Causes of cancer

{{Main|Cancer syndrome}}

File:Familial Adenomatous Polyposes colon -2.jpg

Although there are over 50 identifiable hereditary forms of cancer, less than 0.3% of the population are carriers of a cancer-related genetic mutation and these make up less than 3–10% of all cancer cases. The vast majority of cancers are non-hereditary ("sporadic cancers"). Hereditary cancers are primarily caused by an inherited genetic defect. A cancer syndrome or family cancer syndrome is a genetic disorder in which inherited genetic mutations in one or more genes predisposes the affected individuals to the development of cancers and may also cause the early onset of these cancers. Although cancer syndromes exhibit an increased risk of cancer, the risk varies. For some of these diseases, cancer is not the primary feature and is a rare consequence.

Many of the cancer syndrome cases are caused by mutations in tumor suppressor genes that regulate cell growth. Other common mutations alter the function of DNA repair genes, oncogenes and genes involved in the production of blood vessels.{{cite journal | vauthors = Hodgson S | title = Mechanisms of inherited cancer susceptibility | journal = Journal of Zhejiang University Science B | volume = 9 | issue = 1 | pages = 1–4 | date = January 2008 | pmid = 18196605 | pmc = 2170461 | doi = 10.1631/jzus.B073001 }} Certain inherited mutations in the genes BRCA1 and BRCA2 with a more than 75% risk of breast cancer and ovarian cancer. Some of the inherited genetic disorders that can cause colorectal cancer include familial adenomatous polyposis and hereditary non-polyposis colon cancer; however, these represent less than 5% of colon cancer cases.{{Cite book|title=World Cancer Report 2014|publisher=World Health Organization|year=2014|isbn=978-92-832-0429-9|chapter=Chapter 5.5}} In many cases, genetic testing can be used to identify mutated genes or chromosomes that are passed through generations.

• Ataxia–telangiectasia
• Bloom syndrome
• BRCA1 & BRCA2
• Fanconi anemia
• Familial adenomatous polyposis
• Hereditary breast and ovarian cancer
• Hereditary nonpolyposis colorectal cancer
• Li–Fraumeni syndrome
• Nevoid basal-cell carcinoma syndrome
• Von Hippel–Lindau disease
• Werner syndrome
• Xeroderma pigmentosum

{{Further|Carcinogen|Smoking and cancer|Safety of electronic cigarettes}}

Particular substances, known as carcinogens, have been linked to specific types of cancer. Common examples of non-radioactive carcinogens are inhaled asbestos, certain dioxins, and tobacco smoke. Although the public generally associates carcinogenicity with synthetic chemicals, it is equally likely to arise in both natural and synthetic substances.{{Cite journal|date=2000-01-17|title=Paracelsus to parascience: the environmental cancer distraction|journal=Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis|language=en|volume=447|issue=1|pages=3–13|doi=10.1016/S0027-5107(99)00194-3|pmid=10686303 |last1=Ames|first1=Bruce N.|last2=Gold|first2=Lois Swirsky|bibcode=2000MRFMM.447....3A }} It is estimated that approximately 20,000 cancer deaths and 40,000 new cases of cancer each year in the U.S. are attributable to occupation.{{cite web|url=https://www.cdc.gov/niosh/topics/cancer/|title=National Institute for Occupational Safety and Health- Occupational Cancer|publisher=United States National Institute for Occupational Safety and Health|access-date=13 October 2007}} Every year, at least 200,000 people die worldwide from cancer related to their workplace. Millions of workers run the risk of developing cancers such as lung cancer and mesothelioma from inhaling asbestos fibers and tobacco smoke, or leukemia from exposure to benzene at their workplaces.{{cite press release|title=WHO calls for prevention of cancer through healthy workplaces|date=27 April 2007|publisher=World Health Organization|url=https://www.who.int/mediacentre/news/notes/2007/np19/en/index.html|archive-url=https://web.archive.org/web/20070501165935/http://www.who.int/mediacentre/news/notes/2007/np19/en/index.html|url-status=dead|archive-date=May 1, 2007|access-date=13 October 2007}} Cancer related to one's occupation is believed to represent between 2–20% of all cases.{{cite journal | vauthors = Irigaray P, Newby JA, Clapp R, Hardell L, Howard V, Montagnier L, Epstein S, Belpomme D | title = Lifestyle-related factors and environmental agents causing cancer: an overview | journal = Biomedicine & Pharmacotherapy | volume = 61 | issue = 10 | pages = 640–58 | date = December 2007 | pmid = 18055160 | doi = 10.1016/j.biopha.2007.10.006 }} Most cancer deaths caused by occupational risk factors occur in the developed world. Job stress does not appear to be a significant factor at least in lung, colorectal, breast and prostate cancers.{{cite journal | vauthors = Heikkilä K, Nyberg ST, Theorell T, Fransson EI, Alfredsson L, Bjorner JB, Bonenfant S, Borritz M, Bouillon K, Burr H, Dragano N, Geuskens GA, Goldberg M, Hamer M, Hooftman WE, Houtman IL, Joensuu M, Knutsson A, Koskenvuo M, Koskinen A, Kouvonen A, Madsen IE, Magnusson Hanson LL, Marmot MG, Nielsen ML, Nordin M, Oksanen T, Pentti J, Salo P, Rugulies R, Steptoe A, Suominen S, Vahtera J, Virtanen M, Väänänen A, Westerholm P, Westerlund H, Zins M, Ferrie JE, Singh-Manoux A, Batty GD, Kivimäki M | display-authors = 6 | title = Work stress and risk of cancer: meta-analysis of 5700 incident cancer events in 116,000 European men and women | journal = BMJ | volume = 346 | pages = f165 | date = February 2013 | pmid = 23393080 | pmc = 3567204 | doi = 10.1136/bmj.f165 }} Participation in Operation Ranchhand in Vietnam during the Vietnam war, or living near a golf course, or living on a farm would increase the risk of non-Hodgkins lymphoma due to exposure to the chemical 2,4-D. When 2,4-D is mixed with another chemical pesticide or herbicide, 2,4-T, at a 50:50 ratio, they are collectively known as Agent Orange.

