Etiology

Japanese: 病因

It was the German pathologist Virchow who believed that cancer is made up of cancer cells, and that these cancer cells develop when normal cells undergo change. The German zoologist Boveri already proposed the "chromosomal abnormality theory of cancer" in 1914. In recent years, it has become widely known that cancer is a genetic disease, in that it develops due to the multi-stage occurrence of genetic mutations (genetic changes) and epigenetic changes (changes in which genetic changes are fixed within cells and are passed on to daughter cells even after cell division, without involving changes to the genes themselves, such as gene mutation or amplification; a typical example is the silencing of gene expression through methylation of the gene promoter region). The cause of these genetic changes is called the "etiology" of cancer.
(1) Occupational Cancer With regard to the etiology of cancer, Pott of England reported on scrotal cancer occurring in chimney sweeps nearly 100 years before Virchow. This is considered the first epidemiological description of so-called "occupational cancer." In Japan, Yamagiwa Katsusaburo succeeded in inducing skin cancer in rabbits by applying coal tar to their ears in 1915. In addition to scrotal cancer in chimney sweeps, bladder cancer in dye factory workers is another typical example of "occupational cancer."
(2) External factors The causes of cancer are generally divided into two main types: external factors (external factors) and internal factors (endogenous factors in the broad sense). External factors are factors that are present in the environment surrounding an individual (living organism), such as chemicals, radiation, ultraviolet rays, viruses, and bacteria. In contrast, endogenous factors are factors that are present on the living organism's side. Endogenous factors can be further divided into internal environmental factors (endogenous factors in the narrow sense) and genetic factors.
There are various external factors known to cause human cancer. In 1981, British epidemiologists Doll and Peto estimated the contribution of each environmental factor to cancer deaths in Americans based on numerous epidemiological scientific studies (Figure 1-4-3). According to Doll and Peto's report, it is estimated that about one-third of human cancers can be prevented by quitting smoking. The proportion of cancer deaths that can be prevented by improving diet is also about one-third, and more than 10% are cancers caused by infectious diseases such as viruses and bacteria. Inoue et al. recently reported the results of a study based on an epidemiological analysis of the contribution of environmental factors to cancer deaths in Japanese people, estimating that for Japanese men, smoking is 30%, alcohol consumption is 10%, and cancers caused by infectious diseases are 23%. On the other hand, for Japanese women, it is estimated that smoking is 5%, alcohol consumption is 2.5%, and infectious diseases are 17.5% (Inoue et al., 2012).
Smoking is a risk factor for cancer in the oral cavity, pharyngeal, laryngeal, lung, esophageal, pancreatic, renal pelvis, and bladder. In relation to infectious diseases, Helicobacter pylori (gastric cancer), hepatitis B and C viruses (liver cancer), Epstein-Barr virus (lymphoma, nasopharyngeal cancer, gastric cancer), human T-cell leukemia-lymphoma virus (adult T-cell leukemia-lymphoma), human papillomavirus (cervical cancer), human herpesvirus type 8 (Kaposi's sarcoma), and liver fluke (biliary tract cancer) are known. Identifying direct factors (initiators) of human cancer and modifying factors (promoters) that promote carcinogenesis from the environment, such as various chemicals contained in tobacco smoke and infectious diseases that are clearly directly involved in human cancer, will provide extremely important information for taking measures to prevent cancer.
Orally ingested dietary carcinogenic factors include salt and nitroso compounds, which are known to cause stomach cancer, heterocyclic amines, which are known to cause colon cancer, and aflatoxin B1 (a mold toxin), which is known to cause liver cancer. Other external factors include ultraviolet light, ionizing radiation, and asbestos, which is known to cause pleural mesothelioma.
