Medicine in focus
DNA methylation, epimutations and cancer predisposition

https://doi.org/10.1016/j.biocel.2008.09.006Get rights and content

Abstract

Hereditary cancer syndromes caused by germline mutations give rise to distinct spectra of cancers with characteristic clinico-pathological features. Many of these hereditary cancer genes are silenced by methylation in a similar spectrum of sporadic cancers. It is likely that the initiating event in some of those cases of sporadic cancer is the somatic epigenetic inactivation (epimutation) of the same hereditary cancer gene. Recently, it has been shown that epimutations of certain hereditary cancer genes can be constitutional i.e. present throughout the soma. These epimutations may be inherited or arise very early in the germline. The heritability of these epimutations is very low as in most cases they are erased by passage through the germline. In other cases, predisposition to epimutations rather than the epimutations themselves can be inherited. These cases are characterised by Mendelian inheritance and are likely to be associated with sequence variants. Other sequence variants and environmental influences may also affect methylation propensity at a global level.

Introduction

This review will assess the role of epimutations, in particular epimutations of hereditary cancer genes, in the development of cancer. It will consider the evidence that there are cases of cancer in which epimutations not only directly predispose to the cancer, but are also widespread through adjacent tissues and unrelated tissues indicating a soma-wide event.

Epigenetic silencing of tumour suppressor genes associated with promoter methylation in tandem with an overall global reduction in DNA methylation is considered to be a hallmark of cancer cells (Esteller, 2008). As promoter methylation can lead to silencing that is mitotically transmissible, the term “epimutation”, was introduced for any heritable change such as methylation that did not affect the actual sequence of the DNA (Holliday, 1987).

It is important to clarify the terms “somatic”, “constitutional” and “germline” used to describe epimutations in this review. We will endeavour to use the terms as tightly as possible within this review while acknowledging that they may be more loosely used in the literature.

By “somatic”, we refer to any epimutations that are observed in the tumour. The somatic epimutation may also be present as a precursor lesion in the apparently non-cancerous tissue from which the tumour arises. The presence of methylation in adjacent normal tissues is often referred to as a field effect and indicates that the apparently normal tissue is clonally related to the malignant cells.

By “germline”, we refer to an epimutation that is found in all cells of the body and for which there is conclusive evidence of transmission of an actual epigenetic mark from the previous generation. As germline epimutation is present in every cell in the body, the risk of developing cancer will be similar to that of an individual that carries a germline mutation. However, it is still controversial whether germline epimutations occur in humans (Chong et al., 2007, Horsthemke, 2007, Leung et al., 2007, Suter and Martin, 2007).

By “constitutional”, we refer to an epimutation that is found in all tissues of the body. There may be no, or equivocal, evidence of transmission from the previous generation. The epimutations may have occurred very early in development. In some cases, constitutional epimutations may be mosaic, i.e. they are present in all tissues but not all cells in those tissues have the epimutation.

Germline epimutations are constitutional but not all constitutional mutations are germline. Germline and constitutional epimutations have the common property that the same allele is methylated in all tissues of the individual. Somatic epimutations may arise more than once and thereby different alleles may be affected. Any one of these types of epimutations may be the first step in tumour development and thus directly predispose to cancer.

Section snippets

Hereditary cancer genes and cancer predisposition

Studies of familial cancer have identified a group of genes whose mutational inactivation results in predisposition to a characteristic spectrum of cancers. The tumour suppressor gene, RB which is mutated in retinoblastoma, was the first hereditary cancer gene to be identified (Friend et al., 1986). Subsequently, other tumour suppressor genes operating through a diverse range of mechanisms were identified by their role in other familial cancers e.g. APC mutations were identified as underlying

Methylation of hereditary cancer genes in sporadic tumours

It is reasonable to suppose that cancers with the same underlying driving genetic lesion will resemble each other whether they are sporadic or familial. Thus sporadic retinoblastoma also involves mutational inactivation of the retinoblastoma gene, RB. Similarly, many cases of sporadic colorectal cancer involve mutational inactivation of the APC gene. However, many other cases of sporadic cancers that resemble hereditary cancers but have no mutations in the corresponding hereditary cancer gene

MLH1 and MSH2 epimutations in colorectal carcinoma

Mutations in MLH1 and MSH2 are a frequent cause of hereditary non-polyposis colorectal cancer (HNPCC). The mutations also predispose to a characteristic spectrum of extra-colonic cancers including endometrial, gastric and ovarian cancer. Both genes code for components of the mismatch repair apparatus and their inactivation give rise to microsatellite instability in the tumours, (reviewed in de la Chapelle, 2004).