File:Share-of-cancer-deaths-attributed-to-tobacco.png

Image:Cancer smoking lung cancer correlation from NIH.svg is highly correlated with smoking.]]

Tobacco smoking is associated with many forms of cancer,{{cite journal | vauthors = Sasco AJ, Secretan MB, Straif K | title = Tobacco smoking and cancer: a brief review of recent epidemiological evidence | journal = Lung Cancer | volume = 45 | pages = S3–9 | date = August 2004 | issue = Suppl 2 | pmid = 15552776 | doi = 10.1016/j.lungcan.2004.07.998 }} and causes 80% of lung cancer.{{cite journal | vauthors = Biesalski HK, Bueno de Mesquita B, Chesson A, Chytil F, Grimble R, Hermus RJ, Köhrle J, Lotan R, Norpoth K, Pastorino U, Thurnham D | title = European Consensus Statement on Lung Cancer: risk factors and prevention. Lung Cancer Panel | journal = CA: A Cancer Journal for Clinicians | volume = 48 | issue = 3 | pages = 167–76; discussion 164–6 | year = 1998 | pmid = 9594919 | doi = 10.3322/canjclin.48.3.167 | s2cid = 20891885 | doi-access = free }} Decades of research has demonstrated the link between tobacco use and cancer in the lung, larynx, head, neck, stomach, bladder, kidney, esophagus and pancreas.{{cite journal | vauthors = Kuper H, Boffetta P, Adami HO | title = Tobacco use and cancer causation: association by tumour type | journal = Journal of Internal Medicine | volume = 252 | issue = 3 | pages = 206–24 | date = September 2002 | pmid = 12270001 | doi = 10.1046/j.1365-2796.2002.01022.x | s2cid = 6132726 | doi-access = free }} There is some evidence suggesting a small increased risk of developing myeloid leukemia, squamous cell sinonasal cancer, liver cancer, colorectal cancer, cancers of the gallbladder, the adrenal gland, the small intestine, and various childhood cancers. Seven toxicants in cigarette smoke have been identified that are most associated with respiratory tract carcinogenesis.{{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 Chem Toxicol |volume=49 |issue=11 |pages=2921–33 |date=November 2011 |pmid=21802474 |doi=10.1016/j.fct.2011.07.019 }} The mechanism of action of two of them, acrylonitrile and acrolein, appears to involve oxidative stress and oxidative DNA damage.{{cite journal |vauthors=Pu X, Kamendulis LM, Klaunig JE |title=Acrylonitrile-induced oxidative stress and oxidative DNA damage in male Sprague-Dawley rats |journal=Toxicol Sci |volume=111 |issue=1 |pages=64–71 |date=September 2009 |pmid=19546159 |pmc=2726299 |doi=10.1093/toxsci/kfp133 }}{{cite journal |vauthors=Li L, Jiang L, Geng C, Cao J, Zhong L |title=The role of oxidative stress in acrolein-induced DNA damage in HepG2 cells |journal=Free Radic Res |volume=42 |issue=4 |pages=354–61 |date=April 2008 |pmid=18404534 |doi=10.1080/10715760802008114 }} The other five toxicants, acetaldehyde, cadmium, ethylene oxide, formaldehyde and isoprene act through various mechanisms including direct interaction with DNA. Tobacco smoke contains over fifty known carcinogens, including nitrosamines and polycyclic aromatic hydrocarbons. Tobacco is responsible for about one in three of all cancer deaths in the developed world, and about one in five worldwide.{{cite journal | vauthors = Kuper H, Adami HO, Boffetta P | s2cid = 9172672 | title = Tobacco use, cancer causation and public health impact | journal = Journal of Internal Medicine | volume = 251 | issue = 6 | pages = 455–66 | date = June 2002 | pmid = 12028500 | doi = 10.1046/j.1365-2796.2002.00993.x | doi-access = }} Lung cancer death rates in the United States have mirrored smoking patterns, with increases in smoking followed by dramatic increases in lung cancer death rates and, more recently, decreases in smoking rates since the 1950s followed by decreases in lung cancer death rates in men since 1990.{{cite journal | vauthors = Thun MJ, Jemal A | title = How much of the decrease in cancer death rates in the United States is attributable to reductions in tobacco smoking? | journal = Tobacco Control | volume = 15 | issue = 5 | pages = 345–7 | date = October 2006 | pmid = 16998161 | pmc = 2563648 | doi = 10.1136/tc.2006.017749 }}{{cite journal | vauthors = Dubey S, Powell CA | title = Update in lung cancer 2007 | journal = American Journal of Respiratory and Critical Care Medicine | volume = 177 | issue = 9 | pages = 941–6 | date = May 2008 | pmid = 18434333 | pmc = 2720127 | doi = 10.1164/rccm.200801-107UP }} However, the numbers of smokers worldwide is still rising, leading to what some organizations have described as the tobacco epidemic.{{cite journal | vauthors = Proctor RN | title = The global smoking epidemic: a history and status report | journal = Clinical Lung Cancer | volume = 5 | issue = 6 | pages = 371–6 | date = May 2004 | pmid = 15217537 | doi = 10.3816/CLC.2004.n.016 }}

Electronic cigarettes or e-cigarettes are handheld electronic devices that simulate the feeling of tobacco smoking. Daily long-term use of high voltage (5.0 V) electronic cigarettes may generate formaldehyde-forming chemicals at a greater level than smoking, which was determined to be a lifetime cancer risk of approximately 5 to 15 times greater than smoking.{{cite journal | vauthors = Cooke A, Fergeson J, Bulkhi A, Casale TB | title = The Electronic Cigarette: The Good, the Bad, and the Ugly | journal = The Journal of Allergy and Clinical Immunology. In Practice | volume = 3 | issue = 4 | pages = 498–505 | year = 2015 | pmid = 26164573 | doi = 10.1016/j.jaip.2015.05.022 }} However, the overall safety and long-term health effects of electronic cigarettes is still uncertain.{{Cite journal|last1=Ebbert|first1=Jon O.|last2=Agunwamba|first2=Amenah A.|last3=Rutten|first3=Lila J.|date=January 2015|title=Counseling patients on the use of electronic cigarettes|journal=Mayo Clinic Proceedings|volume=90|issue=1|pages=128–134|doi=10.1016/j.mayocp.2014.11.004 |pmid=25572196|doi-access=free}}

