Prevalence and molecular characteristics of DNA mismatch repair deficient endometrial cancer in a Japanese hospital-based population

2020 ◽  
Vol 51 (1) ◽  
pp. 60-69 ◽  
Author(s):  
Azusa Yamamoto ◽  
Tatsuro Yamaguchi ◽  
Okihide Suzuki ◽  
Tetsuya Ito ◽  
Noriyasu Chika ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Molecular Characteristics ◽  
Variant Of Uncertain Significance ◽  
Dna Mismatch ◽  
Germline Variant ◽  
Uncertain Significance ◽  
Repair Genes

Abstract Background The prevalence and molecular characteristics of defective DNA mismatch repair endometrial cancers in the Japanese population have been underexplored. Data supporting clinical management of patients with Lynch-like syndrome and germline variant of uncertain significance of mismatch repair genes are still lacking. Methods Immunohistochemistry of mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) was performed on formalin-fixed paraffin-embedded sections prepared from resected primary endometrial cancers in 395 women with a median age of 59 years. Genetic and/or epigenetic alterations of the mismatch repair genes were also investigated. Results Loss of expression of one or more mismatch repair proteins was observed in 68 patients (17.2%). A total of 17 out of 68 patients (25%, 4.3% of all cases) were identified as candidates for genetic testing for Lynch syndrome after excluding 51 patients with MLH1 hypermethylated cancer. Fourteen of these 17 patients subjected to genetic testing were found to have Lynch syndrome (n = 5), germline variant of uncertain significance (n = 2) or Lynch-like syndrome (n = 7). Compared with patients with Lynch syndrome, those with germline variant of uncertain significance and Lynch-like syndrome tended to demonstrate an older age at the time of endometrial cancer diagnosis (P = 0.07), less fulfillment of the revised Bethesda guidelines (P = 0.09) and lower prevalence of Lynch syndrome-associated tumors in their first-degree relatives (P = 0.01). Conclusions This study provides useful information for management in patients with DNA mismatch repair endometrial cancer. Specifically, cancer surveillance as recommended in patients with Lynch syndrome might not be necessary in patients with germline variant of uncertain significance and Lynch-like syndrome and their relatives.

scholarly journals SAT-155 High Prevalence Alterations on DNA Mismatch Repair Genes Related to Lynch Syndrome in Pediatric Patients with Adrenocortical Tumor Carried of the Germline Mutation on TP53

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Vânia Balderrama Brondani ◽  
Luciana Ribeiro Montenegro ◽  
Amanda Meneses Ferreira Lacombe ◽  
Mirian Yumie Nishi ◽  
Mariana Ferreira de Assis Funari ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Copy Number ◽  
Pediatric Patients ◽  
Dna Mismatch Repair ◽  
Adult Patients ◽  
Mismatch Repair Genes ◽  
Dna Mismatch ◽  
Dna Mismatch Repair Genes ◽  
Repair Genes

