MutL Homolog 1 Measurement

lynch syndrome (LS) is an autosomal dominant genetic disorder with incomplete penetration caused by a germline mutation in one of the genes of the deoxyribonucleic acid (DNA) mismatch repair system (MMR) namely: mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MHS6), post-meiotic segregation increased 1 homolog 2 (PMS2) or the EpCAM (Epithelial CellAdhesionMolecule) gene, which causes the inactivation of MSH2. Patients with this syndrome have a high relative risk of developing cancers at a young age, led by colorectal cancer (CRC) and endometrial cancer in females. The diagnosis is suspected when the patient’s personal and family history meets the Amsterdam or Bethesda criteria. It is guided by immunohistochemistry (IHC) and/or molecular biology that show loss of expression of one or more proteins of the MMR system and microsatellite instability on tumor DNA. In case of positive IHC and/or molecular biology, the patient should be referred to an oncogenetic consultation for a definitive diagnosis. We present the case of a 49-year-old patient who presented an anaemic syndrome in metrorrhagia. After a clinical, imaging, biological and anatomopathological examination, the diagnosis of LS was made.

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Overexpression of MutL homolog 1 and MutS homolog 2 proteins have reversed prognostic implications for stage I–II colon cancer patients

Biomedical Journal ◽

10.1016/j.bj.2017.01.004 ◽

2017 ◽

Vol 40 (1) ◽

pp. 39-48 ◽

Cited By ~ 7

Author(s):

Shih-Chiang Huang ◽

Shiu-Feng Huang ◽

Ya-Ting Chen ◽

Yu Chang ◽

Yu-Ting Chiu ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Patients ◽

Stage I ◽

Mutl Homolog 1 ◽

Prognostic Implications

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In vitro study of human mutL homolog 1 hypermethylation in inducing drug resistance of esophageal carcinoma

Irish Journal of Medical Science (1971 -) ◽

10.1007/s11845-016-1401-2 ◽

2016 ◽

Vol 186 (2) ◽

pp. 257-263 ◽

Cited By ~ 2

Author(s):

Y. Cao ◽

Y. Chen ◽

Y. Huang ◽

Z. Liu ◽

G. Li

Keyword(s):

Drug Resistance ◽

Esophageal Carcinoma ◽

In Vitro Study ◽

Vitro Study ◽

Mutl Homolog 1

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

Cancers ◽

10.3390/cancers12071853 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1853

Author(s):

Alisa Olkinuora ◽

Annette Gylling ◽

Henrikki Almusa ◽

Samuli Eldfors ◽

Anna Lepistö ◽

...

Keyword(s):

Mismatch Repair ◽

Germline Mutation ◽

Mutation Screening ◽

Gene Mutations ◽

Epigenetic Mechanism ◽

Large Rearrangement ◽

Dna Mismatch ◽

Mmr Genes ◽

Tumor Studies ◽

Mutl Homolog 1

Some 10–50% of Lynch-suspected cases with abnormal immunohistochemical (IHC) staining remain without any identifiable germline mutation of DNA mismatch repair (MMR) genes. MMR proteins form heterodimeric complexes, giving rise to distinct IHC patterns when mutant. Potential reasons for not finding a germline mutation include involvement of an MMR gene not predicted by the IHC pattern, epigenetic mechanism of predisposition, primary mutation in another DNA repair or replication-associated gene, and double somatic MMR gene mutations. We addressed these possibilities by germline and tumor studies in 60 Lynch-suspected cases ascertained through diagnostics (n = 55) or research (n = 5). All cases had abnormal MMR protein staining in tumors but no point mutation or large rearrangement of the suspected MMR genes in the germline. In diagnostic practice, MSH2/MSH6 (MutS Homolog 2/MutS Homolog 6) deficiency prompts MSH2 mutation screening; in our study, 3/11 index individuals (27%) with this IHC pattern revealed pathogenic germline mutations in MSH6. Individuals with isolated absence of MSH6 are routinely screened for MSH6 mutations alone; we found a predisposing mutation in MSH2 in 1/7 such cases (14%). Somatic deletion of the MSH2-MSH6 region, joint loss of MSH6 and MSH3 (MutS Homolog 3) proteins, and hindered MSH2/MSH6 dimerization offered explanations to misleading IHC patterns. Constitutional epimutation hypothesis was pursued in the MSH2 and/or MSH6-deficient cases plus 38 cases with MLH1 (MutL Homolog 1)-deficient tumors; a primary MLH1 epimutation was identified in one case with an MLH1-deficient tumor. We conclude that both MSH2 and MSH6 should be screened in MSH2/6- and MSH6-deficient cases. In MLH1-deficient cases, constitutional epimutations of MLH1 warrant consideration.

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