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ⅥFeature: Prevention and Early Detection for Cancer Carcinogenic Risk Factors JMAJ 44(6): 245–249, 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 environmental factors and genetic factors. Environmental carcinogenic factors include the follow- ing: ionized radiation, etc. as physical factors; benzo [␣] pyrene contained in tobacco smoke, ethyl alcohol, etc. as chemical factors; and various viruses, etc. as biological factors. Meanwhile, abnormalities in DNA repair genes and cell cycle genes have been identified as genetic factors. Now that the mechanisms of carcinogenesis 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 cancer prevention 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 mutations 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 smoking 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 tissue, Lung, Thyroid gland Ultraviolet Skin 2. Chemical factors Benzo [␣] pyrene: Smoking Lung, Head and neck, Esophagus, Bladder Heterocyclic amine: Overcooked meat and fish Mammary gland, Large intestine Ethyl alcohol: Drinking Head and neck, Esophagus Aflatoxin: Aspergillus flavus Liver Asbestos Lung, Pleura Cadmium Prostate 3. Biological factors Hepatitis B virus, hepatitis C virus Liver HTLV-1 (human T-lymphotrophic virus type 1) T cell lymphoma Human papilloma virus Uterine cervix, Esophagus to be directly linked with cancer prevention. In though the incidence of skin cancer 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 reactive oxygen species, 1) Ionized radiation which directs cells toward carcinogenesis. It is well known that ionized radiation may cause gene mutation or chromosome 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 leukemia, lung cancer, increased risk of cancer. Smoking-associated etc. in the population. With respect to the tim- cancers 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, bladder 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- point mutation in the p53 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 Nucleotide excision repair XPC, XPD XPF, XPG Familial breast cancer Breast cancer 3) BRCA1, BRCA2 Recombination repair (?) II . Cell cycle genes Retinoblastoma Retinoblastoma 1) Rb1 Transcriptional control, Cell cycle control Li-Fraumeni syndrome Breast cancer, Soft tissue tumor, 2) p53 Transcriptional control, Brain tumor Cell cycle control Familial melanoma 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) signal transduction 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 Hamartoma 1) PTEN Phosphatase SMAD4 Signal transduction Hereditary papillary renal cell Papillary renal cell carcinoma 2) MET Receptor tyrosine kinase 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 head and neck cancer 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 animals, 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 infection mechanism. In families affected by HNPCC, with hepatitis B virus 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 liver cancer. The hepatitis B generation to generation, family members are virus is a DNA virus, and is known to incorpo-
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