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Carcinogenic Risk FactorsJMAJ 44(6): 245249, 2001

Hiroshi SAEKI* and Keizo SUGIMACHI**

*Assistant Professor and **Professor, Department of Surgery and Science,Graduate School of Medical Sciences, Kyushu University

Abstract: Carcinogenic risk factors can be roughly divided into environmentalfactors and genetic factors. Environmental carcinogenic factors include the follow-ing: ionized radiation, etc. as physical factors; benzo [] pyrene contained in tobaccosmoke, ethyl alcohol, etc. as chemical factors; and various viruses, etc. as biologicalfactors. Meanwhile, abnormalities in DNA repair genes and cell cycle genes havebeen identified as genetic factors. Now that the mechanisms of carcinogenesis havebeen understood from a genetic standpoint, relationships between risk factors andcarcinogenesis have also become comprehensible from the viewpoint of gene abnor-malities. In the future, if susceptibility to cancer becomes predictable based onindividual genetic information, living environment, etc., then individualized cancerprevention will be realized from a new point of view.

Key words: Environmental factors; Genetic factors; Cancer prevention

Introduction

Cancer is a disease caused by gene abnor-malities in any of the cells. However, clear indi-vidual difference exists in the susceptibility tocancer, which is related to carcinogenic riskfactors. Cancer prevention should become pos-sible if risk factors can be avoided.

Rapid advances in recent cancer studies hasmade it possible to theorize on carcinogenicrisk factors. Such risk factors can be roughlydivided into environmental factors and geneticfactors. It has long been known that the inci-dence of cancer differs according to the region,occupation, eating habits, and lifestyles. Suchdifferences occur due to variations in carcino-gens in the environment which induce muta-tions in some genes. Genetic factors, which

This article is a revised English version of a paper originally published inthe Journal of the Japan Medical Association (Vol. 125, No. 3, 2001, pages 297300).

have been identified through studies on famil-ial neoplastic diseases, are considered to be thestate of susceptibility to cancer induced by thetransmission of mutations in cancer-relatedgenes.

In the present report, we review the carcino-genic risk factors that have been studied fromvarious viewpoints.

Environmental Factors

In the epidemiological studies conducted todate, various environmental factors have beenshown to be carcinogenic risk factors. Amongthese, representative factors are listed in Table1. These factors include those whose carcino-genic effects can be avoided by altering life-styles such as a smoking habit, and can be said

Feature: Prevention and Early Detection for Cancer

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to be directly linked with cancer prevention. Inaddition, many gene abnormalities induced bysuch environmental factors have been discov-ered, and molecular targets of environmentalfactors are increasingly being clarified.

1. Physical factors1) Ionized radiation

It is well known that ionized radiation maycause gene mutation or chromosome aberra-tion. The results of an epidemiological surveyof carcinogenesis in atomic bomb victims showincreased incidence of leukemia, lung cancer,etc. in the population. With respect to the tim-ing of carcinogenesis, while the incidence ofleukemia was high between 520 years afterthe exposure to atomic-bomb radiation, that oflung cancer is still high even now, more than 50years since the exposure. Applying the currenttheory that carcinogenesis is the result of themulti-stage carcinogenic process acceleratedby the accumulation of mutations in cancer-related genes, to the above findings, it can beassumed that exposure to ionized radiationmay trigger off any of the steps involved inmultistage carcinogenesis.2) Ultraviolet light

Ultraviolet light is an environmental factorthat is closely associated with skin cancer. Al-

though the incidence of skin cancer is extremelylow in Japan, it is frequently the most or secondmost prevalent cancer in Europe and America.Ultraviolet irradiation may modify DNA basepairs, resulting in the formation of pyrimidinedimers. Moreover, ultraviolet light contributesto the production of a reactive oxygen species,which directs cells toward carcinogenesis.

2. Chemical factors1) Benzo [] pyrene

Smoking is most clearly associated with theincreased risk of cancer. Smoking-associatedcancers include lung cancer, head and neckcancer such as laryngeal and pharyngeal can-cers, esophageal cancer, bladder cancer, pan-creatic cancer as well as uterine cervix cancer.

