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Home , Blastoma, Carcinogenesis, Environmental factor

ⅥFeature: Prevention and Early Detection for

Carcinogenic Risk Factors

JMAJ 44(6): 245–249, 2001

Hiroshi SAEKI* and Keizo SUGIMACHI**

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

Abstract: Carcinogenic risk factors can be roughly divided into environmental factors and genetic factors. Environmental carcinogenic factors include the follow- ing: ionized radiation, etc. as physical factors; benzo [␣] pyrene contained in smoke, ethyl , etc. as chemical factors; and various , etc. as biological factors. Meanwhile, abnormalities in DNA repair genes and cycle genes have been identified as genetic factors. Now that the mechanisms of have been understood from a genetic standpoint, relationships between risk factors and carcinogenesis have also become comprehensible from the viewpoint of gene abnor- malities. In the future, if “susceptibility to cancer” becomes predictable based on individual genetic information, living environment, etc., then individualized will be realized from a new point of view. Key words: Environmental factors; Genetic factors; Cancer prevention

Introduction have been identified through studies on famil- ial neoplastic diseases, are considered to be the Cancer is a disease caused by gene abnor- state of susceptibility to cancer induced by the malities in any of the cells. However, clear indi- transmission of in cancer-related vidual difference exists in the “susceptibility to genes. cancer,” which is related to carcinogenic risk In the present report, we review the carcino- factors. Cancer prevention should become pos- genic risk factors that have been studied from sible if risk factors can be avoided. various viewpoints. Rapid advances in recent cancer studies has made it possible to theorize on carcinogenic Environmental Factors risk factors. Such risk factors can be roughly divided into environmental factors and genetic In the epidemiological studies conducted to factors. It has long been known that the inci- date, various environmental factors have been dence of cancer differs according to the region, shown to be carcinogenic risk factors. Among occupation, eating habits, and lifestyles. Such these, representative factors are listed in Table differences occur due to variations in carcino- 1. These factors include those whose carcino- gens in the environment which induce muta- genic effects can be avoided by altering life- tions in some genes. Genetic factors, which styles such as a habit, and can be said

This article is a revised English version of a paper originally published in the Journal of the Japan Medical Association (Vol. 125, No. 3, 2001, pages 297–300).

JMAJ, June 2001—Vol. 44, No. 6 245 H. SAEKI and K. SUGIMACHI

Table 1 Known Environmental Carcinogenic Factors

Factor Site of carcinogenesis 1. Physical factors Ionized radiation Myelopoietic , Lung, Thyroid gland Skin 2. Chemical factors Benzo [␣] pyrene: Smoking Lung, Head and neck, Esophagus, Bladder Heterocyclic amine: Overcooked meat and fish , Large intestine Ethyl alcohol: Drinking Head and neck, Esophagus Aflatoxin: flavus Liver Asbestos Lung, Pleura Cadmium Prostate 3. Biological factors , hepatitis C virus Liver HTLV-1 ( T-lymphotrophic virus type 1) T cell Human virus Uterine cervix, Esophagus

to be directly linked with cancer prevention. In though the incidence of is extremely addition, many gene abnormalities induced by low in Japan, it is frequently the most or second such environmental factors have been discov- most prevalent cancer in Europe and America. ered, and molecular targets of environmental Ultraviolet irradiation may modify DNA base factors are increasingly being clarified. pairs, resulting in the formation of pyrimidine dimers. Moreover, ultraviolet light contributes 1. Physical factors to the production of a , 1) Ionized radiation which directs cells toward carcinogenesis. It is well known that ionized radiation may cause gene or aberra- 2. Chemical factors tion. The results of an epidemiological survey 1) Benzo [␣] pyrene of carcinogenesis in atomic bomb victims show Smoking is most clearly associated with the increased incidence of , , increased risk of cancer. Smoking-associated etc. in the population. With respect to the tim- include lung cancer, head and neck ing of carcinogenesis, while the incidence of cancer such as laryngeal and pharyngeal can- leukemia was high between 5–20 years after cers, esophageal cancer, , pan- the exposure to atomic-bomb radiation, that of creatic cancer as well as uterine cervix cancer. lung cancer is still high even now, more than 50 Lung cancer is exhibiting a decreasing ten- years since the exposure. Applying the current dency in Europe and America. However, in theory that carcinogenesis is the result of the Japan, lung cancer is the most common cause multi-stage carcinogenic process accelerated of cancer death in males, and its incidence is by the accumulation of mutations in cancer- expected to increase further in the future. This related genes, to the above findings, it can be is attributable to a slower decrease in the smok- assumed that exposure to ionized radiation ing rate as compared with Europe and Amer- may trigger off any of the steps involved in ica. Concerning the carcinogenic substances multistage carcinogenesis. in tobacco smoke, benzo [␣] pyrene is thought 2) Ultraviolet light to have great significance. It is known that Ultraviolet light is an environmental factor benzo [␣] pyrene may cause characteristic that is closely associated with skin cancer. Al- in the gene, a tumor sup-