It has been shown that the MLH1 gene can be methylated in sporadic colorectal

DAPK1 epimutations in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is characterised by high resistance to apoptosis of the leukemic cells. Whereas this has usually been ascribed to high levels of the anti-apoptotic protein BCL2, methylation of the promoter of the pro-apoptotic gene death-associated protein kinase 1 (DAPK1) occurs in almost all cases of CLL (Raval et al., 2007).

DAPK1 has recently been identified as a familial tumour suppressor gene as it has been shown that an upstream mutation underlies the predisposition to

BRCA1 epimutations in sporadic breast cancer

It was originally considered that BRCA1 played little role in sporadic cancer as the occurrence of mutations in sporadic breast and ovarian cancer was very low (Futreal et al., 1994, Merajver et al., 1995). Subsequently, the BRCA1 promoter region was found to be methylated in both sporadic breast cancers and ovarian cancers but BRCA1 methylation was rare outside these two tumour types (Dobrovic and Simpfendorfer, 1997, Bianco et al., 2000, Esteller et al., 2000). Thus BRCA1 methylation was

The role of cis-acting sequence variants

The role of mutations or specific alleles of sequence variants such as single nucleotide polymorphisms (SNPs) in affecting the probability of methylation of CpG islands in cis has become the focus of active investigation (Kerkel et al., 2008). Cis-acting DNA mutations have been shown to cause constitutional epimutations early in development (Horsthemke, 2006, Richards, 2006). One example of epigenetic silencing caused by sequence alterations in cis is the methylation of expanded CGG repeats

Non-specific propensity to methylation

In the studies discussed above, the epimutations appeared to be restricted to single genes rather then being a result of an overall increased propensity to methylation affecting many genes. However, it may also be important to identify individuals that are prone to methylate their promoters non-specifically as they may be prone to epigenetically driven disease.

The number of de novo methylated promoter CpG islands varies markedly between cancers. The term CpG island methylator phenotype positive

Variation in methylation and epimutations

It is at present unclear how much variation in methylation patterns exist in normal somatic tissues at the inter-individual level. Broad patterns of methylation are conserved between different individuals (Behn-Krappa et al., 1991). However, there can be marked variation in overall methylation between individuals and within given individuals over time (Bjornsson et al., 2008). Importantly, it has been shown that DNA methylation patterns do differ in monozygotic twins and that those spending the

Conclusions

The study of methylation in somatic tissues enabling the initial steps of tumourigenesis is still at an early stage. Constitutional methylation at specific tumour suppressor genes clearly underlies some cases which phenocopy hereditary cancer. Depending on the prevalence of such altered methylation, this may have important implications for genetic testing and counseling. Very little is known about what underlies the alterations of methylation patterns found in cancer cells. Genetic variations

Acknowledgments

The term constitutional methylation was to our best knowledge first used by Suet Yi Leung. Ida Candiloro critically read this MS. Alexander Dobrovic was supported by grants from the National Health and Medical Research Council of Australia, the Cancer Council of Victoria, the Susan Komen Foundation and the US Department of Defense Breast Cancer Research Program under award numbers W81XWH-05-1-0500 and W81XWH-06-1-0670. Views and opinions of, and endorsements by the author(s) do not reflect

References (70)

  • H.T. Bjornsson et al.

    Intra-individual change over time in DNA methylation with familial clustering

    JAMA

    (2008)
  • Y.A. Boumber et al.

    An Sp1/Sp3 binding polymorphism confers methylation protection

    PLoS Genet

    (2008)
  • T.L. Chan et al.

    Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer

    Nat Genet

    (2006)
  • J. Chang et al.

    Clinical management of women with genomic BRCA1 and BRCA2 mutations

    Breast Cancer Res Treat

    (2001)
  • H. Chen et al.

    Evidence for heritable predisposition to epigenetic silencing of MLH1

    Int J Cancer

    (2007)
  • S. Chong et al.

    Heritable germline epimutation is not the same as transgenerational epigenetic inheritance

    Nat Genet

    (2007)
  • S.J. Clark et al.

    DNA methylation and gene silencing in cancer: which is the guilty party?

    Oncogene

    (2002)
  • A. de la Chapelle

    Genetic predisposition to colorectal cancer

    Nat Rev Cancer

    (2004)
  • A. Dobrovic et al.

    Methylation of the BRCA1 gene in sporadic breast cancer

    Cancer Res

    (1997)
  • M. Esteller

    Epigenetics in cancer

    N Engl J Med

    (2008)
  • M. Esteller et al.

    Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors

    J Natl Cancer Inst

    (2000)
  • F.A. Feltus et al.

