80 Mesalazine Decreases Microsatellite Instability and Tumor Development in the Villin-Cre Msh2loxp/Loxp Mouse Model of Lynch Syndrome

Background: Lynch Syndrome is an autosomal dominant trait that accounts forapproximately 3% of all cases of colorectal cancer (CRC). It is caused by mutations in DNA mismatch repair (MMR) genes, most commonly MLH1 or MSH2. These MMR defects cause high levels of microsatellite instability (MSI-H) in the tumours. MSI testing of all CRCs to identify potential Lynch Syndrome cases is not practical, so the Bethesda Guidelines, which use clinical and pathological features, were created to identify those tumours most likely to be MSI-H^1. In 2007 Jenkins et. al. created MsPath, a tool based on the pathological features described in the rarely used 3^rd Bethesda criterion, to improve prediction of MSI-H tumours among CRC cases diagnosed before age 60 years^2. Methods: We collected a population-based cohort of 716 CRC cases diagnosed before age 75 years in Newfoundland. For each of these cases we collected family history, performed MSI analysis, and scored a number of pathological features for the purpose of evaluating the accuracy of the Bethesda Criteria and MsPath at predicting MSI-H tumours. Results: Our work validates the MsPath tool in the Newfoundland population for the same age group used to create the tool. We found it identified MSI-H cases with a sensitivity of 95% and specificity of 35% in our population of CRCcases diagnosed before age 60 years (n=290). We also tested this tool on our older population of CRCcases, diagnosed at ages 60 to 74 years (n=426). We found it to be at least as predictive in this population,with a sensitivity of 95% and a specificity of 42%. We then used our entire cohort (N=716) to compare MsPath with the other Bethesda criteria.Bethesda criteria 1, 2, 4 and 5 together predicted MSI-H cases with a sensitivity of 67% and a specificity of 51%. MsPath was better at identifying these cases, with a sensitivity of 95% and a specificity of 39%. Conclusions: We conclude that MsPath can be extended to include patients diagnosed with CRC before age 75 years. As well, we have found that MsPath is a better predictive tool than the Revised Bethesda Guidelines for identifying MSI-H cases within a population-based setting of colorectal cancer. References: 1. Umar, A. et. al. J Natl Cancer Inst 2004;96:261-8 2.Jenkins, M.A. et. al. Gastroenterology 2007;133:48-56

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Apolipoprotein A-I (apoA-I) and apoA-I mimetic peptides inhibit tumor development in a mouse model of ovarian cancer

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1009010107 ◽

2010 ◽

Vol 107 (46) ◽

pp. 19997-20002 ◽

Cited By ~ 125

Author(s):

F. Su ◽

K. R. Kozak ◽

S. Imaizumi ◽

F. Gao ◽

M. W. Amneus ◽

...

Keyword(s):

Ovarian Cancer ◽

Mouse Model ◽

Tumor Development ◽

Apolipoprotein A ◽

Mimetic Peptides

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Mouse model and human patient data suggest critical roles for Pten and p53 in suppressing POLE mutant tumor development

10.1101/2021.10.10.463847 ◽

2021 ◽

Author(s):

Vivian S Park ◽

Meijuan JS Sun ◽

Wesley D Frey ◽

Leonard G Williams ◽

Karl P Hodel ◽

...

Keyword(s):

Dna Damage ◽

Mouse Model ◽

Genome Stability ◽

Nuclear Dna ◽

Tumor Development ◽

Base Substitution ◽

Human Patient ◽

Mutation Burden ◽

P53 Activation ◽

Subsequent Loss

Mutations in the exonuclease domain of POLE are associated with tumors harboring very high mutation burdens. The mechanisms linking this significant mutation accumulation and tumor development remain poorly understood. Pole+/P286R;Trp53+/- mice showed accelerated cancer mortality compared to Pole+/P286R;Trp53+/+ mice. Cells from Pole+/P286R mice showed increased p53 activation, and subsequent loss of p53 permitted rapid growth, implicating canonical p53 loss of heterozygosity in POLE mutant tumor growth. Somewhat surprisingly, however, p53 status had no effect on tumor mutation burden or single base substitution signatures in POLE mutant tumors from mice or humans. Pten has important roles in maintaining genome stability. We find that PTEN mutations are highly enriched in human POLE mutant tumors, including many in POLE signature contexts. One such signature mutation, PTEN-F341V, was previously shown in a mouse model to specifically decrease nuclear Pten and lead to increased DNA damage. We found tumors in Pole+/P286R mice that spontaneously acquired PtenF341V mutations and were associated with significantly reduced nuclear Pten and elevated DNA damage. Taken together with recent published work, our results support the idea that POLE-mediated hypermutagenesis is necessary, but not entirely sufficient, for tumorigenesis. Disabling surveillance of nuclear DNA damage is a likely sufficient factor.

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Using Micro-computed Tomography for the Assessment of Tumor Development and Follow-up of Response to Treatment in a Mouse Model of Lung Cancer

Journal of Visualized Experiments ◽

10.3791/53904 ◽

2016 ◽

Author(s):

Ahmed Hegab ◽

Naofumi Kameyama ◽

Aoi Kuroda ◽

Shizuko Kagawa ◽

Yongjun Yin ◽

...

Keyword(s):

Computed Tomography ◽

Lung Cancer ◽

Mouse Model ◽

Tumor Development ◽

Response To Treatment ◽

Micro Computed Tomography

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Carnitines slow down tumor development of colon cancer in the DMH-chemical carcinogenesis mouse model

Journal of Cellular Biochemistry ◽

10.1002/jcb.24508 ◽

2013 ◽

Vol 114 (7) ◽

pp. 1665-1673 ◽

Cited By ~ 11

Author(s):

Giuseppe Roscilli ◽

Emanuele Marra ◽

Federica Mori ◽

Arianna Di Napoli ◽

Rita Mancini ◽

...