File:Carcinoma_asbestos_body_lung.jpgSome substances cause cancer primarily through their physical, rather than chemical, effects on cells.{{cite book |vauthors=Maltoni CF, Holland JF |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK20770/|title={{harvnb|Holland-Frei Cancer Medicine}} |year=2000 |chapter=16. Physical Carcinogens|publisher=BC Decker |id=NBK20770}} A prominent example of this is prolonged exposure to asbestos, naturally occurring mineral fibers which are a major cause of mesothelioma, which is a cancer of the serous membrane, usually the serous membrane surrounding the lungs. Other substances in this category, including both naturally occurring and synthetic asbestos-like fibers such as wollastonite, attapulgite, glass wool, and rock wool, are believed to have similar effects. Non-fibrous particulate materials that cause cancer include powdered metallic cobalt and nickel, and crystalline silica (quartz, cristobalite, and tridymite). Usually, physical carcinogens must get inside the body (such as through inhaling tiny pieces) and require years of exposure to develop cancer. Common occupational carcinogens include:{{Cite book|title=Robbins Basic Pathology |date=2007|publisher=Saunders/Elsevier |isbn=978-1-4160-2973-1|edition= 8th|location=Philadelphia, PA|at=Table 6–2|oclc=69672074}}

• arsenic
• asbestos
• benzene
• beryllium
• cadmium
• chromium
• ethylene oxide
• nickel
• Plutonium

{{Further|Alcohol and cancer|Diet and cancer|Obesity and cancer}}

Many different lifestyle factors contribute to increasing cancer risk. Together, diet and obesity are related to approximately 30–35% of cancer deaths.{{cite journal | vauthors = Kushi LH, Byers T, Doyle C, Bandera EV, McCullough M, McTiernan A, Gansler T, Andrews KS, Thun MJ | title = American Cancer Society Guidelines on Nutrition and Physical Activity for cancer prevention: reducing the risk of cancer with healthy food choices and physical activity | journal = CA: A Cancer Journal for Clinicians | volume = 56 | issue = 5 | pages = 254–81; quiz 313–4 | year = 2006 | pmid = 17005596 | doi = 10.3322/canjclin.56.5.254 | s2cid = 19823935 | doi-access = free }} Dietary recommendations for cancer prevention typically include an emphasis on vegetables, fruit, whole grains, and fish, and avoidance of processed meat, red meat, animal fats, and refined carbohydrates.{{cite journal | vauthors = Kushi LH, Doyle C, McCullough M, Rock CL, Demark-Wahnefried W, Bandera EV, Gapstur S, Patel AV, Andrews K, Gansler T | title = American Cancer Society Guidelines on nutrition and physical activity for cancer prevention: reducing the risk of cancer with healthy food choices and physical activity | journal = CA: A Cancer Journal for Clinicians | volume = 62 | issue = 1 | pages = 30–67 | date = January 2012 | pmid = 22237782 | doi = 10.3322/caac.20140 | s2cid = 2067308 | doi-access = free }} The evidence to support these dietary changes is not definitive.{{cite journal | vauthors = Wicki A, Hagmann J | title = Diet and cancer | journal = Swiss Medical Weekly | volume = 141 | pages = w13250 | doi = 10.4414/smw.2011.13250 | pmid = 21904992 | year = 2011 | doi-access = free }}

File:Cirrosi micronodular.1427.jpgAlcohol is an example of a chemical carcinogen. The World Health Organization has classified alcohol as a Group 1 carcinogen.{{Cite news|url=http://www.iarc.fr/en/media-centre/pr/2009/pdfs/pr196_E.pdf|title=IARC: IARC Strengthens its Findings on Several Carcinogenic Personal Habits and Household Exposures | date = 2009 | work = International Agency for Research on Cancer - World Health Organization }} In Western Europe 10% of cancers in males and 3% of cancers in females are attributed to alcohol.{{cite journal | vauthors = Schütze M, Boeing H, Pischon T, Rehm J, Kehoe T, Gmel G, Olsen A, Tjønneland AM, Dahm CC, Overvad K, Clavel-Chapelon F, Boutron-Ruault MC, Trichopoulou A, Benetou V, Zylis D, Kaaks R, Rohrmann S, Palli D, Berrino F, Tumino R, Vineis P, Rodríguez L, Agudo A, Sánchez MJ, Dorronsoro M, Chirlaque MD, Barricarte A, Peeters PH, van Gils CH, Khaw KT, Wareham N, Allen NE, Key TJ, Boffetta P, Slimani N, Jenab M, Romaguera D, Wark PA, Riboli E, Bergmann MM | display-authors = 6 | title = Alcohol attributable burden of incidence of cancer in eight European countries based on results from prospective cohort study | journal = BMJ | volume = 342 | pages = d1584 | date = April 2011 | pmid = 21474525 | pmc = 3072472 | doi = 10.1136/bmj.d1584 }} Worldwide, 3.6% of all cancer cases and 3.5% of cancer deaths are attributable to alcohol.{{Cite journal|last=Boffetta|date=August 2006|title=The burden of cancer attributable to alcohol drinking|journal=International Journal of Cancer|volume=119 |issue=4|pages=884–7|doi=10.1002/ijc.21903|pmid=16557583|hdl=2434/22728|s2cid=14938863|hdl-access=free}} In particular, alcohol use has been shown to increase the risk of developing cancers of the mouth, esophagus, pharynx, larynx, stomach, liver, ovaries, and colon.{{Cite web|url=https://pubs.niaaa.nih.gov/publications/arh25-4/263-270.htm|title=Alcohol Consumption and the Risk of Cancer|website=pubs.niaaa.nih.gov|language=en|access-date=2018-03-22|archive-date=21 February 2018|archive-url=https://web.archive.org/web/20180221200307/https://pubs.niaaa.nih.gov/publications/arh25-4/263-270.htm|url-status=dead}} The main mechanism of cancer development involves increased exposure to acetaldehyde, a carcinogen and breakdown product of ethanol.{{cite journal | vauthors = Theruvathu JA, Jaruga P, Nath RG, Dizdaroglu M, Brooks PJ | title = Polyamines stimulate the formation of mutagenic 1,N2-propanodeoxyguanosine adducts from acetaldehyde | journal = Nucleic Acids Research | volume = 33 | issue = 11 | pages = 3513–20 | date = 2005 | pmid = 15972793 | pmc = 1156964 | doi = 10.1093/nar/gki661 }} Acetaldehyde induces DNA interstrand crosslinks, a form of DNA damage. These can be repaired by an inaccurate replication-coupled DNA repair pathway.{{cite journal |vauthors=Hodskinson MR, Bolner A, Sato K, Kamimae-Lanning AN, Rooijers K, Witte M, Mahesh M, Silhan J, Petek M, Williams DM, Kind J, Chin JW, Patel KJ, Knipscheer P |title=Alcohol-derived DNA crosslinks are repaired by two distinct mechanisms |journal=Nature |volume=579 |issue=7800 |pages=603–608 |date=March 2020 |pmid=32132710 |pmc=7116288 |doi=10.1038/s41586-020-2059-5 |bibcode=2020Natur.579..603H }} This repair pathway results in increased mutation frequency and altered mutational spectrum. Other mechanisms have been proposed, including alcohol-related nutritional deficiencies, changes in DNA methylation, and induction of oxidative stress in tissues.{{Cite journal | vauthors = Poschl G | date = May 2004 | title = Alcohol and Cancer | journal = Alcohol and Alcoholism | volume = 39 | issue = 3 |pages = 155–165 | doi = 10.1093/alcalc/agh057 | pmid = 15082451 | doi-access = free }}