(3) Internal environmental factors In addition to external factors, there are also factors that occur naturally within the body (internal factors). One of the most important internal factors is errors that occur during DNA replication during cell proliferation. In order for cells to continue to proliferate, DNA must be replicated repeatedly, and during this replication, errors occur at a certain frequency, albeit at a very low frequency. The frequency of DNA replication errors is thought to be approximately ^{10 −4} ^/ base/replication (1 in 10 ⁴ bases per replication), and most replication errors are repaired by the proofreading function of the DNA replication enzyme itself and the action of other repair enzymes. However, in rare cases, an error may be overlooked, and this will be fixed in the cell as a genetic mutation after the next replication. This phenomenon is called spontaneous mutation, and its frequency is thought to be about ¹⁰ ⁻⁹ to ^{10 −10} ^/ base per cell division. In addition to replication and repair errors, the increase in oxidative stress (reactive oxygen) caused by organisms breathing using oxygen (aerobic respiration) is also a factor in inducing DNA damage. In addition to oxygen respiration, other causes of reactive oxygen species include fat metabolism, inflammation, and immune responses, which means that oxidative DNA damage caused by reactive oxygen species occurs frequently and on a daily basis. Of course, most oxidative DNA damage is usually repaired by the action of repair enzymes, but in rare cases, mistakes can occur, just like replication errors. It is desirable to avoid situations that generate excessive amounts of reactive oxygen species as much as possible ("12 New Rules for Preventing Cancer"). Additionally, changes in the activity of DNA methyltransferases and demethylases, as well as continuous stimulation by hormones, are also thought to be internal factors in the development of cancer.
(4) Genetic factors Representative genetic factors include the APC gene, which is the causative gene for familial adenomatous polyposis (FAP), a known hereditary form of colorectal cancer, and mismatch repair genes such as MLH1, MSH2, and MSH6, which are the causative genes for hereditary nonpolyposis colorectal cancer (HNPCC). In the case of genetic factors that cause these "hereditary cancers," which occur frequently in families, it is relatively easy to identify the causative genes because the rate at which individuals who have the causative gene develop cancer (penetrance) is very high. Genetic analyses of hereditary cancer pedigrees over the past 20 years have identified the causative genes for more than 30 types of hereditary cancer. In addition to hereditary cancers such as familial adenomatous polyposis, hereditary nonadenomatous colorectal cancer, and Li-Fraumeni syndrome, which are caused by a single genetic abnormality, familial cancers that show familial clustering include cancers that are thought to be caused by the combined effects of multiple genetic factors (multifactorial). When multiple genetic factors are involved, genetic analysis is not easy because the penetrance of cancer development due to individual factors is low, making it difficult to identify the causative gene. Recently, Lichtenstein et al. in Finland used cancer registry data for twins to examine the contribution of genetic and environmental factors to 11 types of human cancer. There is a possibility that some genetic factors are involved in human cancer, and a statistically significant contribution of genetic predisposition was detected, especially in colorectal cancer, breast cancer, and prostate cancer. The contribution rates are estimated to be 35%, 7%, and 42%, respectively. It is noteworthy that, for example, in the case of colon cancer, hereditary cancers whose causative genes have been identified account for only a few percent of all cancers, so most genetic factors are thought to involve multiple factors (multifactors) with low penetrance, such as constitution or ethnic or racial specific factors. [Nakagama Hitoshi]
■ References
Doll R, Peto R eds: The Causes of Cancer, Oxford University Press, Oxford, 1981.
Inoue M, et al: Attributable causes of cancer in Japan in 2005 – systematic assessment to estimate current burden of cancer attributable to known preventable risk factors in Japan. Ann Oncol, 23:1362-1369, 2012.
Lichtenstein P, et al: Environmental and heritable factors in the causation of cancer-analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med, 343: 78-85, 2000.

