Molecular Basis of Mismatch Repair Protein Deficiency in Tumors from Lynch Suspected Cases with Negative Germline Test Results

Olkinuora, Alisa; Gylling, Annette; Almusa, Henrikki; Eldfors, Samuli; Lepistö, Anna; Mecklin∥, Jukka–Pekka; Nieminen, Taina T.; Peltomäki, Païvi

doi:10.3390/cancers12071853

Cited by 9 publications

(7 citation statements)

References 37 publications

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“…So, the pathogenic variants do not necessarily appear in one or two specific genes like MLH1 or MSH2 , and even the MSI status can be stable among affected people due to the absence of Knudson's second hit, and further tumor‐specified features will not happen as well, but the pathogen variant can still be passed down to the next generation. In the study of Olkinuora A et al, It was concluded that the analysis of MLH1 and MSH2 genes is not fully trusted, and therefore multi‐gene panels and protein status tests should be considered for all genes 32 . According to our data, females have a higher percentage of MLH1 and MSH2 carriers, which is in line with Muller.…”

Section: Discussionsupporting

confidence: 83%

Rare single‐nucleotide variants of MLH1 and MSH2 genes in patients with Lynch syndrome

Mirabdolhosseini,

Yaghoob Taleghani,

Rejali

et al. 2023

Cancer Reports

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BackgroundApproximately 5% of colorectal cancers (CRCs) are hereditary. Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), is the most common form of recognized hereditary CRC. Although Iran, as a developing country, has a high incidence of CRC, the spectrum of variants has yet to be thoroughly investigated.AimsThis study aimed to investigate pathogenic and non‐pathogenic variants in MLH1 and MSH2 genes in Iranian patients with suspected Lynch syndrome (sLS).Methods and resultsIn the present study, 25 peripheral blood samples were collected from patients with sLS and high microsatellite instability (MSI‐H). After DNA extraction, all samples underwent polymerase chain reaction and Sanger sequencing to identify the variants in the exons of MLH1 and MSH2 genes. The identified variants were interpreted using prediction tools, and were finally reported under ACMG guidelines. In our study population, 13 variants were found in the MLH1 gene and 8 in the MSH2 gene. Interestingly, 7 of the 13 MLH1 variants and 3 of the 8 MSH2 variants were novel, whereas the remaining variants were previously reported or available in databases. In addition, some patients with sLS did not have variants in the exons of the MLH1 and MSH2 genes. The variants detected in the MLH1 and MSH2 genes had specific characteristics regarding the number, area of occurrence, and their relationship with demographic and clinicopathologic features.ConclusionOverall, our results suggest that analysis of MLH1 and MSH2 genes alone is insufficient in the Iranian population, and more comprehensive tests are recommended for detecting LS.

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Section: Discussionsupporting

confidence: 83%

Rare single‐nucleotide variants of MLH1 and MSH2 genes in patients with Lynch syndrome

Mirabdolhosseini,

Yaghoob Taleghani,

Rejali

et al. 2023

Cancer Reports

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“…Hypotheses were pursued that somatic deletion of the MSH2-MSH6 region and hindered MSH2/MSH6 dimerization would lead to abnormal IHC patterns [ 24 , 25 ]. In this case, one explanation would be proposed that the somatic frameshift mutation, c.3261dupC (p.Phe1088LeufsTer5), within the (C)8 tract in exon 5 of the MSH6 gene attributed to the loss of the MSH2-MSH6 interaction region and reduced MSH6 protein expression, secondary to defective binding to MSH2 protein (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Rare germline mutation and MSH2-&MSH6 + expression in a double primary carcinoma of colorectal carcinoma and endometrial carcinoma: a case report