Some specific foods have been linked to specific cancers. Studies have shown that individuals that eat red or processed meat have a higher risk of developing breast cancer, prostate cancer, and pancreatic cancer.{{Cite book|title=World Cancer Report 2014|last=Stewart|first=Bernard | name-list-style = vanc |publisher=World Health Organization|year=2014|isbn=978-92-832-0429-9 |pages=124–33}} This may be partially explained by the presence of carcinogens in food cooked at high temperatures.{{Cite journal | first = Lynnette R. | last = Ferguson | name-list-style = vanc | date = February 2010 | title = Meat and cancer |journal=Meat Science|volume=84|issue=2|pages=308–313|doi=10.1016/j.meatsci.2009.06.032| pmid = 20374790 }} Several risk factors for the development of colorectal cancer include high intake of fat, alcohol, red and processed meats, obesity, and lack of physical exercise.{{Cite journal|date=2011|title=Colorectal Cancer 2011 Report: Food, Nutrition, Physical Activity, and the Prevention of Colorectal Cancer|url=https://www.wcrf.org/sites/default/files/Colorectal-Cancer-2011-Report.pdf|journal=World Cancer Research Fund & American Institute for Cancer Research|access-date=2018-03-22|archive-date=2019-05-22|archive-url=https://web.archive.org/web/20190522192942/https://www.wcrf.org/sites/default/files/Colorectal-Cancer-2011-Report.pdf|url-status=dead}} A high-salt diet is linked to gastric cancer. Aflatoxin B1, a frequent food contaminate, is associated with liver cancer. Betel nut chewing has been shown to cause oral cancers.{{cite journal | vauthors = Park S, Bae J, Nam BH, Yoo KY | title = Aetiology of cancer in Asia | journal = Asian Pacific Journal of Cancer Prevention | volume = 9 | issue = 3 | pages = 371–80 | year = 2008 | pmid = 18990005 | url = http://www.apocpcontrol.org/page/popup_paper_file_view.php?pno=MzcxIFBhcmsucCZrY29kZT04MjI=&pgubun=i | format = PDF | access-date = 2014-07-17 | archive-url = https://web.archive.org/web/20110904052252/http://www.apocpcontrol.org/page/popup_paper_file_view.php?pno=MzcxIFBhcmsucCZrY29kZT04MjI=&pgubun=i | archive-date = 2011-09-04 | url-status = dead }}

The relationship between diet and the development of particular cancers may partly explain differences in cancer incidence in different countries. For example, gastric cancer is more common in Japan due to the frequency of high-salt diets and colon cancer is more common in the United States due to the increased intake of processed and red meats.{{cite book | vauthors = Brenner H, Rothenbacher D, Arndt V | chapter = Epidemiology of Stomach Cancer | volume = 472 | pages = 467–77 | year = 2009 | pmid = 19107449 | doi = 10.1007/978-1-60327-492-0_23 | isbn = 978-1-60327-491-3 | series = Methods in Molecular Biology | issue = 5450 | pmc = 2166976 | title = Cancer Epidemiology }} Immigrant communities tend to develop the cancer risk profile of their new country, often within one to two generations, suggesting a substantial link between diet and cancer.{{cite journal | vauthors = Buell P, Dunn JE | title = Cancer Mortality among Japanese Issei and Nisei of California | journal = Cancer | volume = 18 | issue = 5 | pages = 656–64 | date = May 1965 | pmid = 14278899 | doi = 10.1002/1097-0142(196505)18:5<656::AID-CNCR2820180515>3.0.CO;2-3 | s2cid = 39881987 | doi-access = }}{{Cite journal|last1=Parkin|first1=D. M.|last2=Khlat|first2=M.|date=May 1996|title=Studies of cancer in migrants: rationale and methodology|journal=European Journal of Cancer|volume=32A|issue=5|pages=761–771 |pmid=9081351|doi=10.1016/0959-8049(96)00062-7}}

