scholarly journals Diversity of genetic events associated with MLH1 promoter methylation in Lynch syndrome families with heritable constitutional epimutation

2018 ◽  
Vol 20 (12) ◽  
pp. 1589-1599 ◽  
Author(s):  
Julie Leclerc ◽  
Cathy Flament ◽  
Tonio Lovecchio ◽  
Lucie Delattre ◽  
Emilie Ait Yahya ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Promoter Methylation ◽  
Mlh1 Promoter ◽  
Genetic Events

MLH1 promoter methylation in suspected Estonian Lynch syndrome families

2010 ◽  
Author(s):  
Egle Rebane ◽  
Martin Kask ◽  
Olga Kostina ◽  
Wally Anderson
Keyword(s):  
Lynch Syndrome ◽  
Promoter Methylation ◽  
Mlh1 Promoter

scholarly journals Molecular Analysis of Colorectal Cancers Suggests a High Frequency of Lynch Syndrome in Indonesia

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6245
Author(s):  
Susanti Susanti ◽  
Satrio Wibowo ◽  
Gilang Akbariani ◽  
Naomi Yoshuantari ◽  
Didik Setyo Heriyanto ◽  
...  
Keyword(s):  
Overall Survival ◽  
Lynch Syndrome ◽  
Promoter Methylation ◽  
Young Patients ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Sporadic Groups ◽  
Mlh1 Promoter ◽  
Modified Dna ◽  
The Uk

There is about three times higher incidence of young patients <50 years old with colorectal cancer, termed EOCRC, in Indonesia as compared to Europe, the UK and USA. The aim of this study was to investigate the frequency of Lynch Syndrome (LS) in Indonesian CRC patients. The previously described Nottingham Lynch Syndrome Test (N_LyST) was used in this project. N_LyST is a robust high-resolution melting (HRM)-based test that has shown 100% concordance with standard reference methods, including capillary electrophoresis and Sanger sequencing. The test consisted of five mononucleotide microsatellite markers (BAT25, BAT26, BCAT25, MYB, EWSR1), BRAF V600E mutation and MLH1 region C promoter for methylation (using bisulphite-modified DNA). A total of 231 archival (2016–2019) formalin-fixed, paraffin-embedded (FFPE) tumour tissues from CRC patients collected from Dr. Sardjito General Hospital Yogyakarta, Indonesia, were successfully tested and analysed. Among those, 44/231 (19.05%) were MSI, 25/231 (10.82%) were harbouring BRAF V600E mutation and 6/231 (2.60%) had MLH1 promoter methylation. Almost all—186/197 (99.45%)—MSS cases were MLH1 promoter unmethylated, while there were only 5/44 (11.36%) MSI cases with MLH1 promoter methylation. Similarly, only 9/44 (20.45%) of MSI cases were BRAF mutant. There were 50/231 (21.65%) EOCRC cases, with 15/50 (30%) regarded as MSI, as opposed to 29/181 (16.02%) within the older group. In total, 32/231 patients (13.85%) were classified as “Probable Lynch” (MSI, BRAF wildtype and MLH1 promoter unmethylated), which were enriched in EOCRC as compared to older patients (24% vs. 11.05%, p = 0.035). Nonetheless, 30/50 (76.00%) cases among the EOCRC cases were non-LS (sporadic) and were significantly associated with a left-sided tumour. The overall survival of both “Probable Lynch” and non-LS (sporadic) groups (n = 227) was comparable (p = 0.59), with follow up period of 0–1845 days/61.5 months. Stage, node status, histological grading and ECOG score were significantly associated with patient overall survival (p < 0.005), yet only ECOG was an independent factor for OS (HR: 4.38; 95% CI: 1.72–11.2; p = 0.002). In summary, this study is the first to reveal a potentially higher frequency of LS among CRC patients in Indonesia, which may partially contribute to the reported much higher number of EOCRC as compared to the incidence in the West.

scholarly journals Prognostic value of MLH1 promoter methylation in male patients with esophageal squamous cell carcinoma

2017 ◽  
Vol 13 (4) ◽  
pp. 2745-2750 ◽  
Author(s):  
Dongping Wu ◽  
Xiaoying Chen ◽  
Yan Xu ◽  
Haiyong Wang ◽  
Guangmao Yu ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Promoter Methylation ◽  
Prognostic Value ◽  
Mlh1 Promoter ◽  
Male Patients

scholarly journals Reporting Subclonal Immunohistochemical Staining of Mismatch Repair Proteins in Endometrial Carcinoma in the Times of Ever-Changing Guidelines

2021 ◽  
Author(s):  
Ashley Scheiderer ◽  
Courtney Riedinger ◽  
Kristopher Kimball ◽  
Larry Kilgore ◽  
Amila Orucevic
Keyword(s):  
Genetic Testing ◽  
Endometrial Carcinoma ◽  
Mismatch Repair ◽  
Promoter Methylation ◽  
Methylation Status ◽  
Nuclear Staining ◽  
Mlh1 Promoter ◽  
History Of ◽  
The Times