Lung cancer is exhibiting a decreasing ten-dency in Europe and America. However, inJapan, lung cancer is the most common causeof cancer death in males, and its incidence isexpected to increase further in the future. Thisis attributable to a slower decrease in the smok-ing rate as compared with Europe and Amer-ica. Concerning the carcinogenic substancesin tobacco smoke, benzo [] pyrene is thoughtto have great significance. It is known thatbenzo [] pyrene may cause characteristicpoint mutation in the p53 gene, a tumor sup-

H. SAEKI and K. SUGIMACHI

Table 1 Known Environmental Carcinogenic Factors

Factor Site of carcinogenesis

1. Physical factorsIonized radiationUltraviolet

2. Chemical factorsBenzo [] pyrene: SmokingHeterocyclic amine: Overcooked meat and fishEthyl alcohol: DrinkingAflatoxin: Aspergillus flavusAsbestosCadmium

3. Biological factorsHepatitis B virus, hepatitis C virusHTLV-1 (human T-lymphotrophic virus type 1)Human papilloma virus

Myelopoietic tissue, Lung, Thyroid glandSkin

Lung, Head and neck, Esophagus, BladderMammary gland, Large intestineHead and neck, EsophagusLiverLung, PleuraProstate

LiverT cell lymphomaUterine cervix, Esophagus

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pressor gene,1) which is considered to be oneof the mechanisms of carcinogenesis due totobacco smoke.2) Ethyl alcohol

Heavy drinking is also associated with theincidence of head and neck cancer as well asgastrointestinal cancer. With regard to esoph-ageal cancer in particular, alcohol intake hasbeen shown to trigger carcinogenesis coopera-tively with tobacco smoke. The results of ourstudies have also shown that heavy drinkingand smoking frequently leads to multiple can-cers in the head and neck and in the esopha-gus.2) Furthermore, in patients with esophageal

CARCINOGENIC RISK FACTORS

cancer who consume a large amount of alcoholand tobacco, the incidence of p53 gene abnor-malities is 90% or higher,3) suggesting the pos-sibility that the p53 gene is the molecular targetfor the carcinogenesis of esophageal cancerdue to drinking and smoking.3) Heterocyclic amine

Heterocyclic amine is known to be a carcino-genic substance in overcooked meat and fish.In experiments using rats, the substance hasbeen reported to induce both colon and pros-tate cancer in male animals, and breast cancerin female animals. In epidemiological surveys,intake of overcooked meat and fish is also said

Hereditary nonpolyposis coloncancer (HNPCC)

Xeroderma pigmentosum (XP)

Familial breast cancer

Retinoblastoma

Li-Fraumeni syndrome

Familial melanomaWilms tumorvon Hippel-Lindau disease

Familial adenomatouspolyposis (FAP)Familial gastric cancerNeurofibromatosis type II

Juvenile polyposis

Hereditary papillary renal cellcarcinomaMultiple endocrine neoplasiatype II (MEN2)Neurofibromatosis type 1

Table 2 Genetic Carcinogenic Factors

Disease Related tumors Responsible gene Function

Colon cancer, Cancer of uterinebody

Skin cancer

Breast cancer

Retinoblastoma

Breast cancer, Soft tissue tumor,Brain tumorMelanomaWilms tumorAngioblastoma, Renal cancer,Retinal angioma

Colon cancer

Gastric cancerAcoustic neurinoma

Hamartoma

Papillary renal cell carcinoma

Adrenal pheochromocytomaMedullary carcinoma of thyroidNeurofibroma

I . DNA repair genes1) MLH1, MSH2

MSH6, PMS1PMS2

2) XPA, XPBXPC, XPDXPF, XPG

3) BRCA1, BRCA2II . Cell cycle genes

1) Rb1

2) p53

3) p164) WT15) VHL

III. Genes responsible fortissue organization

1) APC

2) E-cadherin3) NF2

IV. Signal transduction genes1) PTEN

SMAD42) MET

3) RET

4) NF1

DNA mismatch repair

Nucleotide excision repair

Recombination repair (?)