When deoxycholate was added to the food of mice so that their feces contained deoxycholate at about the same level present in feces of human on a high fat diet, 45% to 56% of the mice developed colon cancer over the next 10 months, while none of the mice on a diet without deoxycholate developed cancer.{{cite journal |vauthors=Prasad AR, Prasad S, Nguyen H, Facista A, Lewis C, Zaitlin B, Bernstein H, Bernstein C |title=Novel diet-related mouse model of colon cancer parallels human colon cancer |journal=World J Gastrointest Oncol |volume=6 |issue=7 |pages=225–43 |date=July 2014 |pmid=25024814 |pmc=4092339 |doi=10.4251/wjgo.v6.i7.225 |doi-access=free }}{{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 = 863–71 | date = August 2011 | pmid = 21267546 | pmc = 3149672 | doi = 10.1007/s00204-011-0648-7 | bibcode = 2011ArTox..85..863B }} A recent prospective human study investigating the relationship between microbial metabolites and cancer found a strong correlation between circulating deoxycholate as well as other specific bile acids and colorectal cancer risk in women.{{cite journal |vauthors=Loftfield E, Falk RT, Sampson JN, Huang WY, Hullings A, Murphy G, Weinstein SJ, Albanes D, Freedman ND, Sinha R |title=Prospective Associations of Circulating Bile Acids and Short-Chain Fatty Acids With Incident Colorectal Cancer |journal=JNCI Cancer Spectr |volume=6 |issue=3 |pages= |date=May 2022 |pmid=35583137 |pmc=9115675 |doi=10.1093/jncics/pkac027 }}

In the United States, excess body weight is associated with the development of many types of cancer and is a factor in 14–20% of all cancer deaths. Every year, nearly 85,000 new cancer diagnoses in the United States are related to obesity. Individuals who underwent bariatric surgery for weight loss have reduced cancer incidence and mortality.

There is an association between obesity and colon cancer, post-menopausal breast cancer, endometrial cancer, kidney cancer, and esophageal cancer. Obesity has also been linked with the development of liver cancer.{{cite journal | vauthors = Alzahrani B, Iseli TJ, Hebbard LW | title = Non-viral causes of liver cancer: does obesity led inflammation play a role? | journal = Cancer Letters | volume = 345 | issue = 2 | pages = 223–9 | date = April 2014 | pmid = 24007864 | doi = 10.1016/j.canlet.2013.08.036 }} The current understanding regarding the mechanism of cancer development in obesity relates to abnormal levels of metabolic proteins (including insulin-like growth factors) and sex hormones (estrogens, androgens and progestogens). Adipose tissue also creates an inflammatory environment which may contribute to the development of cancers.{{cite journal | vauthors = Gilbert CA, Slingerland JM | title = Cytokines, obesity, and cancer: new insights on mechanisms linking obesity to cancer risk and progression | journal = Annual Review of Medicine | volume = 64 | issue = 1 | pages = 45–57 | date = 2013-01-14 | pmid = 23121183 | doi = 10.1146/annurev-med-121211-091527 }} Adipose tissue dysregulation can result in oxidative stress leading to oxidative DNA damage and cancer associated genetic instability.{{cite journal |vauthors=Kompella P, Vasquez KM |title=Obesity and cancer: A mechanistic overview of metabolic changes in obesity that impact genetic instability |journal=Mol Carcinog |volume=58 |issue=9 |pages=1531–1550 |date=September 2019 |pmid=31168912 |pmc=6692207 |doi=10.1002/mc.23048 }}

Physical inactivity is believed to contribute to cancer risk not only through its effect on body weight but also through negative effects on immune system and endocrine system. More than half of the effect from diet is due to overnutrition rather than from eating too little healthy foods.

File:Breast cancer gross appearance.jpg of the breast. The tumor is the pale, crab-shaped mass at the center, surrounded by normal, yellow fatty tissue.]]

Some hormones play a role in the development of cancer by promoting cell proliferation.{{cite book|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK20759/|title=Holland-Frei Cancer Medicine|vauthors=Henderson BE, Bernstein L, Ross RK|publisher=B.C. Decker|year=2000|isbn=978-1-55009-113-7|veditors=Bast RC, Kufe DW, Pollock RE|edition= 5th |chapter=13. Hormones and the Etiology of Cancer|ref={{harvid|Holland-Frei Cancer Medicine}} }} Insulin-like growth factors and their binding proteins play a key role in cancer cell growth, differentiation and apoptosis, suggesting possible involvement in carcinogenesis.{{cite journal | vauthors = Rowlands MA, Gunnell D, Harris R, Vatten LJ, Holly JM, Martin RM | title = Circulating insulin-like growth factor peptides and prostate cancer risk: a systematic review and meta-analysis | journal = International Journal of Cancer | volume = 124 | issue = 10 | pages = 2416–29 | date = May 2009 | pmid = 19142965 | pmc = 2743036 | doi = 10.1002/ijc.24202 }}

Hormones are important agents in sex-related cancers such as cancer of the breast, endometrium, prostate, ovary, and testis, and also of thyroid cancer and bone cancer. For example, the daughters of women who have breast cancer have significantly higher levels of estrogen and progesterone than the daughters of women without breast cancer. These higher hormone levels may explain why these women have higher risk of breast cancer, even in the absence of a breast-cancer gene. Similarly, men of African ancestry have significantly higher levels of testosterone than men of European ancestry, and have a correspondingly much higher level of prostate cancer. Men of Asian ancestry, with the lowest levels of testosterone-activating androstanediol glucuronide, have the lowest levels of prostate cancer.

Other factors are also relevant: obese people have higher levels of some hormones associated with cancer and a higher rate of those cancers. Women who take hormone replacement therapy have a higher risk of developing cancers associated with those hormones. On the other hand, people who exercise far more than average have lower levels of these hormones, and lower risk of cancer. Osteosarcoma may be promoted by growth hormones.