Figure 1-4-3
Environmental carcinogens ">

Figure 1-4-3

Source : Internal Medicine, 10th Edition About Internal Medicine, 10th Edition Information

Japanese:

癌は癌細胞からなり，その癌細胞は正常細胞が変化して発生すると考えたのは，ドイツの病理学者Virchowである．ドイツの動物学者Boveriは1914年にすでに「癌の染色体異常説」を唱えている．最近では，癌は細胞に遺伝子変異（ジェネティックな変化）やエピジェネティックな変化（遺伝子の変異や増幅などといった遺伝子自体の変化を伴わずに，遺伝的な変化が細胞内で固定されて細胞分裂後も娘細胞に引き継がれるような変化のこと．遺伝子のプロモーター領域のメチル化による遺伝子発現のサイレンシングが代表的）が多段階的に起きることにより発生するという「癌は遺伝子の病気」ということは広く知られている．これらの遺伝的変化を引き起こす原因となるものを癌の「病因」という．
（1）職業癌
　癌の病因に関しては，Virchowよりも実に100年近くも前に，イギリスのPottが煙突掃除人に発生する陰囊癌について報告している．いわゆる「職業癌」に関する最初の疫学的記載とされる．日本では，山極勝三郎が1915年にウサギの耳にコールタールを塗布することにより皮膚癌を発生させることに成功している．煙突掃除人における陰囊癌のほかにも，染色工場従事者における膀胱癌などは「職業癌」の代表的なものの1つである．
（2）外的要因
　癌の原因は，外的要因（外因）と内的要因（広義の内因）の大きく2種類に分けるのが一般的である．外因とは個体（生体）を取り巻く環境中に存在する要因のことであり，化学物質，放射線，紫外線，ウイルス，細菌などがあげられる．これに対し内因とは生体側に存在する要因のことである．内因はさらに内的な環境要因（狭義の内因）と遺伝的要因に分けることができる．
　ヒト癌の原因としての外的要因としては種々のものが知られている．イギリスの疫学研究者DollとPetoは1981年に数多くの疫学的科学研究に基づいて，米国人の癌死亡における各環境要因の寄与率を推定し報告した（図1-4-3）．DollとPetoらの報告によると，ヒト癌のうち禁煙により予防可能なものが全体の約3分の1と推計されている．その他食生活の改善により予防できる癌死亡の割合が同じく約3分の1，ウイルスや細菌などの感染症に起因する癌が10％以上としている．井上らは最近，日本人の癌死亡における環境要因の寄与率に関する疫学的解析に基づいた研究成果を報告し，日本人男性では喫煙が30％，飲酒が10％，感染症に起因する癌は23％と推定している．一方，女性では喫煙が5％，飲酒が2.5％，感染症が17.5％と推定している（井上ら，2012）．
　喫煙が発癌の危険因子として寄与する癌種としては，口腔癌，咽頭癌，喉頭癌，肺癌，食道癌，膵臓癌，腎盂癌，膀胱癌などがある．感染症と癌との関連では，Helicobacter pylori菌（胃癌），B型およびC型肝炎ウイルス（肝臓癌），Epstein-Barrウイルス（リンパ腫・鼻咽頭癌，胃癌），ヒトT細胞性白血病リンパ腫ウイルス（成人T細胞白血病リンパ腫），ヒトパピローマウイルス（子宮頸癌），ヒトヘルペスウイルス8型（Kaposi肉腫），肝吸虫（胆道癌）などが知られている．タバコ煙中に含まれる種々の化学物質やヒト癌への直接的な関与が明らかな感染症など，ヒト癌の直接的な要因（イニシエーター）や発癌を促進する修飾要因（プロモーター）を環境中から同定することは，癌の予防策を講じるうえできわめて重要な情報を提供することになる．
　経口的に摂取される食事性の発癌要因としては，胃癌の原因としての食塩やニトロソ化合物，大腸癌の原因としてのヘテロサイクリックアミン類，さらには肝臓癌の原因としてアフラトキシンB1（カビ毒類）などが知られている．外的な要因としてはそのほかに，紫外線や電離放射線，胸膜中皮腫の原因としてのアスベスト（石綿）などが知られている．
（3）内的環境要因
