Editing Carcinogen (section)

==Major carcinogens implicated in the four most common cancers worldwide==
In this section, the carcinogens implicated as the main causative agents of the four most common cancers worldwide are briefly described. These four cancers are lung, breast, colon, and stomach cancers.  Together they account for about 41% of worldwide cancer incidence and 42% of cancer deaths (for more detailed information on the carcinogens implicated in these and other cancers, see references<ref>{{cite book | vauthors = Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K | date = 2008 | chapter = Cancer and aging as consequences of un-repaired DNA damage. | title = New Research on DNA Damages | veditors = Kimura H, Suzuki A | publisher = [[Nova Science Publishers, Inc.]] | location = New York | pages = 1–47 | chapter-url = https://www.novapublishers.com/catalog/product_info.php?products_id=43247 | archive-url = https://web.archive.org/web/20141025091740/https://www.novapublishers.com/catalog/product_info.php?products_id=43247 | archive-date=2014-10-25 | isbn = 978-1-60456-581-2}}</ref>).

===Lung cancer===
[[Lung cancer]] (pulmonary carcinoma) is the most common cancer in the world, both in terms of cases (1.6 million cases; 12.7% of total cancer cases) and deaths (1.4 million deaths; 18.2% of total cancer deaths).<ref name=Ferlay>{{cite journal | vauthors = Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM | title = Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008 | journal = International Journal of Cancer | volume = 127 | issue = 12 | pages = 2893–2917 | date = December 2010 | pmid = 21351269 | doi = 10.1002/ijc.25516 | s2cid = 23583962 | doi-access = free }}</ref>  Lung cancer is largely caused by tobacco smoke. Risk estimates for lung cancer in the United States indicate that tobacco smoke is responsible for 90% of lung cancers. Other factors are implicated in lung cancer, and these factors can interact synergistically with [[smoking]] so that total attributable risk adds up to more than 100%. These factors include occupational exposure to carcinogens (about 9-15%), [[radon]] (10%) and outdoor air pollution (1-2%).<ref>{{cite journal | vauthors = Alberg AJ, Ford JG, Samet JM | title = Epidemiology of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition) | journal = Chest | volume = 132 | issue = 3 Suppl | pages = 29S–55S | date = September 2007 | pmid = 17873159 | doi = 10.1378/chest.07-1347 }}</ref>

Tobacco smoke is a complex mixture of more than 5,300 identified chemicals. The most important carcinogens in tobacco smoke have been determined by a "Margin of Exposure" approach.<ref>{{cite journal | vauthors = Cunningham FH, Fiebelkorn S, Johnson M, Meredith C | title = A novel application of the Margin of Exposure approach: segregation of tobacco smoke toxicants | journal = Food and Chemical Toxicology | volume = 49 | issue = 11 | pages = 2921–2933 | date = November 2011 | pmid = 21802474 | doi = 10.1016/j.fct.2011.07.019 }}</ref> Using this approach, the most important tumorigenic compounds in tobacco smoke were, in order of importance, [[acrolein]], [[formaldehyde]], [[acrylonitrile]], 1,3-butadiene, cadmium, acetaldehyde, ethylene oxide, and isoprene. Most of these compounds cause DNA damage by forming DNA adducts or by inducing other alterations in DNA.{{Citation needed|date=December 2019|reason=removed citation to book from predatory publisher}}  DNA damages are subject to error-prone DNA repair or can cause replication errors. Such errors in repair or replication can result in mutations in tumor suppressor genes or oncogenes leading to cancer.

