AGA Institute and CAP Quality Measure Development for Detection of MMR Deficiency and Lynch Syndrome Management

Background Regular colonoscopy even with short intervals does not prevent all colorectal cancers (CRC) in Lynch syndrome (LS). In the present study, we asked whether cancers detected under regular colonoscopy surveillance (incident cancers) are phenotypically different from cancers detected at first colonoscopy (prevalent cancers). Methods We analyzed clinical, histological, immunological and mutational characteristics, including panel sequencing and high through-put coding microsatellite (cMS) analysis, in 28 incident and 67 prevalent LS CRCs. Results Incident cancers presented with lower UICC and T stage compared to prevalent cancers (p<0.0005). The majority of incident cancers (21/28) were detected after previous colonoscopy without any pathological findings. On the molecular level, incident cancers presented with a significantly lower KRAS codon 12/13 (1/23, 4.3% vs. 11/21, 52%; p=0.0005) and pathogenic TP53 mutation frequency (0/17, 0% vs. 7/21, 33.3%; p=0.0108,) compared to prevalent cancers; 10/17 (58.8%) incident cancers harbored one or more truncating APC mutations, all showing mutational signatures of mismatch repair (MMR) deficiency. The proportion of MMR deficiency-related mutational events was significantly higher in incident compared to prevalent CRC (p=0.018). Conclusions LS CRC diagnosed under regular colonoscopy surveillance are biologically distinct, suggesting that the preventive effectiveness of colonoscopy in LS depends on the molecular subtypes of tumors.

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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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CMS Quality Measure Development—Reply

JAMA ◽

10.1001/jama.2020.12073 ◽

2020 ◽

Vol 324 (12) ◽

pp. 1214

Author(s):

Rishi K. Wadhera ◽

Karen E. Joynt Maddox ◽

Robert W. Yeh

Keyword(s):

Measure Development ◽

Quality Measure

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Implementing population-based screening for Lynch syndrome.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.6600 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 6600-6600 ◽

Cited By ~ 1

Author(s):

Lars Henrik Jensen ◽

Anders Bojesen ◽

Lene Byriel ◽

Michael Hardt-Madsen ◽

Katrine Urth Hansen ◽

...

Keyword(s):

Colorectal Cancer ◽

Molecular Markers ◽

Lynch Syndrome ◽

Protein Expression ◽

Genetic Counselling ◽

Cancer Care ◽

Screening Program ◽

Population Based ◽

Mmr Deficiency ◽

Colorectal Cancer Patients

6600 Background: A myriad of molecular markers has been proposed and tested with the promise of improving cancer care. Few have been validated and even fewer have been implemented in daily clinic. The most common hereditary colorectal cancer entity, Lynch Syndrome, can be identified in a subset of colorectal cancer patients by screening molecular markers for mismatch-repair (MMR) deficiency. We wanted to implement this screening in a Danish region, optimize quality, and describe the results. Methods: All colorectal cancer (CRC) patients diagnosed from October 2010 to September 2012 in the Region of Southern Denmark were included. Immunohistochemistry (IHC) was performed for protein expression of the MLH1, PMS2, MSH2, and MSH6 genes followed by MLH1 methylation analysis in cases with loss of pMLH1. Hereafter the indications for genetic counselling were lack of any MMR-protein – and in case missing pMLH1only those with no promoter-methylation of MLH1. Patients were included irrespectively of stage, post-mortem diagnosis, surgery, or other treatment. Accepted reasons for missed data were insufficient or autolyzed tumor material, but not data missing due to death, no surgery, or any logistic problem. Every 3-6 months the national pathology database was checked for missing data and feedback was given to the clinicians to ensure enrolling of all CRC patients. Results: CRC were diagnosed in 2,120 patients in a population of 1,200,000 with informative data for 1,932 patients at the time of analysis. 1,680 had normal protein expression of all four MMR-genes. 209 lacked pMLH1 of which 11 were not methylated. Loss of pMSH2, isolated pMSH6 or pPMS2 was seen in 23, 11, and 9 cases, respectively. Thus, the established screening program was positive in 54 patients. These patients are offered further genetic counselling and testing. Conclusions: Screening for Lynch Syndrome was feasible in a geographically defined area involving several clinical departments. Molecular screening for hereditary MMR-deficiency was positive in 54 of 1932 patients (2.8 %). Implementation of molecular markers in cancer care can be optimized by support from national databases and formalized quality feed back to the clinicians. Clinical trial information: NCT01216930.

