Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer
Abstract
Epimutations in the germline, such as methylation of the MLH1 gene, may contribute to hereditary cancer syndrome in human, but their transmission to offspring has never been documented. Here we report a family with inheritance, in three successive generations, of germline allele-specific and mosaic hypermethylation of the MSH2 gene, without evidence of DNA mismatch repair gene mutation. Three siblings carrying the germline methylation developed early-onset colorectal or endometrial cancers, all with microsatellite instability and MSH2 protein loss. Clonal bisulfite sequencing and pyrosequencing showed different methylation levels in different somatic tissues, with the highest level recorded in rectal mucosa and colon cancer tissue, and the lowest in blood leukocytes. This mosaic state of germline methylation with different tissue distribution could act as the first hit and provide a mechanism for genetic disease inheritance that may deviate from the mendelian pattern and be overlooked in conventional leukocyte-based genetic diagnosis strategy.
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As a consequence, transcription from this gene extended into the gene under investigation, causing abnormal promoter methylation and gene silencing.
“As a consequence, transcription from this gene extended into the gene under investigation, causing abnormal promoter methylation and gene silencing.”
From A critical view on transgenerational epigenetic inheritance in humans (2018) · cites this paper as [15]
Most cases of segregation of abnormal DNA methylation patterns in families with rare diseases turned out to be caused by an underlying genetic variant.
“Most cases of segregation of abnormal DNA methylation patterns in families with rare diseases, however, turned out to be caused by an underlying genetic variant14–16 (see below).”
From A critical view on transgenerational epigenetic inheritance in humans (2018) · cites this paper as [15]
In these cases, the abnormal DNA methylation of the gene under investigation was linked to a mutation in a neighboring gene that removed the transcription termination signal.
“In these cases, the abnormal DNA methylation of the gene under investigation was linked to a mutation in a neighboring gene that removed the transcription termination signal (Fig. 1b).”
From A critical view on transgenerational epigenetic inheritance in humans (2018) · cites this paper as [15]
Several studies including Guéant et al. have reported the co-segregation of an abnormal DNA methylation pattern (epimutation) with a rare disease in two or more generations of certain families.
“Several studies14–16 including a recent study by Guéant et al.18 in this journal, have reported the co-segregation of an abnormal DNA methylation pattern (called “epimutation”) with a rare disease in two or more generations of certain families.”
From A critical view on transgenerational epigenetic inheritance in humans (2018) · cites this paper as [15]
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- Authors
- Chan, T. L., Yuen, S. T., Kong, C. K., Chan, Y. W., Chan, A. S., Ng, W. F., Tsui, W. Y., Lo, M. W., Tam, W. Y., Li, V. S., & Leung, S. Y.
- Affiliations
- Queen Mary Hospital (CN)
- Yan Chai Hospital (HK)
- Corresponding author
- Yuen, Siu Tsan
- Leung, Suet Yi
- Venue
- Nature Genetics
- Published
- 2006-09-03
- Volume
- 38
- Issue
- 10
- Pages
- 1178-1183
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2013521944
- Cited by
- 324
- References
- 21
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 6 · 2023: 3 · 2022: 3 · 2021: 6 · 2020: 14 · 2019: 13 · 2018: 8 · 2017: 8 · 2016: 12 · 2015: 12 · 2014: 24 · 2013: 23 · 2012: 26
- FWCI
- 22.54
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Keywords
- MSH2, epimutations, Lynch syndrome, microsatellite instability, endometrial cancer, DNA mismatch repair, germline mosaicism, tissue-specific methylation, non-Mendelian inheritance, MLH1 promoter methylation
- MeSH terms
- Adult, Colorectal Neoplasms, Hereditary Nonpolyposis, Female, Humans, Male, Pedigree, Germ-Line Mutation, DNA Methylation, MutS Homolog 2 Protein
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