 10 endometrioid (all grades), 2 clear cell, 4 mixed. There were no serous cancers. There were median 58 mut (9-546), 14 (88%) had hyper or ultra mutated EC. 5 EC were driven by somatic POLE mut (3 known hotspot, 1 likely pathogenic), all ultra-mutated phenotype, resulting in multiple somatic MSH6 muts with isolated IHC MSH6 loss. 4 EC had MSH2/MSH6 IHC loss with corresponding double somatic mut in MSH2. 5 had one somatic mut corresponding to the MMR protein loss, assessment of LOH in these cases is pending. Two cases are unexplained: 40 yo with IHC MLH1 loss, 47mut; 69 yo, IHC MSH6 loss, 12 mut. In this cohort of LLS, somatic muts were frequently observed in ARID1A (13,81%), PTEN (10,63%) & PIK3CA(9,56%), in keeping with non serous histologies. Conclusions: In line with our prior report that pt with LLS had benign personal & family cancer histories compared with LS pts, we have identified that in 56% of LLS EC either POLE mut or double somatic MMR mut likely underpins the MMR IHC loss. As such, in these LLS EC cases, somatic tumor profiling may help to rule out LS. Further testing is ongoing to increase cohort size.

scholarly journals MSH3 Protein Expression and Nodal Status in MLH1-Deficient Colorectal Cancers

2012 ◽  
Vol 18 (11) ◽  
pp. 3142-3153 ◽  
Author(s):  
Luigi Laghi ◽  
Paolo Bianchi ◽  
Gabriele Delconte ◽  
Giuseppe Celesti ◽  
Giuseppe Di Caro ◽  
...  
Keyword(s):  
Protein Expression ◽  
Nodal Status ◽  
Colorectal Cancers

scholarly journals Antitumor immunity in dMMR colorectal cancers requires interferon-induced CCL5 and CXCL10

2020 ◽  
Author(s):  
Courtney Mowat ◽  
Shayla R. Mosley ◽  
Afshin Namdar ◽  
Daniel Schiller ◽  
Kristi Baker
Keyword(s):  
T Cells ◽  
Signaling Pathways ◽  
Genomic Instability ◽  
Antitumor Immunity ◽  
Tumor Infiltrating Lymphocytes ◽  
Colorectal Cancers ◽  
Critical Component ◽  
Chemokine Production ◽  
Dna Mismatch ◽  
Tumor Killing

SummaryColorectal cancers (CRCs) deficient in DNA mismatch repair (dMMR) are heavily infiltrated by CD8+ tumor infiltrating lymphocytes (TILs) and are associated with a better prognosis than the majority of CRCs. The immunogenicity of dMMR CRCs is commonly attributed to abundant neoantigen generation due to their extreme genomic instability. However, lack of neoantigenic overlap between these and other CRCs necessitates study of antigen-independent mechanisms of immune activation by dMMR CRCs in order identify therapeutic strategies for treating MMR proficient CRCs. We show here using organoid cocultures and orthotopic models that a critical component of dMMR CRC’s immunogenicity is the activation and recruitment of systemic CD8+ T cells into the tumor epithelium by overexpression of the chemokines CCL5 and CXCL10. This is dependent on endogenous activation of the cGAS/STING and IFN signaling pathways by the damaged DNA in dMMR CRCs. These signaling pathways remain sensitive to exogenous stimulation in other CRCs, identifying an attractive therapeutic avenue for increasing TIL infiltration into normally immune resistant CRC subtypes. We have thus identified a key neoantigen-independent mechanism that underlies the ability for dMMR CRCs to recruit TILs into the tumor epithelium. Given that TIL recruitment is a prerequisite for effective tumor killing either by the endogenous immune system or in the context of immunotherapies, treatments that activate IFN-induced chemokine-production by tumor cells promise to improve the prognosis of patients with many different CRC subsets.Statement of SignificanceA critical component of antitumor immunity in dMMR CRCs is their ability to recruit T cells into the tumor epithelium as a prerequisite to tumor cell killing. This occurs because their extensive genomic instability leads to endogenous activation of cGAS/STING and overexpression of CCL5 and CXCL10.

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