Epimutation and disease
Generally, disease susceptibility is determined based on changes not only in DNA sequences but also in the activities of genes and chromosomal regions. Epigenetic regulation has attracted attention as a mechanism underlying changes of activities of genes and chromosomal regions. Epigenetic modification regulates gene activity and is essential for cell division and histogenesis. Genetically, phenotype diversity of identical cells is thought to be caused by differences in epigenetic profiles. Epimutations have also recently been recognized as the first step of tumorigenesis of cancers and are thought to be direct dispositions to cancers .
2. What is epimutation?
Epimutation affects one or both alleles and decreases the gene product by inhibiting transcription. Tumor cells are typical examples of the results of epimutation that occurs at a high frequency in mammals. Epimutation in cancer generally occurs in somatic cells with tumor progression. Various epimutations are present in cancers and are frequently observed in tumor suppressor genes [1-4].
Germline epimutation which occurs in germ cells is defined as those changes maintained in fertilization and embryogenesis and present in all somatic cells in the mature body. Transmission of epigenetic characteristics through generations has been reported. The cancer risk is similar in individuals carrying a germline epimutation. However, epimutation is not necessarily inherited, and inheritance patterns that do not follow Mendel’s laws have been reported [5-8]. Complete elimination of epimutation in spermatogenesis has also been shown . Only inheritance of maternal epimutation has been confirmed, suggesting that elimination of epimutation in oogenesis is less likely to occur [8-9]. Several genomic imprinting-associated somatic cell abnormalities are thought to be caused by germline epimutation . Constitutional epimutation is defined as those changes observed in all tissues in the body due to occurrence in an early step of embryogenesis before differentiation into the three germ layers. Not all cells possess this type of epimutation, leading to a mosaic pattern at the cell level, and it is unclear if this epimutation is transmitted from the previous generation. All epimutation types are a first step leading to tumorigenesis and may be direct causes of carcinogenesis .
3. Germline epimutation and disease
Epimutation is not only involved in cancer, but is also observed in genomic imprinting (Table 1). Since a gene transmitted from one parent is selectively expressed in genomic imprinting, a hereditary disease develops when the gene is defective, even though the allelic gene is normal. The characteristic phenotype of genomic imprinting is maintained by imprinting control centers (ICs). ICs are short sequences present in the gene to be imprinted. Hemiallelic methylation of ICs results in transcription of the other allele, controlling imprinting . Diverse gene aberrations in these ICs, such as micro defects, have been discovered, and these are considered to be the causes of epimutations observed in very rare neurobehavioral congenital familial diseases such as Angelman syndrome (AS), Prader-Willi syndrome (PWS), and Beckwith-Wiedemann syndrome (BWS). PWS is characterized by hypotonia in the neonatal period, increased appetite, overeating and subsequent obesity after infancy, characteristic desires, mild mental retardation, and hypoplasia of the external genitalia. In contrast, AS is characterized by severe mental retardation, epilepsy, and awkward movement. However, the causative genetic locus is located in the q11-q13 region on the long arm of chromosome 15 in both diseases. PWS and AS are caused by chromosomal 15q11q13 deletion in many cases, but there are a few cases of imprinting mutation causing abnormal genomic imprinting. In imprinting mutation, the parental chromosome is normal, but the imprinting of 15q11-q13 is changed to the opposite pattern. Familial cases of imprinting mutations are known, and minute deletions upstream of the
|germline, constitutional||Lynch syndrome|
|constitutional||Sporadic breast cancer|
BWS is a congenital disease with a high reported risk of embryonal fetal tumors, such as Wilms tumor, hepatoblastoma, and rhabdomyosarcoma. The p15.5 region on the short arm of chromosome 11 (11p15.5) has been identified as the causative locus. There are two imprinting domains in 11p15.5: the C
Epimutation also occurs due to genomic changes, such as insertion, deletion, and changes in the length of tandem repeat sequences, which are termed copy number variations (CNVs) . In α-thalassemia, another well-known epimutation-associated disease, the deleted region of the
4. Epimutation of DNA mismatch repair genes
A study on familial cancer showed that a gene group inactivated by mutation in characteristic regions produces a predisposition to cancer. Mutation of a tumor suppressor gene,
Regarding DNA repair genes, methylation of
Gazzoli et al. first demonstrated that
It remains unclear whether constitutional epimutation is transmitted from the mother or father or occurs
