Link between smoking and cancer

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Link between smoking and cancer


Landmark studies on the evidence for the carcinogenicity of tobacco were published in 1950[1][2]. Comprehensive epidemiological studies over many years have established a clear link between tobacco smoking and a number of cancer types. There are over 60 known carcinogens in cigarette smoke, the most important of which are polycyclic aromatic hydrocarbons, N-nitrosamines, aromatic amines, 1,3-butadiene, benzene, aldehydes, and ethylene oxide due to their carcinogenicity and levels[3].

Tobacco smoking and tobacco smoke, smokeless tobacco and second-hand tobacco smoke are all classified by the International Agency for Research on Cancer (IARC) as Group 1 carcinogens (carcinogenic to humans)[4]. IARC first classified tobacco smoking as a Group 1 carcinogen in 1986[5], and has since published monographs on the carcinogenic risk of smokeless tobacco[4][6], and updated evidence for tobacco smoking[4][7]. The summary of IARC classifications of evidence for the link between tobacco and specific cancer types can be found in Table 1.

There is sufficient evidence that smoking is a risk factor for 16 cancer types: lung, oral cavity, pharynx, oesophagus, stomach, bowel, liver, pancreas, nasal cavity and paranasal sinuses, larynx, uterine cervix, ovary, urinary bladder, kidney, ureter and bone marrow (myeloid leukaemia)[4]. There is limited evidence for a link between tobacco smoking and breast cancer[4].

There is sufficient evidence that smokeless tobacco (such as chewing tobacco and snuff) are risk factors for cancers of the oral cavity, oesophagus and pancreas[4].


Table 1. IARC levels of evidence for a link between tobacco and different cancer types

Risk factor Sufficient evidence of carcinogenicity Limited evidence of carcinogenicity Evidence suggesting lack of carcinogenicity
Tobacco smoking Oral cavity, pharynx, oesophagus, stomach, bowel, liver, pancreas, nasal cavity and paranasal sinuses, larynx, lung, uterine cervix, ovary, urinary bladder, kidney, ureter, bone marrow (myeloid leukaemia) Female breast Endometrium (postmenopausal), thyroid
Second-hand smoke Lung Larynx, pharynx
Smokeless tobacco Oral cavity, oesophagus, pancreas
Parental smoking (cancer in the offspring) Hepatoblastoma Childhood leukaemia

Source: IARC 2012[4]


The IARC monograph and US Surgeon General’s report on the health consequences of smoking contain detailed reviews of the epidemiological evidence for the link between tobacco and specific cancer types[4][8].

Meta-analyses of the evidence linking tobacco use with cancer show that the risk of developing cancer increases with the amount of tobacco smoked, duration of smoking and earlier starting age[9][10][11][12].

Studies have also demonstrated that the risk of developing cancer decreases with increased time since quitting[9][12][13]. Recent studies have reported that among current smokers, life expectancy drops by 10 years or more[13][14]. However, adults who quit smoking regained some years of life compared with those who continued to smoke[13][14]. Adults who had quit smoking at 25 to 34 years of age gained around 10 years, those who quit aged 35 to 44 gained nine years and those who quit aged 45 to 54 gained about six years of life, compared with those who continued to smoke”[13].

Given that a number of cancer types associated with tobacco use, such as pancreatic cancer, are often diagnosed at an advanced stage and cannot be prevented through any other known lifestyle changes or interventions, avoiding exposure to tobacco smoke is one of the only measures available for actively reducing individual risk[8].

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Biological mechanisms

The U.S. Surgeon General’s report How Tobacco Smoke Causes Disease outlines a number of biological mechanisms involved in the major established pathways of cancer causation by cigarette smoking, involving[3]:

  1. The exposure of the body to carcinogens in the aerodigestive tract, blood, and urine;
  2. The formation of covalent bonds between these carcinogens and DNA (known as DNA adducts); and
  3. The resulting accumulation of permanent mutations in critical genes which lead to uncontrolled cell growth and the development of cancer.

There are over 60 established carcinogens in tobacco smoke. Polycyclic aromatic hydrocarbons (PAH), N-nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N’-nitrosonornicotine (NNN), aromatic amines, 1,3-butadiene, benzene, aldehydes, and ethylene oxide are among the most important carcinogens because of their carcinogenicity and their high levels in cigarette smoke[3].