Zhang,

Huang,

Liu

et al. 2024

Diagn Pathol

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Background Multiple primary malignancies are rare in cancer patients, and risk factors may include genetics, viral infection, smoking, radiation, and other environmental factors. Lynch syndrome (LS) is the most prevalent form of hereditary predisposition to double primary colorectal and endometrial cancer in females. LS, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is a common autosomal dominant condition. Pathogenic germline variants in the DNA mismatch repair (MMR) genes, namely MLH1, MSH2, MSH6, and PMS2, and less frequently, deletions in the 3’ end of EPCAM cause LS. It manifested itself as loss of MMR nuclear tumor staining (MMR protein deficient, dMMR). Case presentation This case study describes a double primary carcinoma in a 49-year-old female. In June 2022, the patient was diagnosed with highly to moderately differentiated endometrioid adenocarcinoma. The patient’s mother died of esophageal cancer at age 50, and the father died of undefined reasons at age 70. Immunohistochemical stainings found ER (++), PR (++), P53 (+), MSH2 (-), MSH6 (+), MLH1 (+), and PMS2 (+). MMR gene sequencing was performed on endometrial tumor and peripheral blood samples from this patient. The patient carried two pathogenic somatic mutations in the endometrial tumor, MSH6 c.3261dupC (p.Phe1088LeufsTer5) and MSH2 c.445_448dup (p.Val150fs), in addition to a rare germline mutation MSH6 c.133G > C (p.Gly45Arg). Two years ago, the patient was diagnosed with moderately differentiated adenocarcinoma in the left-half colon. Immunohistochemical stainings found MSH2(-), MSH6(+), MLH1(+), and PMS2(+) (data not shown). Conclusions In the case of a patient with double primary EC and CRC, a careful evaluation of the IHC and the genetic data was presented. The patient carried rare compound heterozygous variants, a germline missense mutation, and a somatic frameshift mutation of MSH6, combined with a novel somatic null variant of MSH2. Our study broadened the variant spectrum of double primary cancer and provided insight into the molecular basis for abnormal MSH2 protein loss and double primary carcinoma.

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“…The average base coverage depth for the analyzed samples was 2332. Subsequently, a SALSA MLPA kit P003 from MRC-Holland (Amsterdam, The Netherlands) was used to screen the DNA samples for other large genomic rearrangements in MLH1 as described before [ 26 , 27 ]. A dosage quotient of approximately 0.5 was interpreted as a heterozygous deletion of MLH1 exons.…”

Section: Methodsmentioning

confidence: 99%

Testing for Lynch Syndrome in Endometrial Carcinoma: From Universal to Age-Selective MLH1 Methylation Analysis

Pasanen

Loukovaara

Kaikkonen

et al. 2022

Cancers

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International guidelines recommend universal screening of endometrial carcinoma (EC) patients for Lynch syndrome (LS). This screening is generally based on mismatch repair (MMR) protein immunohistochemistry followed by MLH1 methylation analysis of MLH1-negative cases to exclude the likely sporadic cases from germline testing. As LS-associated EC is uncommon in the elderly, age-selective methylation testing could improve cost-efficiency. We performed MMR immunohistochemistry on 821 unselected ECs (clinic-based cohort) followed by a MLH1 promoter methylation test of all MLH1/PMS2-negative tumors. Non-methylated MLH1-deficient cases underwent NGS and MLPA-based germline analyses to identify MLH1 mutation carriers. A reduction in the test burden and corresponding false negative rates for LS screening were investigated for various age cut-offs. In addition, the age distribution of 132 MLH1 mutation carriers diagnosed with EC (registry-based cohort) was examined. A germline MLH1 mutation was found in 2/14 patients with non-methylated MLH1-deficient EC. When compared to a universal methylation analysis, selective testing with a cut-off age of 65 years, would have reduced the testing effort by 70.7% with a false negative rate for LS detection of 0% and 3% in the clinic and registry-based cohorts, respectively. The use of age-selective methylation analysis is a feasible way of reducing the costs and laboratory burden in LS screening for EC patients.

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Molecular Basis of Mismatch Repair Protein Deficiency in Tumors from Lynch Suspected Cases with Negative Germline Test Results

Cited by 9 publications

References 37 publications

Rare single‐nucleotide variants of MLH1 and MSH2 genes in patients with Lynch syndrome

Rare single‐nucleotide variants of MLH1 and MSH2 genes in patients with Lynch syndrome

Rare germline mutation and MSH2-&MSH6 + expression in a double primary carcinoma of colorectal carcinoma and endometrial carcinoma: a case report

Testing for Lynch Syndrome in Endometrial Carcinoma: From Universal to Age-Selective MLH1 Methylation Analysis

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