Molecular pathology and epidemiology
Genetic and epigenetic alterations in carcinogenesis

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Abstract

Precise and deliberate observations on tumors stand true for decades, and then meet mechanistic explanations. The presence of genetic alterations in tumors is now widely accepted, and explains the irreversible nature of tumors. However, observations on tissue differentiation indicated that it shares something in common with carcinogenesis, that is, “epigenetic” changes. Now, DNA methylation in CpG sites is known to be precisely regulated in tissue differentiation, and is supposed to be playing key roles. Many tumor suppressor genes are known to be inactivated by the hypermethylation of their promoter regions. DNA methylation is connected to histone deacetylation and chromatin structure, and regulatory enzymes of DNA methylation are being cloned. Dedifferentiation, dis(dys)differentiation and convergence of cancer cells were studied phenotypically and biochemically, and are now explained from molecular aspects of disturbances in tissue-specific transcription factors. Spontaneous regression of malignant tumors enchanted researchers, and it is now noticed that genes inactivated by hypermethylation are frequently involved in tumors that relatively often undergo spontaneous regression. Carcinogenic mechanisms of some carcinogens seem to involve modifications of epigenetic switch, and some dietary factors also have the possibility to modify the switches. Based on the growing understanding of the roles of DNA methylation, several new methodologies were developed to make a genome-wide search for changes in DNA methylation. Now, a wave of new findings is in sight.

Introduction

It is both an old and contemporary subject to understand the roles of the two mechanisms for carcinogenesis, genetic alterations with changes in DNA sequences and epigenetic alterations without changes in DNA sequence 1, 2, 3.

Solid evidence has been accumulated for base-pair change, deletion, insertion, recombination and amplification of oncogenes, tumor suppressor genes and genes related to metastasis and invasion [4]. The genetic alteration mechanism has also been supported by the presence of many endogenous and exogenous chemicals, being able to cause changes in DNA sequences [5]. The irreversible nature observed in cancerous and pre-cancerous phenotypes also backed up the genetic alteration mechanism. In one page of the history of cancer research, the genetic alteration mechanism was almost exclusively accepted by the scientific community to explain carcinogenesis.

On the other hand, some cancer researchers kept in mind that embryogenesis and differentiation, which are characterized by specific patterns of gene expressions in specific tissues and organs, proceed without any alterations in DNA sequences. They knew that the irreversibility of phenotypes in differentiated organs is not due to any genetic alterations, but due to “epigenetic change.” The researchers have been enchanted by the mechanisms underlying such “epigenetic change,” which could be potentially shared by the process of carcinogenesis. In a recent page of cancer research, methylation of DNA, namely, methylation in CpG islands of the promoter or enhancer regions of genes, came up as one plausible mechanism for the “epigenetic change” [1]. The relation between methylation of DNA and carcinogenesis is now being intensively studied.

The authors of this review would like to dedicate this article to Dr. Ruggero Montesano, who is a very good friend of mine (TS), on the occasion of his retirement from his long service in the International Agency for Research on Cancer. He and I reciprocally visited Lyon and Tokyo and enjoyed discussing science over many pages of cancer research. At the very beginning of our friendship, Ruggero and I discussed the principal nature of carcinogenesis, genetic alterations and epigenetic changes. At that time, technology had not yet matured to reveal even the sequences of DNA. Progress in molecular biology soon made it easy to read DNA sequences, and provided us with new information on the methylation status of DNA, revealing answers to some of our discussions and some leaving others unanswered. This article is based on mutually shared thoughts through our conversations.

Section snippets

Involvement of aberrant methylations in cancer cells

Hirohashi et al. of the National Cancer Center, Tokyo, first found that E-cadherin was not expressed in advanced stages of hepatocellular carcinomas, which would yield a preferable condition for cell–cell detachment and the metastatic process [6]. Soon after this, it was also found that some advanced hepatocellular carcinomas lacking expression of E-cadherin did not show any sign of gene mutation but had hypermethylation of CpG islands in the promoter region of the E-cadherin gene [7].

