Biomarker: MLH1

Histology type: endometrial carcinoma

Country: Japan

Region: Tokorozawa

Study type: retrospective study

Followed up time :

Subgroup 1 name : retained

Subgroup 1 number: 138

Subgroup 2 name: loss

Subgroup 2 number: 53

Conclusion: MMR-related proteins expression was identified as an independent prognostic factor for OS, suggesting that MMR was a key biomarker for further investigations of endometrial cancers.

Sample type : tissue

Sample method: immunohistochemistry

Expression pattern : loss

Expression elevation: For all of the four markers detection, a nuclear immunoreaction was taken into account for evaluation. The lesions were considered as positive for each marker if tumor cells in the interest area showed immunoreactive intensity stronger than or equal to positive controls. The lesions were considered as negative for each marker if tumor cells showed complete loss of immunoreaction. Cases that at least one of four proteins was judged as negative were assigned to MMR-deficient cases and the remainder cases were assigned to MMR-retained cases.

Funtion Uniprot: Heterodimerizes with PMS2 to form MutL alpha, a component of the post-replicative DNA mismatch repair system (MMR). DNA repair is initiated by MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH3) binding to a dsDNA mismatch, then MutL alpha is recruited to the heteroduplex. Assembly of the MutL-MutS-heteroduplex ternary complex in presence of RFC and PCNA is sufficient to activate endonuclease activity of PMS2. It introduces single-strand breaks near the mismatch and thus generates new entry points for the exonuclease EXO1 to degrade the strand containing the mismatch. DNA methylation would prevent cleavage and therefore assure that only the newly mutated DNA strand is going to be corrected. MutL alpha (MLH1-PMS2) interacts physically with the clamp loader subunits of DNA polymerase III, suggesting that it may play a role to recruit the DNA polymerase III to the site of the MMR. Also implicated in DNA damage signaling, a process which induces cell cycle arrest and can lead to apoptosis in case of major DNA damages. Heterodimerizes with MLH3 to form MutL gamma which plays a role in meiosis.

UniProt ID: P40692

UniProt Link: https://www.uniprot.org/uniprotkb/P40692/entry

Molecular function from UniProt:

Tissue specificity from UniProt: Colon, lymphocytes, breast, lung, spleen, testis, prostate, thyroid, gall bladder and heart.

Subcellular UniProt: #Chromosome #Nucleus

Alternative name from UniProt:

Recommended name: DNA mismatch repair protein Mlh1

Gene name from HGNC: MLH1 (COCA2, FCC2, HNPCC, HNPCC2)

HPA class: Cancer-related genes Disease related genes Human disease related genes Plasma proteins

AlphaFold DB: P40692

AlphaFold Link: https://alphafold.ebi.ac.uk/entry/P40692

HPA link: https://www.proteinatlas.org/ENSG00000076242-MLH1

Tissue specificity RNA from HPA: Low tissue specificity

Tissue expression from HPA: General nuclear expression.

Single cell type specificity Low cell type specificity

Immune cell specificity: Low immune cell specificity

Subcellular summary HPA Located in Nucleoplasm

Cancer prognostic summary HPA Prognostic marker in liver cancer (unfavorable)

Pathology link: https://www.proteinatlas.org/ENSG00000076242-MLH1/pathology

Pathology endo: https://www.proteinatlas.org/ENSG00000076242-MLH1/pathology/endometrial+cancer

Survival figure legend: Kaplan-Meier survival curves of all cases according to mismatch repair (MMR) status. (

Survival curve link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302284/figure/F1/

Phenotype ID: 609310$158320 $ 276300$ 608089$ 619096$114500

Disease: Hereditary non-polyposis colorectal cancer 2 (HNPCC2) $ Mismatch repair cancer syndrome 1 (MMRCS1)$ Muir-Torre syndrome (MRTES) $Endometrial cancer (ENDMC) $Mismatch repair cancer syndrome 2 (MMRCS2) $Colorectal cancer (CRC) $

Note1: The disease is caused by variants affecting the gene represented in this entry $ The disease is caused by variants affecting the gene represented in this entry $The disease is caused by variants affecting the gene represented in this entry $Disease susceptibility is associated with variants affecting the gene represented in this entry $The disease is caused by variants affecting the gene represented in this entry $Disease susceptibility may be associated with variants affecting the gene represented in this entry

OMIM: 120436

OMIM link1: https://www.omim.org/entry/609310 $ https://www.omim.org/entry/276300 $ https://www.omim.org/entry/158320 $ $https://www.omim.org/entry/608089 $ $ https://www.omim.org/entry/114500

OMIM link2: https://www.omim.org/entry/120436

HGNC ID: HGNC:7127

HGNC link: https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:7127