　環境要因としては，外的要因のほかに体内において自然に発生する要因（内的要因）がある．内的要因として最も重要なものの1つは，細胞増殖の際のDNA複製に伴うエラーである．細胞が増殖し続けるためにはDNAの複製を繰り返し行わなければならないが，この複製の際にきわめて低頻度ながら，ある頻度で間違い（エラー）を起こす．このDNA複製エラーの頻度はおおよそ10⁻⁴/塩基/複製（1回の複製あたり10⁴塩基に1個の割合）と考えられているが，ほとんどの複製エラーはDNA複製酵素自身がもつ校正機能やその他の修復酵素類の働きにより修復される．しかしまれに間違いを見過ごすことがあり，これが次の複製を経て遺伝子変異として細胞内で固定されることになる．この現象を自然突然変異というが，その頻度は1回の細胞分裂で10^－⁹～10^－¹⁰/塩基程度と考えられている．複製・修復エラーのほかにも，生物が酸素を使った呼吸（好気的呼吸）を行うことにより酸化的なストレス（活性酸素）が増えることもDNA損傷誘発の一因となる．活性酸素を発生する原因としては，酸素呼吸のほかにも脂肪代謝や炎症・免疫反応などがあげられ，活性酸素による酸化的なDNA損傷はかなりの高頻度で日常的に発生していることになる．もちろん，通常は修復系酵素の働きにより酸化的DNA損傷はほとんど修復されているが，複製エラーと同様にまれに間違いを起こすことがある．活性酸素を過剰に発生するような状況はできるだけ回避するのが望ましいことになる（「がんを防ぐための新12カ条」）．このほか，DNAのメチル基転移酵素や脱メチル化酵素の活性変化や，ホルモンによる持続的刺激も癌発生の内的要因の1つと考えられている．
（4）遺伝的要因
　遺伝的要因の代表的なものとしては，遺伝性の大腸癌として知られる家族性大腸腺腫症（familial adenomatous polyposis：FAP）の原因遺伝子であるAPC遺伝子や，遺伝性非腺腫性大腸癌（hereditary nonpolyposis colorectal cancer：HNPCC）の原因遺伝子であるMLH1やMSH2，MSH6などのミスマッチ修復遺伝子がある．家族性に癌が高頻度に発生するこれら「遺伝性癌」の原因となる遺伝的要因の場合には，原因遺伝子を有する個体が癌を発症する率（浸透率：penetrance）が非常に高いことから，その原因遺伝子を特定することが比較的容易である．過去20年以上にわたる遺伝性癌家系の遺伝学解析から，これまでに30種以上の遺伝性癌の原因遺伝子が同定されている．家族的な集積がみられる家族性癌には，単一の遺伝子異常により癌を発生する家族性大腸腺腫症や遺伝性非腺腫性大腸癌，Li-Fraumeni症候群などの遺伝性癌のほかに，複数の遺伝的要因（多因子）による複合的な働きで癌を発生していると想定されるものがある．多因子の遺伝的要因が関与する場合には，個々の因子による癌発症の浸透率が低いために遺伝的解析が容易でなく，原因遺伝子の同定が困難である．　最近，フィンランドのLichtensteinらは双生児の癌登録データを用い，11部位のヒト癌の遺伝的な要因と環境要因の寄与について検討した．ヒト癌においては何らかの遺伝的要因が関与する可能性があり，特に大腸癌，乳癌，前立腺癌では統計的有意に遺伝素因の寄与が検出された．その寄与率はおのおの35％，7％，42％と推計されている．注目すべき点は，たとえば大腸癌において原因遺伝子が解明された遺伝性癌の癌全体に占める割合が数％前後であることを考えると，遺伝的要因のほとんどは浸透率の低い，いわゆる体質とか民族・人種に固有な複数の要因（多因子）が関与したものであると考えられる．［中釜　斉］
■文献
Doll R, Peto R eds: The Causes of Cancer, Oxford University Press, Oxford, 1981.
Inoue M, et al: Attributable causes of cancer in Japan in 2005 – systematic assessment to estimate current burden of cancer attributable to known preventable risk factors in Japan. Ann Oncol, 23:1362-1369, 2012.
Lichtenstein P, et al: Environmental and heritable factors in the causation of cancer-analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med, 343: 78-85, 2000.　

図1-4-3
環境中の発癌要因">

図1-4-3

出典　内科学第10版内科学第10版について　情報

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