246 JMAJ, June 2001—Vol. 44, No. 6 CARCINOGENIC RISK FACTORS

Table 2 Genetic Carcinogenic Factors

Disease Related tumors Responsible gene Function

I . DNA repair genes Hereditary nonpolyposis colon Colon cancer, Cancer of uterine 1) MLH1, MSH2 DNA mismatch repair cancer (HNPCC) body MSH6, PMS1 PMS2 Xeroderma pigmentosum (XP) Skin cancer 2) XPA, XPB excision repair XPC, XPD XPF, XPG Familial Breast cancer 3) BRCA1, BRCA2 Recombination repair (?) II . genes Retinoblastoma 1) Rb1 Transcriptional control, Cell cycle control Li-Fraumeni syndrome Breast cancer, Soft tissue tumor, 2) p53 Transcriptional control, Cell cycle control Familial Melanoma 3) p16 Cell cycle control Wilms tumor Wilms tumor 4) WT1 Transcriptional control von Hippel-Lindau disease Angioblastoma, Renal cancer, 5) VHL Transcriptional control Retinal angioma

III. Genes responsible for tissue organization Familial adenomatous Colon cancer 1) APC Membrane structure and polyposis (FAP) Familial gastric cancer Gastric cancer 2) E-cadherin Cell adhesion Neurofibromatosis type II Acoustic neurinoma 3) NF2 Cell adhesion IV. Signal transduction genes Juvenile polyposis 1) PTEN Phosphatase SMAD4 Signal transduction Hereditary papillary renal cell Papillary renal cell 2) MET carcinoma Multiple endocrine neoplasia Adrenal pheochromocytoma 3) RET Receptor tyrosine kinase type II (MEN2) Medullary carcinoma of thyroid Neurofibromatosis type 1 Neurofibroma 4) NF1 Signal transduction

pressor gene,1) which is considered to be one cancer who consume a large amount of alcohol of the mechanisms of carcinogenesis due to and tobacco, the incidence of p53 gene abnor- tobacco smoke. malities is 90% or higher,3) suggesting the pos- 2) Ethyl alcohol sibility that the p53 gene is the molecular target Heavy drinking is also associated with the for the carcinogenesis of esophageal cancer incidence of as well as due to drinking and smoking. gastrointestinal cancer. With regard to esoph- 3) Heterocyclic amine ageal cancer in particular, alcohol intake has Heterocyclic amine is known to be a carcino- been shown to trigger carcinogenesis coopera- genic substance in overcooked meat and fish. tively with tobacco smoke. The results of our In experiments using rats, the substance has studies have also shown that heavy drinking been reported to induce both colon and pros- and smoking frequently leads to multiple can- tate cancer in male , and breast cancer cers in the head and neck and in the esopha- in female animals. In epidemiological surveys, gus.2) Furthermore, in patients with esophageal intake of overcooked meat and fish is also said