DNA methylation in normal development and organogenesis

A few observations in biology and cancer made Ruggero and I (TS) keep “epigenetic changes” in mind. As already briefly mentioned, the first observation was the development of normal tissues and organs where any alterations in DNA sequences are absent. The absence is supported by a classical report of production of tadpoles from erythrocyte nuclei [34]and by a recent report of production of live animals from somatic cell nuclei [35]. However, cells that have once been differentiated in a tissue

Spontaneous regression of malignant tumors

The second observation that made us bear “epigenetic change” in our minds was the presence of spontaneous regression of malignant tumors. Generally, cases that show spontaneous regression of a tumor are disregarded as those that were misdiagnosed as having a tumor in the first place. However, an intensive survey of the literature revealed 504 cases that definitely had malignant tumors, diagnosed by qualified pathologists, but definitely underwent spontaneous regression [47]. Among the 504

Dedifferentiation, disdifferentiation and decarcinogenesis

Abnormal changes in cellular phenotypes in cancers, which are not necessarily related to unregulated growth, also made us think of some “epigenetic changes” in carcinogenesis. These changes can be classified into “dedifferentiation,” “dis(dys)differentiation,” and “decarcinogenesis.”

Dedifferentiation or undifferentiation is defined as a phenomenon where various phenotypes in cells with normal differentiation disappear and those in more undifferentiated cells appear in malignant cells. The most

Genetic and epigenetic changes caused by chemical carcinogens, through DNA and protein modifications

Carcinogenic mechanisms of many carcinogens are attributed to their binding to DNA, and their interactions with proteins have not been evaluated sufficiently. Mechanisms underlying carcinogenesis must be inherited after cell replications. However, this does not necessarily lead to the conclusion that carcinogens exert their effects through binding to DNA. First, what is inherited after cell replications are not only the DNA sequences, but also the epigenetic information of DNA, such as the CpG

CpG methylation as the major cause of epigenetic change

Although several definitions exist for “epigenetic change,” the authors prefer it to be defined as a modification of DNA that is heritable even after cell replication. This definition rules out simple changes in expression levels of various genes, but focuses on the primary changes responsible for carcinogenesis.

DNA methylation seems to be the most important mechanism for “epigenetic change” at present. First, CpG methylation is inherited even after DNA replication by maintenance methylation.

Genome-wide search for aberrant methylations

All the information above strongly indicates that “epigenetic change” plays important roles in carcinogenesis, along with genetic alterations. The major limitation in this field had been that the analysis of the aberrant methylation was limited to known genes.

From this viewpoint, several new technologies were developed to search for aberrant methylations in the entire genome (Table 3). The methylation-sensitive-representational difference analysis (MS-RDA) method is based on the digestion of

Epilogue

The roles of epigenetic changes in carcinogenesis were reviewed, both phenomenologically and mechanistically. It has to be confessed that the role of “epigenetic changes” in carcinogenesis is still unclear and needs much more research. New research in this field is expected to uncover hitherto unreported and unthought mechanisms of carcinogenesis. The authors expect that crucial mechanisms would be shared in embryogenesis and in carcinogenesis. Homeogene stories were not touched in this review.

References (89)

  • M. Nagao et al.

    Interaction of N-methyl-N′-nitro-N-nitrosoguanidine with ascites hepatoma cells in vitro

    Biochim. Biophys. Acta

    (1969)
  • A.E. Rogers

    Methyl donors in the diet and responses to chemical carcinogens

    Am. J. Clin. Nut.

    (1995)
  • T. Bestor et al.

    Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells. The carboxyl-terminal domain of the mammalian enzymes is related to bacterial restriction methyltransferases

    J. Mol. Biol.

    (1988)
  • R. Holliday

    Endogenous DNA methylation and epimutagenesis

    Mutat. Res.

    (1998)
  • P.A. Jones et al.

    Cancer epigenetics comes of age

    Nat. Genet.

    (1999)
  • T. Sugimura et al.

    Multiple genetic alterations in human carcinogenesis

    Environ. Health Perspect.

    (1992)
  • J.C. Barrett

    Mechanisms of multistep carcinogenesis and carcinogen risk assessment

    Environ. Health Perspect.

    (1993)
  • K. Yoshiura et al.