Transcriptional control,Cell cycle controlTranscriptional control,Cell cycle controlCell cycle controlTranscriptional controlTranscriptional control

Membrane structure andsignal transductionCell adhesionCell adhesion

PhosphataseSignal transductionReceptor tyrosine kinase

Receptor tyrosine kinase

Signal transduction

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to be associated with the occurrence of breastcancer and colon cancer.4,5)

3. Biological factorsBiological carcinogenic factors include vari-

ous viruses. For example, chronic hepatitis andhepatic cirrhosis owing to persistent infectionwith hepatitis B virus or hepatitis C virus havebeen epidemiologically proven to be related tothe occurrence of liver cancer. The hepatitis Bvirus is a DNA virus, and is known to incorpo-rate its partially deleted DNA into genomes inthe hepatocyte. On the other hand, the hepa-titis C virus is an RNA virus, whose genes donot encode reverse transcriptase. Therefore, itdoes not incorporate its DNA into the hostsgenomes, and its contribution to carcinogenesisis unclear.

Genetic FactorsCarcinogenesis is often sporadically observed,

but sometimes concentrates in certain families.The causes of such familial neoplastic diseaseswere unknown for many years, however, inrecent aggressive studies on cancer-related genes,the Rb1 gene which is responsible for retino-blastoma was identified in 1986, and subse-quently, a succession of genes responsible forhereditary neoplastic syndrome have been iden-tified. As shown in Table 2, these genes includeDNA repair genes, cell cycle genes, genes re-sponsible for tissue organization, signal trans-duction genes, etc. Abnormalities of such genesalso represent carcinogenic risk factors, andshould be isolated from the above-mentionedenvironmental factors as genetic factors.

1. DNA repair genes1) DNA mismatch repair

Hereditary nonpolyposis colon cancer(HNPCC) is a hereditary neoplastic diseasewhich occurs in individuals with abnormalitiesin DNA mismatch repair genes.6,7) Normally,adenine and thymine or cytosine and guanineare paired by hydrogen bond and form DNA

double-helices. When a base is substituted byanother inappropriate base which forms a mis-match with the other base during DNA replica-tion, the base pair will be removed from thestrand and the DNA strands will be repaired.This system is called the mismatch repairmechanism. In families affected by HNPCC,where gene mutations involved in the mis-match repair mechanism are transmitted fromgeneration to generation, family members areknown to be susceptible not only to coloncancer but also to cancer of the uterine body,pancreatic cancer, gastric cancer, etc.2) Nucleotide excision repair

Xeroderma pigmentosum (XP) is a recessivehereditary neoplastic disease, and is associatedwith the abnormalities in genes involved in therepair of DNA damage caused by ultravioletlight.8) Ultraviolet irradiation may modify DNAbase pairs and cause the formation of pyrimi-dine dimers, but in the cells without the ab-normality, such abnormality will be correctedthrough the nucleotide excision repair system.In the genes of patients with XP, abnormalitiesin some of the proteins involved in the nucle-otide excision repair system are present, andpyrimidine dimers will not be excised, resultingin a susceptibility to skin cancer.

2. Cell cycle genes1) Rb1 gene

Retinoblastoma is a malignant neoplastic dis-ease occurring in 1 in 15,000 individuals. Bilat-eral retinoblastoma is always considered to behereditary. In 1986, the Rb1 gene, which isresponsible for the disease, was cloned,9) andit thus became apparent that the RB proteinencoded by the gene plays an important role incell cycle control.2) p53 gene

In Li-Fraumeni syndrome various organs areaffected, leading to the manifestation of breastcancer, soft tissue tumor, brain tumor, etc. Theconcept that the syndrome was caused by asingle-gene abnormality was therefore ques-tioned. However, in 1990, the disease was proven

H. SAEKI and K. SUGIMACHI

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to be an autosomal dominant hereditary dis-ease associated with inherited mutation in thep53 gene.10)

ConclusionAs carcinogenic risk factors, environmental

factors including benzo [] pyrene containedin tobacco smoke and ethyl alcohol, as wellas genetic factors including abnormalities inDNA repair genes and cell cycle genes havebeen identified. In addition, the mechanism ofcarcinogenesis has been understood from agenetic standpoint, the relationship betweenrisk factors and carcinogenesis is beginningto be understood from the viewpoint of geneabnormalities. In the future, if susceptibilityto cancer becomes predictable based on indi-vidual genetic information, living environ-ments, etc., then cancer prevention from a newpoint of view, for example, individualized pro-phylaxis, as well as early diagnosis or treatmentin light of individual risk factors, will be real-ized. Further studies in various areas includingepidemiology and experimental medicine isanticipated.

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