JMAJ, June 2001—Vol. 44, No. 6 247 H. SAEKI and K. SUGIMACHI

to be associated with the occurrence of breast double-helices. When a base is substituted by cancer and colon cancer.4,5) another inappropriate base which forms a mis- match with the other base during DNA replica- 3. Biological factors tion, the base pair will be removed from the Biological carcinogenic factors include vari- strand and the DNA strands will be repaired. ous viruses. For example, chronic hepatitis and This system is called the mismatch repair hepatic cirrhosis owing to persistent mechanism. In families affected by HNPCC, with or hepatitis C virus have where gene mutations involved in the mis- been epidemiologically proven to be related to match repair mechanism are transmitted from the occurrence of . The hepatitis B generation to generation, family members are virus is a DNA virus, and is known to incorpo- known to be susceptible not only to colon rate its partially deleted DNA into in cancer but also to cancer of the uterine body, the hepatocyte. On the other hand, the hepa- , gastric cancer, etc. titis C virus is an RNA virus, whose genes do 2) Nucleotide excision repair not encode reverse transcriptase. Therefore, it Xeroderma pigmentosum (XP) is a recessive does not incorporate its DNA into the hosts’ hereditary neoplastic disease, and is associated genomes, and its contribution to carcinogenesis with the abnormalities in genes involved in the is unclear. repair of DNA damage caused by ultraviolet light.8) Ultraviolet irradiation may modify DNA Genetic Factors base pairs and cause the formation of pyrimi- dine dimers, but in the cells without the ab- Carcinogenesis is often sporadically observed, normality, such abnormality will be corrected but sometimes concentrates in certain families. through the nucleotide excision repair system. The causes of such familial neoplastic diseases In the genes of patients with XP, abnormalities were unknown for many years, however, in in some of the involved in the nucle- recent aggressive studies on cancer-related genes, otide excision repair system are present, and the Rb1 gene which is responsible for retino- pyrimidine dimers will not be excised, resulting was identified in 1986, and subse- in a susceptibility to skin cancer. quently, a succession of genes responsible for hereditary neoplastic syndrome have been iden- 2. Cell cycle genes tified. As shown in Table 2, these genes include 1) Rb1 gene DNA repair genes, cell cycle genes, genes re- Retinoblastoma is a malignant neoplastic dis- sponsible for tissue organization, signal trans- ease occurring in 1 in 15,000 individuals. Bilat- duction genes, etc. Abnormalities of such genes eral retinoblastoma is always considered to be also represent carcinogenic risk factors, and hereditary. In 1986, the Rb1 gene, which is should be isolated from the above-mentioned responsible for the disease, was cloned,9) and environmental factors as genetic factors. it thus became apparent that the RB encoded by the gene plays an important role in 1. DNA repair genes cell cycle control. 1) DNA mismatch repair 2) p53 gene Hereditary nonpolyposis colon cancer In Li-Fraumeni syndrome various organs are (HNPCC) is a hereditary neoplastic disease affected, leading to the manifestation of breast which occurs in individuals with abnormalities cancer, soft tissue tumor, brain tumor, etc. The in DNA mismatch repair genes.6,7) Normally, concept that the syndrome was caused by a adenine and thymine or cytosine and guanine single-gene abnormality was therefore ques- are paired by hydrogen bond and form DNA tioned. However, in 1990, the disease was proven

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to be an autosomal dominant hereditary dis- 2) Morita, M., Kuwano, H., Ohno, S. et al.: Mul- ease associated with inherited mutation in the tiple occurrence of carcinoma in the upper p53 gene.10) aerodigestive tract associated with esophageal cancer: Reference to smoking, drinking and family history. Int J Cancer 1994; 58: 207–210. Conclusion 3) Saeki, H., Ohno, S., Araki, K. et al.: Alcohol consumption and smoking in rela- As carcinogenic risk factors, environmental tion to high frequency of p53 protein accumu- factors including benzo [␣] pyrene contained lation in oesophageal sequamous cell carci- in tobacco smoke and ethyl alcohol, as well noma in the Japanese. Br J Cancer 2000; 82: as genetic factors including abnormalities in 1892–1894. DNA repair genes and cell cycle genes have 4) Zheng, W., Gustafson, D.R., Sinha, R. et al.: been identified. In addition, the mechanism of Well-done meat intake and the risk of breast carcinogenesis has been understood from a cancer. J Natl Cancer Inst 1998; 90: 1724–1729. 5) Gerhardsson de Verdier, M., Hagman, U., genetic standpoint, the relationship between Peters, R.K. et al.: Meat, cooking methods and risk factors and carcinogenesis is beginning : A case-referent study in to be understood from the viewpoint of gene Stockholm. Int J Cancer 1991; 49: 520–525. abnormalities. In the future, if “susceptibility 6) Fishel, R., Lescoe, M.K., Rao, M.R. et al.: The to cancer” becomes predictable based on indi- human mutator gene homolog MSH2 and vidual genetic information, living environ- its association with hereditary nonpolyposis ments, etc., then cancer prevention from a new colon cancer. Cell 1993; 75: 1027–1038. point of view, for example, individualized pro- 7) Leach, F.S., Nicolaides, N.C., Papadopoulos, N. et al.: Mutations of a mutS homolog in hered- phylaxis, as well as early diagnosis or treatment itary nonpolyposis colorectal cancer. Cell 1993; in light of individual risk factors, will be real- 75: 1215–1225. ized. Further studies in various areas including 8) Lehmann, A.R.: Nucleotide excision repair and experimental medicine is and the link with . Trends Biochem anticipated. Sci 1995; 20: 402–405. 9) Lee, W.H., Bookstein, R., Hong, F. et al.: Human retinoblastoma susceptibility gene: Cloning, REFERENCES identification, and sequence. Science 1987; 235: 1394–1399. 1) Denissenko, M.F., Pao, A., Tang, M. et al.: 10) Malkin, D., Li, F.P., Strong, L.C. et al.: Germ Preferential formation of benzo [␣] pyrene line p53 mutations in a familial syndrome of adducts at lung cancer mutational hotspots in breast cancer, , and other . p53. Science 1996; 274: 430–432. Science 1990; 250: 1233–1238.

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