    Silencing of the E-cadherin invasion-suppressor gene by CpG methylation in human carcinomas

    Proc. Natl. Acad. Sci. USA

    (1995)
  • Y. Kanai et al.

    The E-cadherin gene is silenced by CpG methylation in human hepatocellular carcinomas

    Int. J. Cancer

    (1997)
  • J.R. Graff et al.

    E-cadherin expression is silenced by DNA hypermethylation in human breast and prostate carcinomas

    Cancer Res.

    (1995)
  • V. Greger et al.

    Frequency and parental origin of hypermethylated RB1 alleles in retinoblastoma

    Hum. Genet.

    (1994)
  • A. Merlo et al.

    5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers

    Nat. Med.

    (1995)
  • J.G. Herman et al.

    Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers

    Cancer Res.

    (1995)
  • M. Gonzalez-Zulueta et al.

    Methylation of the 5′ CpG island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissues correlates with gene silencing

    Cancer Res.

    (1995)
  • K.W. Lo et al.

    Hypermethylation of the p16 gene in nasopharyngeal carcinoma

    Cancer Res.

    (1996)
  • M.L. Gonzalgo et al.

    Low frequency of p16/CDKN2A methylation in sporadic melanoma: comparative approaches for methylation analysis of primary tumors

    Cancer Res.

    (1997)
  • D.F. Jarrard et al.

    Deletional, mutational, and methylation analyses of CDKN2 (p16/MTS1) in primary and metastatic prostate cancer

    Genes Chrom. Cancer

    (1997)
  • H. Hirabayashi et al.

    p16INK4, pRB, p53 and cyclin D1 expression and hypermethylation of CDKN2 gene in thymoma and thymic carcinoma

    Int. J. Cancer

    (1997)
  • B. Martinez-Delgado et al.

    Hypermethylation of a 5′ CpG island of p16 is a frequent event in non-Hodgkin's lymphoma

    Leukemia

    (1997)
  • J.G. Herman et al.

    Distinct patterns of inactivation of p15INK4B and p16INK4A characterize the major types of hematological malignancies

    Cancer Res.

    (1997)
  • M. Iravani et al.

    Methylation of the multi tumor suppressor gene-2 (MTS2, CDKN1, p15INK4B) in childhood acute lymphoblastic leukemia

    Oncogene

    (1997)
  • J.G. Herman et al.

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

    Proc. Natl. Acad. Sci. USA

    (1994)
  • J.G. Herman et al.

    Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma

    Proc. Natl. Acad. Sci. USA

    (1998)
  • C.C. Gurin et al.

    Causes and consequences of microsatellite instability in endometrial carcinoma

    Cancer Res.

    (1999)
  • W. Lou et al.

    Methylation of the CD44 metastasis suppressor gene in human prostate cancer

    Cancer Res.

    (1999)
  • J.B. Nelson et al.

    Methylation of the 5′ CpG island of the endothelin B receptor gene is common in human prostate cancer

    Cancer Res.

    (1997)
  • A. Dobrovic et al.

    Methylation of the BRCA1 gene in sporadic breast cancer

    Cancer Res.

    (1997)
  • Y.E. Whang et al.

    Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression

    Proc. Natl. Acad. Sci. USA

    (1998)
  • J.P. Issa et al.

    HIC1 hypermethylation is a late event in hematopoietic neoplasms

    Cancer Res.

    (1997)
  • H. Fujii et al.

    Methylation of the HIC-1 candidate tumor suppressor gene in human breast cancer

    Oncogene

    (1998)
  • M. Sato et al.

    The H-cadherin (CDH13) gene is inactivated in human lung cancer

    Hum. Genet.

    (1998)
  • M. Esteller et al.

    Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia

    Cancer Res.

    (1999)
  • H. Tanaka et al.

    Methylation of the 5′ CpG island of the FHIT gene is closely associated with transcriptional inactivation in esophageal squamous cell carcinomas

    Cancer Res.

    (1998)
  • M.A. DiBerardino et al.

    Feeding tadpoles cloned from Rana erythrocyte nuclei

    Proc. Natl. Acad. Sci. USA

    (1986)

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