An in-frame deletion mutation in MLH1 drives Lynch syndrome-associated colorectal cancer
Abstract Lynch syndrome (LS) is the most common inherited disorder predisposing individuals to colorectal cancer (CRC). It results from germline defects in DNA mismatch repair (MMR) genes, which are critical for maintaining genomic integrity. Here, we demonstrate that the expression of the MMR genes...
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| Language: | English |
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BMC
2025-07-01
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| Series: | BMC Cancer |
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| Online Access: | https://doi.org/10.1186/s12885-025-14554-6 |
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| author | Xiaojuan Lin Ce Bian Dongni Liang Lin Li Qingqing Tang Qingli Li |
| author_facet | Xiaojuan Lin Ce Bian Dongni Liang Lin Li Qingqing Tang Qingli Li |
| author_sort | Xiaojuan Lin |
| collection | DOAJ |
| description | Abstract Lynch syndrome (LS) is the most common inherited disorder predisposing individuals to colorectal cancer (CRC). It results from germline defects in DNA mismatch repair (MMR) genes, which are critical for maintaining genomic integrity. Here, we demonstrate that the expression of the MMR genes MLH1 and PMS2 are significantly reduced in colon tumor tissues from a proband with CRC, potentially resulting from inherited mutations in the MLH1 gene in LS cases. We identified a previously unreported in-frame deletion mutation in the MLH1 gene, classified as a variant of uncertain significance (VUS) due to its undefined role in oncogenesis. The majority of functionally inactive mutants were located in the residues Phe614 to Lys617, which form crucial hydrogen bonds. Taken together, our data reveals a correlation between this mutation and increased susceptibility to LS-associated tumors. The study offers a valuable insight for evaluating cancer susceptibility in carriers of MLH1 mutants, potentially elucidating the functional roles of MLH1 in oncogenesis. |
| format | Article |
| id | doaj-art-4ec4b22df5bb41cd94cb1618896ca7f1 |
| institution | Kabale University |
| issn | 1471-2407 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj-art-4ec4b22df5bb41cd94cb1618896ca7f12025-08-20T03:43:11ZengBMCBMC Cancer1471-24072025-07-012511810.1186/s12885-025-14554-6An in-frame deletion mutation in MLH1 drives Lynch syndrome-associated colorectal cancerXiaojuan Lin0Ce Bian1Dongni Liang2Lin Li3Qingqing Tang4Qingli Li5Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan UniversityDepartment of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan UniversityDepartment of Pathology, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan UniversityDepartment of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan UniversityWest China Clinical Medical College, Sichuan UniversityDepartment of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan UniversityAbstract Lynch syndrome (LS) is the most common inherited disorder predisposing individuals to colorectal cancer (CRC). It results from germline defects in DNA mismatch repair (MMR) genes, which are critical for maintaining genomic integrity. Here, we demonstrate that the expression of the MMR genes MLH1 and PMS2 are significantly reduced in colon tumor tissues from a proband with CRC, potentially resulting from inherited mutations in the MLH1 gene in LS cases. We identified a previously unreported in-frame deletion mutation in the MLH1 gene, classified as a variant of uncertain significance (VUS) due to its undefined role in oncogenesis. The majority of functionally inactive mutants were located in the residues Phe614 to Lys617, which form crucial hydrogen bonds. Taken together, our data reveals a correlation between this mutation and increased susceptibility to LS-associated tumors. The study offers a valuable insight for evaluating cancer susceptibility in carriers of MLH1 mutants, potentially elucidating the functional roles of MLH1 in oncogenesis.https://doi.org/10.1186/s12885-025-14554-6In-frame deletion mutationMLH1Lynch syndromeColorectal cancer |
| spellingShingle | Xiaojuan Lin Ce Bian Dongni Liang Lin Li Qingqing Tang Qingli Li An in-frame deletion mutation in MLH1 drives Lynch syndrome-associated colorectal cancer BMC Cancer In-frame deletion mutation MLH1 Lynch syndrome Colorectal cancer |
| title | An in-frame deletion mutation in MLH1 drives Lynch syndrome-associated colorectal cancer |
| title_full | An in-frame deletion mutation in MLH1 drives Lynch syndrome-associated colorectal cancer |
| title_fullStr | An in-frame deletion mutation in MLH1 drives Lynch syndrome-associated colorectal cancer |
| title_full_unstemmed | An in-frame deletion mutation in MLH1 drives Lynch syndrome-associated colorectal cancer |
| title_short | An in-frame deletion mutation in MLH1 drives Lynch syndrome-associated colorectal cancer |
| title_sort | in frame deletion mutation in mlh1 drives lynch syndrome associated colorectal cancer |
| topic | In-frame deletion mutation MLH1 Lynch syndrome Colorectal cancer |
| url | https://doi.org/10.1186/s12885-025-14554-6 |
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