Abstract Background: Adrenocortical cancer (ACC) is a rare malignant neoplasia associated with a variable clinical presentation. Pediatric patients generally have a better prognosis when compared to adults. In addition, unlike in adults where ACC which is usually sporadic, 50-80% of pediatric ACC is associated with genetic disorders such as Beckwith-Wiedemann and Li-Fraumeni syndromes. Recently, was showed that 3-5% of adult patients with ACC presented germline variants in DNA mismatch repair genes such as MSH2 and MSH6, the cause of Lynch syndrome (LS). The prevalence of these alterations in pediatric ACC is unknown. We aimed to investigate the prevalence of germline alterations in DNA mismatch repair genes among pediatric and adult patients with adrenocortical tumors (benign and malignant) carriers of the germline TP53 p.R337H mutation. Methods: 35 patients selected (30 pediatric and 5 adult) with functional tumors. ACC was diagnosed in 4 pediatric and in all adult patients. NGS was performed in 35 DNA blood samples by HNPCC MASTR Plus for the identification of SNV in 4 genes (MLH1, MSH2, MSH6, and PMS2) and 3’ UTR of EPCAM. Copy number variation (CNV) analyses were done by Copy Number Targeted Resequencing Analysis (CONTRA) and MLPA. The variants were classified, according to ACMG (American College Medical Genome) by Varsome platform. The protein expression was evaluated by Immunohistochemistry (IHC): MLH1 (clone ES05), MSH2 (FE11), MSH6 (EP49), and PMS2 (EP51). All patients were evaluated for variants in TP53. Results: NGS: 2 children presented 2 pathogenic allelic variants associated with LS (2/30, 6.6%), both patients with benign outcome and follow up of 4 years: 1 deletion in MLH1 (c.1500_1502del) and 1 nonsense in the MSH6 gene (c.328C>T p.Arg110X. CNV: MLPA specific for MLH1/MSH2 showed a normal copy number. ICH: the loss of expression in MLH1/PMS2 was identified in only one case without allelic variants. Discussion: Although our cohort is small, we observed 2 allelic pathogenic variants associated with LS among pediatric with adrenocortical tumors. It is higher than the prevalence of colorectal and endometrial cancer (3.2%) in LS. A personal and family history of LS tumors should be strongly considered for genetic risk assessment in pediatric patients with ACT. If the association with TP53 alteration can influence the tumor’s behavior with early clinical presentation, as seen in hereditary nonpolyposis colorectal cancer, it needs to be investigated. The patients with both alterations must be followed with surveillance, according to the US Multi-Society task force guideline for Lynch syndrome and for Li-Fraumeni syndrome.

Yield of Lynch Syndrome Surveillance for Patients With Pathogenic Variants in DNA Mismatch Repair Genes

2020 ◽  
Vol 18 (5) ◽  
pp. 1112-1120.e1 ◽  
Author(s):  
Anne Goverde ◽  
Ellis L. Eikenboom ◽  
Ellemieke L. Viskil ◽  
Marco J. Bruno ◽  
Michael Doukas ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Mismatch Repair Genes ◽  
Dna Mismatch ◽  
Pathogenic Variants ◽  
Dna Mismatch Repair Genes ◽  
Syndrome Surveillance ◽  
Repair Genes

scholarly journals Relationship between DNA Mismatch Repair Deficiency and Endometrial Cancer

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Kenta Masuda ◽  
Kouji Banno ◽  
Megumi Yanokura ◽  
Yusuke Kobayashi ◽  
Iori Kisu ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Target Genes ◽  
Dna Mismatch Repair ◽  
Cpg Islands ◽  
Promoter Regions ◽  
Dna Mismatch ◽  
Aberrant Dna Methylation ◽  
Familial Tumor

Some cases of endometrial cancer are associated with a familial tumor and are referred to as hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome). Lynch syndrome is thought to be induced by germline mutation of the DNA mismatch repair (MMR) gene. An aberration in the MMR gene prevents accurate repair of base mismatches produced during DNA replication. This phenomenon can lead to an increased frequency of errors in target genes involved in carcinogenesis, resulting in cancerization of the cell. On the other hand, aberrant DNA methylation is thought to play a key role in sporadic endometrial carcinogenesis. Hypermethylation of unmethylated CpG islands in the promoter regions of cancer-related genes associated with DNA repair leads to the cell becoming cancerous. Thus, both genetic and epigenetic changes are intricately involved in the process through which cells become cancerous. In this review, we introduce the latest findings on the DNA mismatch repair pathway in endometrial cancer.

scholarly journals POLYMORPHISM OF DNA MISMATCH REPAIR GENES IN ENDOMETRIAL CANCER

2015 ◽  
Vol 37 (1) ◽  
pp. 44-47 ◽  
Author(s):  
T Poplawski ◽  
A Sobczuk ◽  
J Sarnik ◽  
E Pawlowska ◽  
J Blasiak
Keyword(s):  
Endometrial Cancer ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Positive Association ◽  
Peripheral Blood Lymphocytes ◽  
Dna Mismatch ◽  
Dna Mismatch Repair Genes ◽  
Repair Genes ◽  
Hmlh1 Gene ◽  
Common Malignancy