Some treatments and prevention approaches leverage this cause by artificially reducing hormone levels, and thus discouraging hormone-sensitive cancers. Because steroid hormones are powerful drivers of gene expression in certain cancer cells, changing the levels or activity of certain hormones can cause certain cancers to cease growing or even undergo cell death. Perhaps the most familiar example of hormonal therapy in oncology is the use of the selective estrogen-receptor modulator tamoxifen for the treatment of breast cancer. Another class of hormonal agents, aromatase inhibitors, now have an expanding role in the treatment of breast cancer.

{{Main|Infectious causes of cancer}}

Worldwide, approximately 18% of cancer cases are related to infectious diseases.{{Cite journal|date=2012-06-01|title=Global burden of cancers attributable to infections in 2008: a review and synthetic analysis|journal=The Lancet Oncology |volume=13|issue=6|pages=607–615|doi=10.1016/S1470-2045(12)70137-7|pmid=22575588 |last1=De Martel|first1=Catherine|last2=Ferlay|first2=Jacques|last3=Franceschi|first3=Silvia|last4=Vignat|first4=Jérôme|last5=Bray|first5=Freddie|last6=Forman|first6=David|last7=Plummer|first7=Martyn}} This proportion varies in different regions of the world from a high of 25% in Africa to less than 10% in the developed world. Viruses are the usual infectious agents that cause cancer but bacteria and parasites also contribute. Infectious organisms that increase the risk of cancer are frequently a source of DNA damage or genomic instability.

File:HPV causing cervical cancer.jpg

Viral infection is a major risk factor for cervical and liver cancer.{{cite journal | vauthors = De Paoli P, Carbone A | title = Carcinogenic viruses and solid cancers without sufficient evidence of causal association | journal = International Journal of Cancer | volume = 133 | issue = 7 | pages = 1517–29 | date = October 2013 | pmid = 23280523 | doi = 10.1002/ijc.27995 | s2cid = 38402898 | doi-access = free }} A virus that can cause cancer is called an oncovirus. These include human papillomavirus (cervical carcinoma), Epstein–Barr virus (B-cell lymphoproliferative disease and nasopharyngeal carcinoma), Kaposi's sarcoma herpesvirus (Kaposi's sarcoma and primary effusion lymphomas), hepatitis B and hepatitis C viruses (hepatocellular carcinoma), and Human T-cell leukemia virus-1 (T-cell leukemias).

In Western developed countries, human papillomavirus (HPV), hepatitis B virus (HBV) and hepatitis C virus (HCV) are the most common oncoviruses.{{cite journal | vauthors = Anand P, Kunnumakkara AB, Kunnumakara AB, Sundaram C, Harikumar KB, Tharakan ST, Lai OS, Sung B, Aggarwal BB | title = Cancer is a preventable disease that requires major lifestyle changes | journal = Pharmaceutical Research | volume = 25 | issue = 9 | pages = 2097–116 | date = September 2008 | pmid = 18626751 | pmc = 2515569 | doi = 10.1007/s11095-008-9661-9 }}{{Erratum|doi=10.1007/s11095-008-9690-4|pmid=18626751}} In the United States, HPV causes most cervical cancers, as well as some cancers of the vagina, vulva, penis, anus, rectum, throat, tongue and tonsils.{{Cite web|url=https://www.cdc.gov/cancer/hpv/index.htm|title=Human Papillomavirus (HPV) and Cancer|date=January 2, 2018|website=CDC|access-date=March 22, 2018}} Among high-risk HPV viruses, the HPV E6 and E7 oncoproteins inactivate tumor suppressor genes when infecting cells. In addition, the oncoproteins independently induce genomic instability in normal human cells, leading to an increased risk of cancer development.{{cite journal | vauthors = Münger K, Baldwin A, Edwards KM, Hayakawa H, Nguyen CL, Owens M, Grace M, Huh K | title = Mechanisms of human papillomavirus-induced oncogenesis | journal = Journal of Virology | volume = 78 | issue = 21 | pages = 11451–60 | date = November 2004 | pmid = 15479788 | pmc = 523272 | doi = 10.1128/JVI.78.21.11451-11460.2004 }} Individuals with chronic hepatitis B virus infection are more than 200 times more likely to develop liver cancer than uninfected individuals.{{cite book |chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK20828/ | chapter = 21. Hepatitis Viruses |id=NBK20828 | last1 = Sung | first1 = Max W. | last2 = Thung | first2 = Swan N. | last3 = Acs | first3 = George |title={{harvnb|Holland-Frei Cancer Medicine}} |year=2000 | publisher = BC Decker }} Liver cirrhosis, whether from chronic viral hepatitis infection or excessive alcohol use, is independently associated with the development of liver cancer, but the combination of cirrhosis and viral hepatitis presents the highest risk of liver cancer development.