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Overlooking MMR deficiency in carriers of certain pathogenic variants by routine MSI and/or IHC testing in Lynch syndrome: Implications for a wider MMR deficiency testing.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e16107 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e16107-e16107

Author(s):

Marija Staninova Stojovska ◽

Katerina Kubelka Sabit ◽

Dzengis Jasar ◽

Rubens Jovanovic ◽

Nadica Matevska ◽

...

Keyword(s):

Lynch Syndrome ◽

Positive Result ◽

Splice Site Mutation ◽

The Other ◽

Sporadic Colorectal Cancer ◽

Site Mutation ◽

Potential Implication ◽

Mmr Genes ◽

Pathogenic Variants ◽

Mmr Deficiency

e16107 Background: DNA mismatch repair (MMR) deficiency occurs in both inherited/sporadic colorectal cancer (CRC) and endometrial cancer, but it may also be found in some other types of cancer. At present, MMR status testing in clinical practice is recommended for all CRC patients in order to identify those who should be offered genetic testing for the Lynch syndrome (LS), inform disease prognosis, and guide therapeutic management.There are two commonly accepted methods for MMR deficiency analysis, one based on the detection of microsatellite instability (MSI) by PCR and the other based on the detection of protein expression of the MMR genes using immunohistochemistry (IHC). The objective of this study was to evaluate the concordance between IHC and MSI in tumors from 18 LS patients with known pathogenic germline variants in MMR genes (MLH1, MSH2, PMS2 and MSH6). Methods: The MSI testing was performed using the five gene Bethesda panel (BAT25, BAT26, D2S123, D5S346, D17S250) while the IHC testing was done with the use of a standard 4 antibody panel (MLH1, MSH2, PMS2 and MSH6). Results: High concordance of the two methods was observed in 13/18 (72.2%) patients, mainly with disruptive mutations in the МLH1, MSH2 and PMS2 genes. Inconsistent results were obtained in 5/18 (28.8%) patients, of whom two had a positive result only with the use of the PCR method [carriers of MLH1 c.62C > T (p.Ala21Val) and c.244A > G (p.Thr82Ala) missense variants], other two had a positive result only with IHC [carriers of MSH6 c.3514dupA (p.Arg1172LysfsTer5) and c.2384T > C (p.Ile795Thr)] and one patient had normal results using both methods (carrier of MSH6 c.457+1G > T splice site mutation that results in exon 3 skipping). A positive predictive value of either MSI or IHC used as a single methods for screening was 83.3%, which indicates that a substantial number of cases with MMR tumors can be misdiagnosed by using only either one or the other of these two methods. Conclusions: These results have a potential implication not only for LS screening in CRC patients, but also for the detection of the MMR deficiency in patients with various tumors that might benefit from the checkpoint inhibitor immunotherapy. The use of extended MSI NGS panels might provide a higher sensitivity for the detection of MMR deficiency compared to the standard MSI or ICH testing.

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Germline and Tumor Whole Genome Sequencing as a Diagnostic Tool to Resolve Suspected Lynch Syndrome

10.1101/2020.03.12.20034991 ◽

2020 ◽

Author(s):

Bernard J. Pope ◽

Mark Clendenning ◽

Christophe Rosty ◽

Khalid Mahmood ◽

Peter Georgeson ◽

...

Keyword(s):

Lynch Syndrome ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Gene Mutations ◽

Gene Promoter ◽

Whole Genome ◽

Pathogenic Variants ◽

Tumor Sequencing ◽

Mmr Deficiency ◽

Complex Structural

AbstractBackgroundPeople who develop mismatch repair (MMR) deficient cancer in the absence of a germline MMR gene pathogenic variant or hypermethylation of the MLH1 gene promoter in their tumor are classified as having suspected Lynch syndrome (SLS). We applied germline whole genome sequencing (WGS) and targeted and genome-wide tumor sequencing approaches to identify the underlying cause of tumor MMR-deficiency in SLS.MethodsGermline WGS was performed on 14 cancer-affected people with SLS, including two sets of first-degree relatives. Tumor tissue was sequenced for somatic MMR gene mutations by targeted, whole exome sequencing or WGS. Germline pathogenic variants, including complex structural rearrangements and non-coding variants, were assessed for the MMR genes. Tumor mutation burden and mutational signatures.ResultsGermline WGS identified pathogenic MMR variants in 3 of the 14 (21.4%) SLS cases including a 9.5Mb inversion disrupting exons 1-7 of MSH2 in a mother and daughter. Excluding these 3 MMR carriers, tumor sequencing identified at least two somatic MMR gene mutations in 8/11 (72.7%) tumors tested, supporting a non-inherited cause of tumor MMR-deficiency. In the second mother-daughter pair, the combined analysis of germline and tumor by WGS supported a somatic rather than inherited cause of their tumor MMR-deficiency, through presence of double somatic MSH2 mutations in their respective tumors.ConclusionGermline WGS of people with SLS improved the identification of Lynch syndrome. When coupled with tumor sequencing, >70% of the people with SLS were resolved as having double somatic MMR mutations and a non-inherited cause for their tumor MMR-deficiency.