A number of these carcinogens, and the products that they are metabolised into, are found in the blood, breath and urine of smokers. Most carcinogens in cigarette smoke require metabolic activation to convert them into the form that binds DNA, forming DNA adducts[3].

Persistent DNA adducts can cause miscoding during normal DNA replication. Gene mutations can cause the loss of normal functions that control the growth of cells. Ultimately, this uncontrolled growth leads to cancer[3].

The U.S. Surgeon General’s report outlines the link between a number of tobacco carcinogens and the specific cancer types they are associated with[3]:

  • PAH and NNK are major factors in the development of lung cancer.
  • The particulate phase of cigarette smoke is linked to cancers of the larynx, potentially due to PAH.
  • PAH, NNK, and NNN are the most likely causes of oral cancer.
  • N-nitrosamines, as well as acetaldehyde and formaldehyde, are likely candidates for causing nasal tumours.
  • NNK, several other N-nitrosamines and furan are carcinogenic in the liver.
  • NNK and its major metabolite, known as NNAL, are the only known pancreatic carcinogens in tobacco products.
  • NNK and PAH can reach the cervix in humans and are metabolically activated in these tissues.
  • 4-aminobiphenyl and 2-naphthylamine are known human bladder carcinogens, and aromatic amines are thought to be the major cause of bladder cancer in smokers.
  • The most probable cause of leukaemia in smokers is exposure to benzene.

Further to the action of these specific carcinogens, cigarette smoke causes oxidative damage to cells and alters a range of immunological functions, both of which have the potential to affect tobacco carcinogenesis[3].

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Second-hand tobacco smoke

A study of 2004 data found that in one year, over 600,000 deaths worldwide were attributable to second-hand smoke, accounting for 1.0% of worldwide mortality. The majority (47%) of deaths from second-hand smoke occurred in women, 28% in children, and 26% in men[15].

Involuntary smoking (exposure to second-hand smoke) is classified by IARC as a Group 1 carcinogen. There is sufficient evidence that exposure to second-hand or ‘environmental’ tobacco smoke causes lung cancer in humans, and some limited evidence for a link between exposure to second-hand smoke and cancers of the larynx and pharynx[4][7] (see Table 1). Long-term exposure to second-hand tobacco smoke in the home or workplace can elevate lung cancer risk in a non-smoker by up to 30%[16].

Some studies have suggested that second-hand tobacco smoke may also be a risk factor for cancers of the nasal sinus, naso-pharynx, breast, cervix, bladder and kidney[16][17]. Pre- and postnatal exposure to second-hand tobacco smoke may also increase the risk of brain tumours, lymphomas, and acute lymphocytic leukaemia in children[16][18][19].

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Smoking and alcohol

Smoking and alcohol together have a synergistic effect on upper gastrointestinal and aero-digestive cancer risk, meaning the combined effects exceed the risk from either alone[20]. It has been estimated that over 75% of cancers of the upper aero-digestive tract in developed countries can be attributed to this effect. For example, compared non-smoking non-drinkers, the approximate relative risks for developing mouth and throat cancer are up to seven times greater for those who use tobacco, up to six times greater for those who use alcohol, and 35 times greater for those who are regular heavy users of both tobacco and alcohol[21].

While alcohol is an independent risk factor for oral, pharyngeal, laryngeal and oesophageal cancers, the risk is significantly higher when combined with tobacco smoke[22].