Endometrial cancer (EC) is the second most common malignancy associated with hereditary non-polyposis colorectal cancer (HNPCC) family. The development of HNPCC is associated with defects in DNA mismatch repair (MMR) pathway resulting in microsatellite instability (MSI). MSI is present in a greater number of EC than can be accounted for by inherited MMR mutations, therefore alternative mechanisms may underline defective MMR in EC, including polymorphic variation. Aim: We checked the association between EC occurrence and two polymorphisms of MMR genes: a 1032G>A (rs4987188) transition in the hMSH2 gene resulting in a Gly22Asp substitution and a –93G>A (rs1800734) transition in the promoter of the hMLH1 gene. Material and methods: These polymorphisms were genotyped in DNA from peripheral blood lymphocytes of 100 EC patients and 100 age-matched women by restriction fragment length polymorphism PCR. Results: A positive association (OR 4.18; 95% CI 2.23–7.84) was found for the G/A genotype of the –93G>A polymorphism of the hMLH1 gene and EC occurrence. On the other hand, the A allele of this polymorphism was associated with decreased EC occurrence. The Gly/Gly genotype slightly increased the effect of the –93G>A-G/A genotype (OR 4.52; CI 2.41–8.49). Our results suggest that the –93G>A polymorphism of the hMLH1 gene singly and in combination with the Gly322Asp polymorphism of the hMSH2 gene may increase the risk of EC.

scholarly journals Screening of the DNA mismatch repair genes MLH1, MSH2 and MSH6in a Greek cohort of Lynch syndrome suspected families

BMC Cancer ◽  
2010 ◽  
Vol 10 (1) ◽  
Author(s):  
Georgia Thodi ◽  
Florentia Fostira ◽  
Raphael Sandaltzopoulos ◽  
George Nasioulas ◽  
Anastasios Grivas ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Mismatch Repair Genes ◽  
Dna Mismatch ◽  
Dna Mismatch Repair Genes ◽  
Repair Genes

scholarly journals Mismatch repair genes in Lynch syndrome: a review

2009 ◽  
Vol 127 (1) ◽  
pp. 46-51 ◽  
Author(s):  
Felipe Cavalcanti Carneiro da Silva ◽  
Mev Dominguez Valentin ◽  
Fábio de Oliveira Ferreira ◽  
Dirce Maria Carraro ◽  
Benedito Mauro Rossi
Keyword(s):  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Cancer Surveillance ◽  
Mismatch Repair Gene ◽  
Mismatch Repair Genes ◽  
Repair Gene ◽  
Dna Mismatch ◽  
Postmeiotic Segregation ◽  
Repair Genes

Lynch syndrome represents 1-7% of all cases of colorectal cancer and is an autosomal-dominant inherited cancer predisposition syndrome caused by germline mutations in deoxyribonucleic acid (DNA) mismatch repair genes. Since the discovery of the major human genes with DNA mismatch repair function, mutations in five of them have been correlated with susceptibility to Lynch syndrome: mutS homolog 2 (MSH2); mutL homolog 1 (MLH1); mutS homolog 6 (MSH6); postmeiotic segregation increased 2 (PMS2); and postmeiotic segregation increased 1 (PMS1). It has been proposed that one additional mismatch repair gene, mutL homolog 3 (MLH3), also plays a role in Lynch syndrome predisposition, but the clinical significance of mutations in this gene is less clear. According to the InSiGHT database (International Society for Gastrointestinal Hereditary Tumors), approximately 500 different LS-associated mismatch repair gene mutations are known, primarily involving MLH1 (50%) and MSH2 (40%), while others account for 10%. Much progress has been made in understanding the molecular basis of Lynch Syndrome. Molecular characterization will be the most accurate way of defining Lynch syndrome and will provide predictive information of greater accuracy regarding the risks of colon and extracolonic cancer and enable optimal cancer surveillance regimens.

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