===Breast cancer===
[[Breast cancer]] is the second most common cancer [(1.4 million cases, 10.9%), but ranks 5th as cause of death (458,000, 6.1%)].<ref name=Ferlay />  Increased risk of breast cancer is associated with persistently elevated blood levels of [[estrogen]].<ref>{{cite journal | vauthors = Yager JD, Davidson NE | title = Estrogen carcinogenesis in breast cancer | journal = The New England Journal of Medicine | volume = 354 | issue = 3 | pages = 270–282 | date = January 2006 | pmid = 16421368 | doi = 10.1056/NEJMra050776 | s2cid = 5793142 }}</ref>  Estrogen appears to contribute to breast carcinogenesis by three processes; (1) the metabolism of estrogen to genotoxic, [[4-Hydroxyestrone|mutagenic carcinogens]], (2) the stimulation of tissue growth, and (3) the repression of phase II [[detoxification]] enzymes that metabolize [[Reactive oxygen species|ROS]] leading to increased oxidative DNA damage.<ref>{{cite journal | vauthors = Ansell PJ, Espinosa-Nicholas C, Curran EM, Judy BM, Philips BJ, Hannink M, Lubahn DB | title = In vitro and in vivo regulation of antioxidant response element-dependent gene expression by estrogens | journal = Endocrinology | volume = 145 | issue = 1 | pages = 311–317 | date = January 2004 | pmid = 14551226 | doi = 10.1210/en.2003-0817 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Belous AR, Hachey DL, Dawling S, Roodi N, Parl FF | title = Cytochrome P450 1B1-mediated estrogen metabolism results in estrogen-deoxyribonucleoside adduct formation | journal = Cancer Research | volume = 67 | issue = 2 | pages = 812–817 | date = January 2007 | pmid = 17234793 | doi = 10.1158/0008-5472.CAN-06-2133 | s2cid = 24602808 | doi-access =  }}</ref><ref>{{cite journal | vauthors = Bolton JL, Thatcher GR | title = Potential mechanisms of estrogen quinone carcinogenesis | language = EN | journal = Chemical Research in Toxicology | volume = 21 | issue = 1 | pages = 93–101 | date = January 2008 | pmid = 18052105 | pmc = 2556295 | doi = 10.1021/tx700191p }}</ref>

The major estrogen in humans, [[estradiol]], can be metabolized to quinone derivatives that form [[DNA adduct|adducts]] with DNA.<ref name=Yue>{{cite journal | vauthors = Yue W, Santen RJ, Wang JP, Li Y, Verderame MF, Bocchinfuso WP, Korach KS, Devanesan P, Todorovic R, Rogan EG, Cavalieri EL | title = Genotoxic metabolites of estradiol in breast: potential mechanism of estradiol induced carcinogenesis | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 86 | issue = 3–5 | pages = 477–486 | date = September 2003 | pmid = 14623547 | doi = 10.1016/s0960-0760(03)00377-7 | s2cid = 31885800 }}</ref>  These derivatives can cause depurination, the removal of bases from the phosphodiester backbone of DNA, followed by inaccurate repair or replication of the apurinic site leading to mutation and eventually cancer.  This genotoxic mechanism may interact in synergy with estrogen receptor-mediated, persistent cell proliferation to ultimately cause breast cancer.<ref name=Yue /> Genetic background, dietary practices and environmental factors also likely contribute to the incidence of DNA damage and breast cancer risk.

Consumption of [[Alcohol (drug)|alcohol]] has also been linked to an increased risk for breast cancer.<ref>{{cite journal | vauthors = McDonald JA, Goyal A, Terry MB | title = Alcohol Intake and Breast Cancer Risk: Weighing the Overall Evidence | journal = Current Breast Cancer Reports | volume = 5 | issue = 3 | pages = 208–221 | date = September 2013 | pmid = 24265860 | pmc = 3832299 | doi = 10.1007/s12609-013-0114-z }}</ref>

===Colon cancer===

[[Colorectal cancer]] is the third most common cancer [1.2 million cases (9.4%), 608,000 deaths (8.0%)].<ref name=Ferlay /> Tobacco smoke may be responsible for up to 20% of colorectal cancers in the United States.<ref>{{cite journal | vauthors = Giovannucci E, Martínez ME | title = Tobacco, colorectal cancer, and adenomas: a review of the evidence | journal = Journal of the National Cancer Institute | volume = 88 | issue = 23 | pages = 1717–1730 | date = December 1996 | pmid = 8944002 | doi = 10.1093/jnci/88.23.1717 | doi-access =  }}</ref>  In addition, substantial evidence implicates [[bile acid]]s as an important factor in colon cancer.  Twelve studies (summarized in Bernstein et al.<ref name=Bernstein2009>{{cite journal | vauthors = Bernstein H, Bernstein C, Payne CM, Dvorak K | title = Bile acids as endogenous etiologic agents in gastrointestinal cancer | journal = World Journal of Gastroenterology | volume = 15 | issue = 27 | pages = 3329–3340 | date = July 2009 | pmid = 19610133 | pmc = 2712893 | doi = 10.3748/wjg.15.3329 | doi-access = free }}</ref>) indicate that the bile acids deoxycholic acid (DCA) or lithocholic acid (LCA) induce production of DNA-damaging reactive oxygen species or reactive nitrogen species in human or animal colon cells.  Furthermore, 14 studies showed that DCA and LCA induce DNA damage in colon cells.  Also 27 studies reported that bile acids cause programmed cell death ([[apoptosis]]).