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Promoting measurement-based care and quality measure development: The APA mental and behavioral health registry initiative.

Psychological Services ◽

10.1037/ser0000347 ◽

2020 ◽

Vol 17 (3) ◽

pp. 262-270 ◽

Cited By ~ 1

Author(s):

Caroline Vaile Wright ◽

Carol Goodheart ◽

David Bard ◽

Bruce L. Bobbitt ◽

Zeeshan Butt ◽

...

Keyword(s):

Behavioral Health ◽

Measure Development ◽

Quality Measure ◽

Measurement Based Care ◽

Health Registry

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MACRA Palliative Care Quality Measure Development—Testing Summary Report: Measure Name: Feeling Heard and Understood

10.7249/rr-a400-1 ◽

2021 ◽

Keyword(s):

Palliative Care ◽

Measure Development ◽

Care Quality ◽

Quality Measure ◽

Summary Report ◽

Report Measure

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MACRA Palliative Care Quality Measure Development: Summary Report of Alpha Testing

10.7249/wra400-1 ◽

2020 ◽

Author(s):

Anthony Rodriguez ◽

Maria Edelen ◽

Adam Scherling ◽

Julia Bandini ◽

Carrie Farmer ◽

...

Keyword(s):

Palliative Care ◽

Measure Development ◽

Care Quality ◽

Quality Measure ◽

Summary Report

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DNA Mismatch Repair Protein Immunohistochemistry and MLH1 Promotor Methylation Testing for Practical Molecular Classification and the Prediction of Prognosis in Endometrial Cancer

Cancers ◽

10.3390/cancers10090279 ◽

2018 ◽

Vol 10 (9) ◽

pp. 279 ◽

Cited By ~ 7

Author(s):

Jisup Kim ◽

Jin Kong ◽

Wookyeom Yang ◽

Hanbyoul Cho ◽

Doo Chay ◽

...

Keyword(s):

Endometrial Cancer ◽

Lynch Syndrome ◽

Mismatch Repair ◽

Promoter Methylation ◽

Molecular Classification ◽

Clinicopathologic Features ◽

Immune Markers ◽

Dna Mismatch ◽

Sporadic Cancer ◽

Mmr Deficiency

The incidence of endometrial cancer is rapidly increasing worldwide, and its molecular classification has gained importance for new therapeutic approaches. This study sought to examine the clinicopathologic features and immune markers associated with the DNA mismatch repair (MMR) status and MLH1 promoter methylation status of endometrial cancer patients. A total of 173 patients with primary endometrial cancer who had received a hysterectomy were evaluated for four MMR proteins (MLH1, MSH2, MSH6, and PMS2), immune markers (CD8, programmed cell death protein 1 (PD-1), and programmed death-ligand 1 (PD-L1)) and p53 by immunohistochemistry (IHC), followed by an MLH1 methylation test. Patients were classified into MMR deficiency or proficiency, sporadic cancer, or probable Lynch syndrome (PLS), and the clinicopathologic features (including the expression of peritumoral immune markers) and prognosis of each group were compared. Patients with MMR deficiency or PLS showed an increase in immune markers compared those with MMR proficiency or sporadic cancer, respectively, and PLS demonstrated higher immune marker expression than MLH1 promoter methylation. Regarding prognosis, patients with MMR deficiency showed significant adverse overall survival (OS) when in stages I and II. Practical molecular classifications based on p53 staining results, in addition to MMR or PLS status, revealed an increased predictive ability for OS compared with the European Society of Medical Oncologists (ESMO) risk groups. The results of this study suggest that PLS may be a better candidate for an immune checkpoint inhibitor than MMR deficiency. The practical molecular classification contributes not only to the screening of Lynch syndrome, but also assists in predicting the prognosis in endometrial cancer.

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