File:Schistosoma bladder histopathology.jpeg eggs within the lining of the bladder.]]Certain bacterial infections also increase the risk of cancer, as seen in Helicobacter pylori-induced gastric carcinoma.{{cite journal | vauthors = Pagano JS, Blaser M, Buendia MA, Damania B, Khalili K, Raab-Traub N, Roizman B | title = Infectious agents and cancer: criteria for a causal relation | journal = Seminars in Cancer Biology | volume = 14 | issue = 6 | pages = 453–71 | date = December 2004 | pmid = 15489139 | doi = 10.1016/j.semcancer.2004.06.009 | author-link2 = Martin J. Blaser }} The mechanism by which H. pylori causes cancer may involve chronic inflammation or the direct action of some of the bacteria's virulence factors.{{Cite journal|last=Hatakeyama|first=Masanori|date=9 December 2005|title=Helicobacter pylori CagA: a new paradigm for bacterial carcinogenesis|journal=Cancer Science|volume=96|issue=12|pages=835–843|doi=10.1111/j.1349-7006.2005.00130.x|pmid=16367902|doi-access=free|pmc=11159386}} Parasitic infections strongly associated with cancer include Schistosoma haematobium (squamous cell carcinoma of the bladder) and the liver flukes, Opisthorchis viverrini and Clonorchis sinensis (cholangiocarcinoma).{{cite journal | vauthors = Samaras V, Rafailidis PI, Mourtzoukou EG, Peppas G, Falagas ME | title = Chronic bacterial and parasitic infections and cancer: a review | journal = Journal of Infection in Developing Countries | volume = 4 | issue = 5 | pages = 267–81 | date = June 2010 | pmid = 20539059 | doi = 10.3855/jidc.819 | url = http://www.jidc.org/index.php/journal/article/download/20539059/387 | format = PDF | doi-access = free }} Inflammation triggered by the worm's eggs appears to be the cancer-causing mechanism. Certain parasitic infections can also increase the presence of carcinogenic compounds in the body, leading to the development of cancers.{{cite book |last=Mustacchi |first=Piero |chapter=22. Parasites| chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK20917/ |title={{harvnb|Holland-Frei Cancer Medicine}} |year=2000 |publisher=BC Decker |id=NBK20917}} Tuberculosis infection, caused by the mycobacterium M. tuberculosis, has also been linked with the development of lung cancer.{{cite journal | vauthors = Pallis AG, Syrigos KN | title = Lung cancer in never smokers: disease characteristics and risk factors | language = en | journal = Critical Reviews in Oncology/Hematology | volume = 88 | issue = 3 | pages = 494–503 | date = December 2013 | pmid = 23921082 | doi = 10.1016/j.critrevonc.2013.06.011 }}

There is evidence that inflammation itself plays an important role in the development and progression of cancer.{{cite journal|vauthors=Taniguchi K, Karin M|date=February 2014|title=IL-6 and related cytokines as the critical lynchpins between inflammation and cancer|journal=Seminars in Immunology|volume=26|issue=1|pages=54–74|doi=10.1016/j.smim.2014.01.001|pmid=24552665}} Chronic inflammation can lead to DNA damage over time and the accumulation of random genetic alterations in cancer cells.{{cite journal | vauthors = Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A | title = Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability | journal = Carcinogenesis | volume = 30 | issue = 7 | pages = 1073–81 | date = July 2009 | pmid = 19468060 | doi = 10.1093/carcin/bgp127 | doi-access = }} Inflammation can contribute to proliferation, survival, angiogenesis and migration of cancer cells by influencing tumor microenvironment.{{cite journal | vauthors = Mantovani A | title = Molecular pathways linking inflammation and cancer | journal = Current Molecular Medicine | volume = 10 | issue = 4 | pages = 369–73 | date = June 2010 | pmid = 20455855 | doi = 10.2174/156652410791316968 }} Individuals with inflammatory bowel disease are at increased risk of developing colorectal cancers.

{{main|Radiation-induced cancer}}

Up to 10% of invasive cancers are related to radiation exposure, including both non-ionizing radiation and ionizing radiation. Unlike chemical or physical triggers for cancer, ionizing radiation hits molecules within cells randomly. If it happens to strike a chromosome, it can break the chromosome, result in an abnormal number of chromosomes, inactivate one or more genes in the part of the chromosome that it hit, delete parts of the DNA sequence, cause chromosome translocations, or cause other types of chromosome abnormalities.{{cite book|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK20793/|title=Cancer medicine|author=Little JB|publisher=B.C. Decker|year=2000|isbn=978-1-55009-113-7|veditors=Kufe DW, Pollock RE, Weichselbaum RR, Bast RC, Gansler TS, Holland JF, Frei E|edition= 6th|location=Hamilton, Ont|chapter=Chapter 14: Ionizing Radiation}} Major damage normally results in the cell dying, but smaller damage may leave a stable, partly functional cell that may be capable of proliferating and developing into cancer, especially if tumor suppressor genes were damaged by the radiation. Three independent stages appear to be involved in the creation of cancer with ionizing radiation: morphological changes to the cell, acquiring cellular immortality (losing normal, life-limiting cell regulatory processes), and adaptations that favor formation of a tumor. Even if the radiation particle does not strike the DNA directly, it triggers responses from cells that indirectly increase the likelihood of mutations.

File:Squamous cell carcinoma (3).jpg on the sun-exposed skin of the nose.]]Not all types of electromagnetic radiation are carcinogenic. Low-energy waves on the electromagnetic spectrum including radio waves, microwaves, infrared radiation and visible light are thought not to be because they have insufficient energy to break chemical bonds. Non-ionizing radio frequency radiation from mobile phones, electric power transmission, and other similar sources have been described as a possible carcinogen by the World Health Organization's International Agency for Research on Cancer.{{cite web|url=http://www.iarc.fr/en/media-centre/pr/2011/pdfs/pr208_E.pdf|title=IARC classifies radiofrequency electromagnetic fields as possibly carcinogenic to humans|work=World Health Organization}}{{Cite web|url=http://monographs.iarc.fr/ENG/Classification/latest_classif.php|title=IARC Monographs- Classifications|website=monographs.iarc.fr|access-date=2018-03-13|archive-url=https://web.archive.org/web/20170610015529/http://monographs.iarc.fr/ENG/Classification/latest_classif.php|archive-date=2017-06-10|url-status=dead}} However, studies have not found a consistent link between cell phone radiation and cancer risk.{{cite web|url=http://www.cancer.gov/cancertopics/factsheet/Risk/cellphones|title=Cell Phones and Cancer Risk - National Cancer Institute|date=2013-05-08|publisher=Cancer.gov|access-date=2013-12-15}}

Higher-energy radiation, including ultraviolet radiation (present in sunlight), x-rays, and gamma radiation, generally is carcinogenic, if received in sufficient doses. Prolonged exposure to ultraviolet radiation from the sun can lead to melanoma and other skin malignancies.{{cite book |vauthors=Cleaver JE, Mitchell DL |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK20854/|title={{harvnb|Holland-Frei Cancer Medicine}} |year=2000 |chapter=15. Ultraviolet Radiation Carcinogenesis |publisher=BC Decker |id=NBK20854}} The vast majority of non-invasive cancers are non-melanoma skin cancers caused by non-ionizing ultraviolet radiation. Clear evidence establishes ultraviolet radiation, especially the non-ionizing medium wave UVB, as the cause of most non-melanoma skin cancers, which are the most common forms of cancer in the world.