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References

  1. Doll R, Hill AB. Smoking and carcinoma of the lung; preliminary report. Br Med J 1950 Sep 30;2(4682):739-48 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14772469.
  2. Wynder EL, Graham EA. Tobacco smoking as a possible etiologic factor in bronchiogenic carcinoma; a study of 684 proved cases. J Am Med Assoc 1950 May 27;143(4):329-36 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15415260.
  3. 3.0 3.1 3.2 3.3 3.4 3.5 3.6 U.S. Department of Health and Human Services. How tobacco smoke causes disease: the biology and behavioral basis for smoking-attributable disease. A report of the US Surgeon General. Atlanta, Georgia: USDHHS, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2010 Available from: http://www.cdc.gov/tobacco/data_statistics/sgr/index.htm.
  4. 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic risks to humans, volume 100 E. A review of human carcinogens: Personal habits and indoor combustions. Lyon, France: IARC; 2012 Jan 1 Available from: https://monographs.iarc.fr/wp-content/uploads/2018/06/mono100E.pdf.
  5. International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic risks to humans, volume 38. Tobacco smoking. Lyon, France: IARC; 1986.
  6. International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic risks to humans, volume 89. Smokeless tobacco and some tobacco-specific N-nitrosamines. Lyon, France: IARC; 2007.
  7. 7.0 7.1 International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic risks to humans, volume 83. Tobacco smoke and involuntary smoking. Lyon, France: IARC; 2004.
  8. 8.0 8.1 U.S. Department of Health and Human Services. The health consequences of smoking. A report of the Surgeon General. Rockville, MD: USDHHS, Public Health Service, Office of the Surgeon General; 2004.
  9. 9.0 9.1 Lee PN, Forey BA, Coombs KJ. Systematic review with meta-analysis of the epidemiological evidence in the 1900s relating smoking to lung cancer. BMC Cancer 2012 Sep 3;12:385 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22943444.
  10. Lee YC, Cohet C, Yang YC, Stayner L, Hashibe M, Straif K. Meta-analysis of epidemiologic studies on cigarette smoking and liver cancer. Int J Epidemiol 2009 Dec;38(6):1497-511 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19720726.
  11. Research Group for the Development and Evaluation of Cancer Prevention Strategies in Japan, Oze I, Matsuo K, Ito H, Wakai K, Nagata C, et al. Cigarette smoking and esophageal cancer risk: an evaluation based on a systematic review of epidemiologic evidence among the Japanese population. Jpn J Clin Oncol 2012 Jan;42(1):63-73 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22131340.
  12. 12.0 12.1 Bosetti C, Lucenteforte E, Silverman DT, Petersen G, Bracci PM, Ji BT, et al. Cigarette smoking and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (Panc4). Ann Oncol 2012 Jul;23(7):1880-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22104574.
  13. 13.0 13.1 13.2 13.3 Jha P, Ramasundarahettige C, Landsman V, Rostron B, Thun M, Anderson RN, et al. 21st-century hazards of smoking and benefits of cessation in the United States. N Engl J Med 2013 Jan 24;368(4):341-50 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23343063.
  14. 14.0 14.1 Banks E, Joshy G, Weber MF, Liu B, Grenfell R, Egger S, Paige E, Lopez AD, Sitas F and Beral V. Tobacco smoking and all-cause mortality in a large Australian cohort study: findings from a mature epidemic with current low smoking prevalence. BMC Medicine 2019 Apr 23;13:38 Abstract available at http://www.biomedcentral.com/1741-7015/13/38.
  15. Oberg M, Jaakkola MS, Woodward A, Peruga A, Prüss-Ustün A. Worldwide burden of disease from exposure to second-hand smoke: a retrospective analysis of data from 192 countries. Lancet 2011 Jan 8;377(9760):139-46 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21112082.
  16. 16.0 16.1 16.2 U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Coordinating Center for Health Promotion, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health. The health consequences of involuntary exposure to tobacco smoke: A report of the Surgeon General. Atlanta, GA: USDHHS; 2006 Available from: http://www.surgeongeneral.gov/library/reports/secondhandsmoke/report-index.html.
  17. Hemminki K, Chen B. Parental lung cancer as predictor of cancer risks in offspring: clues about multiple routes of harmful influence? Int J Cancer 2006 Feb 1;118(3):744-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16094627.
  18. Chang JS, Selvin S, Metayer C, Crouse V, Golembesky A, Buffler PA. Parental smoking and the risk of childhood leukemia. Am J Epidemiol 2006 Jun 15;163(12):1091-100 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16597704.
  19. Milne E, Greenop KR, Scott RJ, Bailey HD, Attia J, Dalla-Pozza L, et al. Parental prenatal smoking and risk of childhood acute lymphoblastic leukemia. Am J Epidemiol 2012 Jan 1;175(1):43-53 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22143821.
  20. Doll R, Forman D, La Vecchia C, Wouterson R. Alcoholic beverages and cancers of the digestive tract and larynx. Oxford: Blackwell Science Ltd; 1999.
  21. Blot WJ. Alcohol and cancer. Cancer Res 1992 Apr 1;52(7 Suppl):2119s-2123s Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/1544150.
  22. Boyle P, Levin B. World cancer report 2008. Lyon: International Agency for Research on Cancer; 2008 Available from: http://www.iarc.fr/en/publications/pdfs-online/wcr/2008/wcr_2008.pdf.


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