Context.— The current College of American Pathologists reporting guideline for mismatch repair protein (MMRP) immunohistochemistry for Lynch syndrome (LS) screening considers the presence of any positive nuclear staining as intact MMRP expression. This would include tumors with combined areas of subclonal retention and loss of MMRP staining. Objective.— To evaluate the clinical significance of reporting subclonal staining patterns of MMRP immunohistochemistry in endometrial carcinoma. Design.— We retrospectively reviewed 455 consecutive MMRP immunohistochemistry results of endometrial carcinoma in hysterectomy specimens from 2012 through 2017 and identified cases with subclonal MMRP staining. These results were correlated with the patient's personal and family history of LS-associated carcinoma, MLH1 promoter methylation status, and LS genetic testing. Results.— Subclonal staining of MMRP was seen in 48 of 455 cases (10.5%) on review. Thirty cases demonstrated isolated subclonal staining and were reported by pathologists as follows: subclonal (n = 5), complete MMRP loss (n = 4), and intact MMRP (n = 21). Eighteen cases had subclonal staining in combination with complete loss of other MMRP. Cases reported as subclonal or complete MMRP loss had appropriate clinical follow-up. Two of 2 cases with isolated subclonal MSH6 loss tested positive for LS. One of 3 cases with isolated subclonal MLH1/PMS2 loss was negative for MLH1 promoter methylation; LS genetic testing was not performed because of cost. Conclusions.— Our study reveals that LS germline mutation can be detected in endometrial carcinoma patients whose tumors display sole subclonal MMRP staining. Our results stress the importance of reporting subclonal staining patterns to ensure appropriate clinical follow-up.

MLH1 Promoter Methylation, Diet, and Lifestyle Factors in Mismatch Repair Deficient Colorectal Cancer Patients From EPIC-Norfolk

2011 ◽  
Vol 63 (7) ◽  
pp. 1000-1010 ◽  
Author(s):  
Laura J. Gay ◽  
Mark J. Arends ◽  
Panagiota N. Mitrou ◽  
Richard Bowman ◽  
Ashraf E. Ibrahim ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Patients ◽  
Mismatch Repair ◽  
Promoter Methylation ◽  
Lifestyle Factors ◽  
Mlh1 Promoter ◽  
Colorectal Cancer Patients ◽  
Diet And Lifestyle

Improving detection of Lynch syndrome using a reflex immunohistochemistry algorithm for all patients with newly diagnosed colorectal cancer.

2012 ◽  
Vol 30 (34_suppl) ◽  
pp. 98-98
Author(s):  
Minggui Pan ◽  
Elizabeth Hoodfar ◽  
JoAnn Bergoffen ◽  
Regan Fulton ◽  
Laura Hofmeister ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Germline Mutation ◽  
Detection Rate ◽  
Promoter Hypermethylation ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Newly Diagnosed ◽  
Mlh1 Promoter ◽  
Mmr Proteins

98 Background: Identifying patients with Lynch syndrome has profound impact on the clinical care of patients and their families. Previous guidelines based on family history alone have shown low sensitivity. In our medical center, the detection rate of Lynch syndrome was <1% among colorectal cancer cases. Methods: We have developed a system-based algorithm using centralized testing by immunohistochemistry (IHC) for four mismatched repair (MMR) proteins (MLH1, MSH2, MSH6, and PMS2) as a screening method for all newly diagnosed colorectal cancer patients, followed by step wise testing of BRAF mutation, MLH1 promoter hypermethylation, +/- microsatellite instability, and germline mutation. Results: From April 1, 2011, to July 11, 2012, we have screened 116 patients. IHC detected absent expression of at least one of the MMR proteins in 18 cases. Three cases showed missing expression of MSH2/MSH6 and the presence of a germline mutation in MSH6 was confirmed in two cases. The newest case is still being investigated for germline mutation. Of the remaining 15 cases, 10 showed the presence of BRAF V600E mutation, two showed hypermethylation of the MLH1 promoter, and one showed germline MLH1 mutation. Two cases showed no BRAF V600E mutation, no MLH1 promoter hypermethylation or germline gene mutation. Overall, of 116 cases, three cases have confirmed Lynch syndrome with the detection of a germline mutation, two cases most likely have Lynch syndrome but without any detectable germline mutation of MLH1 or PMS2 using the current detecting methods. Conclusions: Our system-based screening algorithm using reflex immunohistochemistry of four MMR proteins has resulted in excellent detection rate of approximately 4% to 5% (5 out of 116 cases), consistent with the expected Lynch syndrome prevalence rate in the population. This represents a marked improvement over our previous family history-based approach in Lynch syndrome screening.

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