Allelic methylation is noted in many cases of Lynch syndrome, but there are some exceptions. Wu et al. investigated germline methylation of
Epimutation is not always inherited and inheritance patterns that do not follow Mendel’s laws have been reported [5-8]. Complete elimination of epimutation in spermatogenesis has also been shown. Only inheritance of maternal epimutation has been found in previous reports, suggesting that elimination of epimutation in oogenesis is less likely to occur [8-9]. In a cohort study of 160 Lynch syndrome patients without germline mutation of mismatch repair genes, constitutive
Epimutation is also related to chronic lymphocytic leukemia (CLL), in which apoptosis of leukemia cells is strongly inhibited. Apoptosis inhibition in CLL is caused by enhanced B-cell lymphoma 2 (BCL2) production and methylation of the
A recent study showed that a specific MMR gene is involved in regulation of cellular dynamics, such as apoptosis. Therefore, the action of specific MMR gene expression of
There have been many reports on the relationship of breast cancer with
MMR gene mutation-induced breast cancer in Lynch syndrome has also recently been described by Buerki et al.  in an investigation of 70 unrelated families with Lynch syndrome. The subjects were 632 females, of whom 51 and 40 carried
5. Epimutation and Lynch syndrome
Lynch syndrome (HNPCC) is a typical familial tumor transmitted through autosomal dominant inheritance, and is observed in about 3% of cases of colorectal cancer . MMR gene aberration is involved in carcinogenesis in Lynch syndrome. Six types of MMR genes have been cloned:
Typical cases of Lynch syndrome-related ovarian cancer develop early, and the tumor is FIGO cancer stage I and non-serous in many cases . Grindedal et al. reported that the prognosis of Lynch syndrome-related invasive ovarian cancer is better than that of invasive cancer in patients carrying a
Lynch syndrome cases with epimutation of the
Epimutation has diverse characteristics: some epimutations are inherited or eliminated in embryogenesis, while others are inherited in patterns that do not follow Mendel’s laws. Cancers associated with epimutations include Lynch syndrome (HNPCC), familial colorectal cancer, CLL, breast cancer, and ovarian cancer. Defined histological characteristics of epimutation-associated tumors have been suggested, and it is possible that the histologic type of cancers will ultimately be identifiable based on the methylation pattern detected in normal tissue, which may reduce the need for invasive tests such as tumor tissue biopsy . Furthermore, elucidation of differences in the methylation pattern between healthy subjects and cancer patients may facilitate low-invasive cancer risk evaluation in healthy individuals.
To develop these techniques, it will be important to identify the causes of methylation. The extent of variation of methylation in normal somatic cell tissues within an individual is unclear, but conservation of the methylation pattern in an individual has been shown . Different DNA methylation patterns in monozygotic twins have been observed, and the difference increased as the twins lived in different environments . Aging-dependent methylation of non-methylated CpG islands has also been shown, and it has been suggested that metabolite ingestion can influence methyl metabolism, such as metabolism of folic acid, choline, vitamin B12, and betaine, and change the methylation pattern. In particular, the influence of environmental factors in early embryogenesis may serve as a predisposition to cancers and other diseases associated with epigenetic changes . Methylation is influenced by environmental factors and aging, in addition to inheritance, as described above, and further studies on the association of these factors with epimutation are required.
Improvement of epigenetic aberration has also been attempted through induction of re-expression of tumor suppressor genes, with some success using DNA methyltransferase (DNMT) inhibitors, azacitidine and decitabine, for blood malignant tumors . However, intense epigenetic therapy using a DNMT inhibitor and a histone deacetylase (HDAC) inhibitor concomitantly did not achieve complete chromosome remodeling, and stable gene re-expression was not obtained . Moreover, reinhibition of re-expressed genes has occurred after suspension of epigenetic therapy in many studies. These findings indicate that there are many problems to be overcome in development of epigenetic therapy.
The authors gratefully acknowledge grant support from the Japan Society for the Promotion of Science (JSPS) through a Grant-in-Aid for Scientific Research (KAKENHI), a Grant-in-Aid for Scientific Research (B) (22390313), a Grant-in-Aid for Scientific Research (C) (22591866), and a Grant-in-Aid for Young Scientists (B) (21791573); the Ichiro Kanehara Foundation; Kobayashi Foundation for Cancer Research; and the Keio University Medical Science Fund through a Research Grant for Life Sciences and Medicine.
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