Keyword(s):

Colon Cancer ◽

Mouse Model ◽

Tumor Development ◽

Chemical Carcinogenesis

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Homozygous KSR1 deletion attenuates morbidity but does not prevent tumor development in a mouse model of RAS-driven pancreatic cancer

PLoS ONE ◽

10.1371/journal.pone.0194998 ◽

2018 ◽

Vol 13 (3) ◽

pp. e0194998

Author(s):

Elizabeth A. Germino ◽

Joseph P. Miller ◽

Lauri Diehl ◽

Carter J. Swanson ◽

Steffen Durinck ◽

...

Keyword(s):

Pancreatic Cancer ◽

Mouse Model ◽

Tumor Development

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Idylla MSI test as a new tool for microsatellite instability detection in sebaceous tumours and keratoacanthomas

Journal of Clinical Pathology ◽

10.1136/jclinpath-2021-207606 ◽

2021 ◽

pp. jclinpath-2021-207606

Author(s):

Loëtitia Favre ◽

Ruiqian Chen ◽

Yaëlle Bellahsen-Harrar ◽

Nicolas Ortonne ◽

Anaïs Pujals

Keyword(s):

Lynch Syndrome ◽

Microsatellite Instability ◽

Sensitivity And Specificity ◽

Molecular Techniques ◽

Molecular Methods ◽

Specific Method ◽

Skin Tumours ◽

Automated Method ◽

Mmr Deficiency ◽

Mmr Proteins

AimSebaceous tumours and keratoacanthomas can be associated with mismatch repair (MMR) deficiency and thus microsatellite instability (MSI). In such tumours, MSI phenotype could be an argument to search for an underlying Muir-Torre syndrome (MTS). MTS has been recognised as a variant of Lynch syndrome, characterised by a deficiency of the MMR proteins. In Lynch syndrome, the sensitivity and specificity of the techniques used to detect MSI is well described, which is not the case for skin tumours. In our hands, immunohistochemistry is a sensitive and specific method to detect MMR deficiency in those tumours. Contrasting with tumours of Lynch spectrum, sensitivity and specificity of molecular methods has not been extensively studied. This study aimed at evaluating two molecular methods to detect MSI phenotype in MTS associated tumours: a commonly used pentaplex PCR using Bethesda markers and the fully automated method using the Idylla MSI assay.MethodsA comparison between PCR, and Idylla was performed on 39 DNA extracted from cutaneous tumours. Immunohistochemistry was used as the gold standard to calculate sensitivity and specificity of both molecular techniques.ResultsConcordant results were found in 32 cases (82%) with pentaplex PCR and in 36 cases (92%) with Idylla. The sensitivity of pentaplex PCR to detect MSI phenotype was 76% whereas Idylla sensitivity was 90%.ConclusionIdylla is more performant than PCR, for the detection of MSI in MTS-associated tumours and is a reliable additional technique to help detecting MTS in these tumours.

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Understanding Inherited Risk in Unselected Newly Diagnosed Patients With Endometrial Cancer

JCO Precision Oncology ◽

10.1200/po.18.00338 ◽

2019 ◽

pp. 1-15

Author(s):

Karen A. Cadoo ◽

Diana L. Mandelker ◽

Semanti Mukherjee ◽

Carolyn Stewart ◽

Deborah DeLair ◽

...

Keyword(s):

Endometrial Cancer ◽

Next Generation Sequencing ◽

Lynch Syndrome ◽

Microsatellite Instability ◽

Mismatch Repair ◽

Cancer Predisposition ◽

Next Generation ◽

Germline Variants ◽

Predisposition Genes ◽

Generation Sequencing

PURPOSE Mutations in DNA mismatch repair genes and PTEN, diagnostic of Lynch and Cowden syndromes, respectively, represent the only established inherited predisposition genes in endometrial cancer to date. The prevalence of other cancer predisposition genes remains unclear. We determined the prevalence of pathogenic germline variants in unselected patients with endometrial cancer scheduled for surgical consultation. PATIENTS AND METHODS Patients prospectively consented (April 2016 to May 2017) to an institutional review board–approved protocol of tumor-normal sequencing via a custom next-generation sequencing panel—the Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets—that yielded germline results for more than 75 cancer predisposition genes. Tumors were assessed for microsatellite instability. Per institutional standards, all tumors underwent Lynch syndrome screening via immunohistochemistry (IHC) for mismatch repair proteins. RESULTS Of 156 patients who consented to germline genetic testing, 118 (76%) had stage I disease. In 104 patients (67%), tumors were endometrioid, and 60 (58%) of those tumors were grade 1. Twenty-four pathogenic germline variants were identified in 22 patients (14%): seven (4.5%) had highly penetrant cancer syndromes and 15 (9.6%) had variants in low-penetrance, moderate-penetrance, or recessive genes. Of these, five (21%) were in Lynch syndrome genes (two MSH6, two PMS2, and one MLH1). All five tumors had concordant IHC staining; two (40%) were definitively microsatellite instability–high by next-generation sequencing. One patient had a known BRCA1 mutation, and one had an SMARCA4 deletion. The remaining 17 variants (71%) were incremental findings in low- and moderate-penetrance variants or genes associated with recessive disease. CONCLUSION In unselected patients with predominantly low-risk, early-stage endometrial cancer, germline multigene panel testing identified cancer predisposition gene variants in 14%. This finding may have implications for future cancer screening and risk-reduction recommendations. Universal IHC screening for Lynch syndrome successfully identifies the majority (71%) of high-penetrance germline mutations.

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