File:Meningioma.jpgSources of ionizing radiation include medical imaging, and radon gas. Ionizing radiation is not a particularly strong mutagen. Medical use of ionizing radiation is a growing source of radiation-induced cancers. Ionizing radiation may be used to treat other cancers, but this may, in some cases, induce a second form of cancer. Radiation can cause cancer in most parts of the body, in all animals, and at any age, although radiation-induced solid tumors usually take 10–15 years, and can take up to 40 years, to become clinically manifest, and radiation-induced leukemias typically require 2–10 years to appear. Radiation-induced meningiomas are an uncommon complication of cranial irradiation.{{cite journal | vauthors = Yamanaka R, Hayano A, Kanayama T | title = Radiation-Induced Meningiomas: An Exhaustive Review of the Literature | journal = World Neurosurgery | volume = 97 | pages = 635–644.e8 | date = January 2017 | pmid = 27713063 | doi = 10.1016/j.wneu.2016.09.094 }} Some people, such as those with nevoid basal cell carcinoma syndrome or retinoblastoma, are more susceptible than average to developing cancer from radiation exposure. Children and adolescents are twice as likely to develop radiation-induced leukemia as adults; radiation exposure before birth has ten times the effect.

Ionizing radiation is also used in some kinds of medical imaging. In industrialized countries, medical imaging contributes almost as much radiation dose to the public as natural background radiation. Nuclear medicine techniques involve the injection of radioactive pharmaceuticals directly into the bloodstream. Radiotherapy deliberately deliver high doses of radiation to tumors and surrounding tissues as a form of disease treatment. It is estimated that 0.4% of cancers in 2007 in the United States are due to CTs performed in the past and that this may increase to as high as 1.5–2% with rates of CT usage during this same time period.{{cite journal | vauthors = Brenner DJ, Hall EJ | title = Computed tomography—an increasing source of radiation exposure | journal = The New England Journal of Medicine | volume = 357 | issue = 22 | pages = 2277–84 | date = November 2007 | pmid = 18046031 | doi = 10.1056/NEJMra072149 | s2cid = 2760372 | url = https://repositorio.unal.edu.co/handle/unal/79492 }}

Residential exposure to radon gas has similar cancer risks as passive smoking. Low-dose exposures, such as living near a nuclear power plant, are generally believed to have no or very little effect on cancer development. Radiation is a more potent source of cancer when it is combined with other cancer-causing agents, such as radon gas exposure plus smoking tobacco.

File:Metastatic malignant melanoma, heart.jpg

The development of donor-derived tumors from organ transplants is exceedingly rare. The main cause of organ transplant associated tumors seems to be malignant melanoma, that was undetected at the time of organ harvest.{{cite journal | vauthors = Dingli D, Nowak MA | title = Cancer biology: infectious tumour cells | journal = Nature | volume = 443 | issue = 7107 | pages = 35–6 | date = September 2006 | pmid = 16957717 | pmc = 2711443 | doi = 10.1038/443035a | bibcode = 2006Natur.443...35D }} There have also been reports of Kaposi's sarcoma occurring after transplantation due to tumorous outgrowth of virus-infected donor cells.{{cite journal | vauthors = Barozzi P, Luppi M, Facchetti F, Mecucci C, Alù M, Sarid R, Rasini V, Ravazzini L, Rossi E, Festa S, Crescenzi B, Wolf DG, Schulz TF, Torelli G | title = Post-transplant Kaposi sarcoma originates from the seeding of donor-derived progenitors | journal = Nature Medicine | volume = 9 | issue = 5 | pages = 554–61 | date = May 2003 | pmid = 12692543 | doi = 10.1038/nm862 | s2cid = 2527251 }}

{{see also|Marjolin's ulcer}}

Physical trauma resulting in cancer is relatively rare.{{cite book |vauthors=Gaeta JF |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK20784/|title={{harvnb|Holland-Frei Cancer Medicine}} |year=2000 |chapter=17. Trauma and Inflammation |publisher=BC Decker |id=NBK20784}} Claims that breaking bones resulted in bone cancer, for example, have never been proven. Similarly, physical trauma is not accepted as a cause for cervical cancer, breast cancer, or brain cancer. One accepted source is frequent, long-term application of hot objects to the body. It is possible that repeated burns on the same part of the body, such as those produced by kanger and kairo heaters (charcoal hand warmers), may produce skin cancer, especially if carcinogenic chemicals are also present.

Frequently drinking scalding hot tea may produce esophageal cancer. Generally, it is believed that the cancer arises, or a pre-existing cancer is encouraged, during the process of repairing the trauma, rather than the cancer being caused directly by the trauma. However, repeated injuries to the same tissues might promote excessive cell proliferation, which could then increase the odds of a cancerous mutation.

In the United States, approximately 3,500 pregnant women have a malignancy annually, and transplacental transmission of acute leukemia, lymphoma, melanoma and carcinoma from mother to fetus has been observed.{{cite journal | vauthors = Tolar J, Neglia JP | title = Transplacental and other routes of cancer transmission between individuals | journal = Journal of Pediatric Hematology/Oncology | volume = 25 | issue = 6 | pages = 430–4 | date = June 2003 | pmid = 12794519 | doi = 10.1097/00043426-200306000-00002 }} Excepting the rare transmissions that occur with pregnancies and only a marginal few organ donors, cancer is generally not a transmissible disease. The main reason for this is tissue graft rejection caused by MHC incompatibility. In humans and other vertebrates, the immune system uses MHC antigens to differentiate between "self" and "non-self" cells because these antigens are different from person to person. When non-self antigens are encountered, the immune system reacts against the appropriate cell. Such reactions may protect against tumor cell engraftment by eliminating implanted cells.

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