Increased apoptosis can result in selective survival of cells that are resistant to induction of apoptosis.<ref name=Bernstein2009 />  Colon cells with reduced ability to undergo apoptosis in response to DNA damage would tend to accumulate mutations, and such cells may give rise to colon cancer.<ref name=Bernstein2009 />  Epidemiologic studies have found that fecal bile acid concentrations are increased in populations with a high incidence of colon cancer.  Dietary increases in total fat or saturated fat result in elevated DCA and LCA in feces and elevated exposure of the colon epithelium to these bile acids.  When the bile acid DCA was added to the standard diet of wild-type mice invasive colon cancer was induced in 56% of the mice after 8 to 10 months.<ref>{{cite journal | vauthors = Bernstein C, Holubec H, Bhattacharyya AK, Nguyen H, Payne CM, Zaitlin B, Bernstein H | title = Carcinogenicity of deoxycholate, a secondary bile acid | journal = Archives of Toxicology | volume = 85 | issue = 8 | pages = 863–871 | date = August 2011 | pmid = 21267546 | pmc = 3149672 | doi = 10.1007/s00204-011-0648-7 | bibcode = 2011ArTox..85..863B }}</ref>  Overall, the available evidence indicates that DCA and LCA are centrally important DNA-damaging carcinogens in colon cancer.

===Stomach cancer===
[[Stomach cancer]] is the fourth most common cancer [990,000 cases (7.8%), 738,000 deaths (9.7%)].<ref name=Ferlay />  ''[[Helicobacter pylori]]'' infection is the main causative factor in stomach cancer.  Chronic [[gastritis]] (inflammation) caused by ''H. pylori'' is often long-standing if not treated.  Infection of gastric epithelial cells with ''H. pylori'' results in increased production of reactive oxygen species (ROS).<ref>{{cite journal | vauthors = Ding SZ, Minohara Y, Fan XJ, Wang J, Reyes VE, Patel J, Dirden-Kramer B, Boldogh I, Ernst PB, Crowe SE | title = Helicobacter pylori infection induces oxidative stress and programmed cell death in human gastric epithelial cells | journal = Infection and Immunity | volume = 75 | issue = 8 | pages = 4030–4039 | date = August 2007 | pmid = 17562777 | pmc = 1952011 | doi = 10.1128/IAI.00172-07 }}</ref><ref>{{cite journal | vauthors = Handa O, Naito Y, Yoshikawa T | title = Redox biology and gastric carcinogenesis: the role of Helicobacter pylori | journal = Redox Report | volume = 16 | issue = 1 | pages = 1–7 | year = 2011 | pmid = 21605492 | pmc = 6837368 | doi = 10.1179/174329211X12968219310756 | doi-access = free }}</ref>  ROS cause oxidative DNA damage including the major base alteration 8-hydroxydeoxyguanosine (8-OHdG).  8-OHdG resulting from ROS is increased in chronic gastritis.  The altered DNA base can cause errors during DNA replication that have mutagenic and carcinogenic potential.  Thus ''H. pylori''-induced ROS appear to be the major carcinogens in stomach cancer because they cause oxidative DNA damage leading to carcinogenic mutations.

Diet is also thought to be a contributing factor in stomach cancer: in Japan, where very salty pickled foods are popular, the incidence of stomach cancer is high.  Preserved meat such as bacon, sausages, and ham increases the risk, while a diet rich in fresh fruit, vegetables, peas, beans, grains, nuts, seeds, herbs, and spices will reduce the risk. The risk also increases with age.<ref>{{cite web |url=http://www.cancerresearchuk.org/about-cancer/type/stomach-cancer/about/stomach-cancer-risks-and-causes |title=Stomach cancer risks and causes |work=Cancer Research UK }}</ref>