scholarly journals Distinct Mutational Profile of Lynch Syndrome Colorectal Cancers Diagnosed under Regular Colonoscopy Surveillance

2021 ◽  
Vol 10 (11) ◽  
pp. 2458
Author(s):  
Aysel Ahadova ◽  
Pauline Luise Pfuderer ◽  
Maarit Ahtiainen ◽  
Alexej Ballhausen ◽  
Lena Bohaumilitzky ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Tp53 Mutation ◽  
Molecular Level ◽  
Colorectal Cancers ◽  
Mutational Signatures ◽  
Short Intervals ◽  
Colonoscopy Surveillance ◽  
Mmr Deficiency ◽  
Kras Codon ◽  
Biological Differences

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). We analyzed clinical, histological, immunological and mutational characteristics, including panel sequencing and high-throughput coding microsatellite (cMS) analysis, in 28 incident and 67 prevalent LS CRCs (n total = 95). 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). In conclusion, our study identifies a set of features indicative of biological differences between incident and prevalent cancers in LS, which should further be monitored in prospective LS screening studies to guide towards optimized prevention protocols.

scholarly journals Distinct mutational profile of Lynch syndrome colorectal cancers diagnosed under regular colonoscopy surveillance

2020 ◽  
Author(s):  
Aysel Ahadova ◽  
Pauline L. Pfuderer ◽  
Maarit Ahtiainen ◽  
Alexej Ballhausen ◽  
Lena Bohaumilitzky ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Tp53 Mutation ◽  
Molecular Level ◽  
Molecular Subtypes ◽  
Colorectal Cancers ◽  
Mutational Signatures ◽  
Short Intervals ◽  
Colonoscopy Surveillance ◽  
Mmr Deficiency ◽  
Kras Codon

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.

Lynch Syndrome and Related Familial Colorectal Cancers

2008 ◽  
Vol 14 (1) ◽  
pp. 1-22 ◽  
Author(s):  
Wael M. Abdel-Rahman ◽  
Paivi Peltomaki
Keyword(s):  
Lynch Syndrome ◽  
Colorectal Cancers

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

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.

scholarly journals RNF43 is mutated less frequently in Lynch Syndrome compared with sporadic microsatellite unstable colorectal cancers

2017 ◽  
Vol 17 (1) ◽  
pp. 63-69 ◽  
Author(s):  
Lochlan J. Fennell ◽  
Mark Clendenning ◽  
Diane M. McKeone ◽  
Saara H. Jamieson ◽  
Samanthy Balachandran ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Colorectal Cancers

Characterisation of heterozygous PMS2 variants in French patients with Lynch syndrome

2020 ◽  
Vol 57 (7) ◽  
pp. 487-499
Author(s):  
Qing Wang ◽  
Julie Leclerc ◽  
Gaëlle Bougeard ◽  
Sylviane Olschwang ◽  
Stéphanie Vasseur ◽  
...  
Keyword(s):  
Family History ◽  
Lynch Syndrome ◽  
Founder Effect ◽  
Predictive Value ◽  
Haplotype Analysis ◽  
Genomic Rearrangements ◽  
Colorectal Cancers ◽  
Amsterdam Criteria ◽  
Insight Into

BackgroundHeterozygous germline PMS2 variants are responsible for about 5% of Lynch syndrome (LS) but their prevalence is most likely underestimated because of complicated routine screening caused by highly homologous pseudogenes. Consequently, there is limited knowledge on the implication of the PMS2 gene in LS.MethodsWe report 200 PMS2 heterozygous variants identified in 195 French patients, including 112 unique variants classified as class-3/4/5.ResultsGenomic rearrangements account for 18% of alterations. The c.137G>T variant was observed in 18% of the patients, but a founder effect could not be clearly identified by haplotype analysis. Among class-4/5 variant carriers, the median age at first tumour onset was 49 years with a predominance of colorectal (80%) and endometrial (8.1%) cancers. Seven patients developed colorectal cancers before the age of 30 with the youngest at the age of 21. Only 6.2% of class-4/5 carriers had a family history fulfilling Amsterdam I/II criteria among patients with available data. Tumours from PMS2 variant carriers exhibited microsatellite instability (96%) and loss of PMS2 expression (76%), confirming the high predictive value of somatic analysis.ConclusionOur results provide further insight into the role of the PMS2 gene in LS. While PMS2 variants are mostly detected in families not fulfilling Amsterdam criteria, which supports their lower penetrance, they can nevertheless cause early-onset cancers, highlighting the variability of their penetrance.

To detect Lynch syndrome patients, which colorectal cancers should be tested for microsatellite instability?

2010 ◽  
Vol 28 (15_suppl) ◽  
pp. 3630-3630
Author(s):  
B. M. Boman ◽  
K. Orio ◽  
N. J. Petrelli ◽  
M. Parker ◽  
C. Somerman ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Microsatellite Instability ◽  
Colorectal Cancers

Implementing population-based screening for Lynch syndrome.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 6600-6600 ◽  
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.

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.

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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