    Predicting aberrant CpG island methylation

    Proc Natl Acad Sci U S A

    (2003)
  • W.D. Foulkes et al.

    Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer

    J Natl Cancer Inst

    (2003)
  • M.F. Fraga et al.

    Epigenetic differences arise during the lifetime of monozygotic twins

    Proc Natl Acad Sci U S A

    (2005)
  • S.H. Friend et al.

    A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma

    Nature

    (1986)
  • P.A. Futreal et al.

    BRCA1 mutations in primary breast and ovarian carcinomas

    Science

    (1994)
  • I. Gazzoli et al.

    A hereditary nonpolyposis colorectal carcinoma case associated with hypermethylation of the MLH1 gene in normal tissue and loss of heterozygosity of the unmethylated allele in the resulting microsatellite instability-high tumor

    Cancer Res

    (2002)
  • V. Greger et al.

    Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma

    Hum Genet

    (1989)
  • N.J. Hawkins et al.

    Sporadic colorectal cancers with microsatellite instability and their possible origin in hyperplastic polyps and serrated adenomas

    J Natl Cancer Inst

    (2001)
  • I. Hedenfalk et al.

    Gene-expression profiles in hereditary breast cancer

    N Engl J Med

    (2001)
  • J.G. Herman et al.

    Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma

    Proc Natl Acad Sci U S A

    (1994)
  • M.O. Hiltunen et al.

    Hypermethylation of the APC (adenomatous polyposis coli) gene promoter region in human colorectal carcinoma

    Int J Cancer

    (1997)
  • M.P. Hitchins et al.

    Erasure of MLH1 methylation in spermatozoa-implications for epigenetic inheritance

    Nat Genet

    (2007)
  • M.P. Hitchins et al.

    Inheritance of a cancer-associated MLH1 germ-line epimutation

    N Engl J Med

    (2007)
  • R. Holliday

    The inheritance of epigenetic defects

    Science

    (1987)

    • Cited by (58)

    • Screening methylation of DNA repair genes in the oral mucosa of chronic smokers

      2018, Archives of Oral Biology
      Citation Excerpt :

      This can be attributed to a methylation percentage ≥50% in MRE11A and PMS2 genes. Those studying methylation should consider that the pattern of methylation may vary in the same individual over time (Bjornsson et al., 2008; Dobrovic & Kristensen, 2009). In the present study, the age of subjects was not correlated with an increase in methylation.

    • Epigenetics and testicular germ cell tumors

      2018, Gene
      Citation Excerpt :

      LINE-1 retrotransposons are highly active in TGCTs and can cause insertional mutagenesis, transcriptional dysregulation, DNA breaks and an increased level of recombination. It is believed that such changes in the LINE-1 retrotransposons contribute to genomic instability and malignant transformation (Dobrovic and Kristensen, 2009). In a study from 2010 Mirabello and associates showed that LINE-1 methylation level can be inherited from the parents and that hypomethylation is associated with risk of testicular cancer (Mirabello et al., 2010).

    • Can MTHFR C677T and A1298C Polymorphisms Alter the Risk and Severity of Sporadic Breast Cancer in Brazilian Women?

      2017, Clinical Breast Cancer
      Citation Excerpt :

      However, published data indicate that some genes can modify the penetrance, thereby modulating the severity or risk for developing cancer.6,7 In addition, epigenetic alterations, such as histone acetylation and methylation of CpG islands, can occur through influence from environmental factors and genome-microbiome interactions, causing gene silencing and a predisposition to tumor development.8-10 The methylenetetrahydrofolate reductase (MTHFR) gene, 1p16.22 region, has 11 exons11 and encodes the 5,10-methylenetetrahydrofolate reductase enzyme.

    • A biophysical approach to cancer dynamics: Quantum chaos and energy turbulence

      2017, BioSystems
      Citation Excerpt :

      Therefore, DNA methylation and histone modification rates are dynamically fluctuant and are difficult to compute. Mapping them will provide a complete description of cancer’s evolutionary dynamics (Dobrovic and Kristensen, 2009). In terms of experimental applications, Whole Genome Bisulfite Sequencing (Methyl- C Seq/WGBS) maps the methylome, ChIP Sequencing (Chromatin Immunoprecipitation) maps the histone profile and RNA Sequencing (RNA-Seq) maps the transcriptome profile of cells.

    • Distinctions between transgenerational and non-transgenerational epimutations

      2014, Molecular and Cellular Endocrinology

    • Does dietary nitrate say NO to cardiovascular ageing? Current evidence and implications for research

      2018, Proceedings of the Nutrition Society
    View all citing articles on Scopus
    View full text
    Crown copyright © 2008 Published by Elsevier Ltd. All rights reserved.