Obesity and cancer

File:Preventable Causes of Cancer in US.png]]

About 75-80% of all cancers in the United States are preventable, if risk factors are avoided{{cite journal |vauthors=Doll R, Peto R |title=The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today |journal=J. Natl. Cancer Inst. |volume=66 |issue=6 |pages=1191–308 |year=1981 |pmid=7017215 |doi= 10.1093/jnci/66.6.1192}} (also see (Cancer prevention). Obesity appears to be the third most important risk factor for cancer in the United States, just behind tobacco and diet (see Figure). Obesity is the source of about 15% of all preventable cancers.{{cite journal |vauthors=Song M, Giovannucci E |title=Estimating the Influence of Obesity on Cancer Risk: Stratification by Smoking Is Critical |journal=J. Clin. Oncol. |volume=34 |issue=27 |pages=3237–9 |year=2016 |pmid=27458311 |doi=10.1200/JCO.2016.67.6916 }}{{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=Pharm. Res. |volume=25 |issue=9 |pages=2097–116 |year=2008 |pmid=18626751 |pmc=2515569 |doi=10.1007/s11095-008-9661-9 }}{{Erratum|doi=10.1007/s11095-008-9690-4|pmid=18626751|checked=yes}}{{cite web |url=http://www.wcrf.org/int/cancer-facts-figures/preventability-estimates/cancer-preventability-estimates-body-fatness |title=Cancer preventability estimates for body fatness {{!}} World Cancer Research Fund International |website=www.wcrf.org |url-status=dead |archive-url=https://web.archive.org/web/20150217052858/http://www.wcrf.org/int/cancer-facts-figures/preventability-estimates/cancer-preventability-estimates-body-fatness |archive-date=2015-02-17}}

In 2018, Chinese researchers performed a systematic review and comprehensive quantitative meta‐analysis of cohort studies reporting body mass index (BMI) and the risk of 23 cancer types, providing epidemiological evidence supporting the association between BMI and cancer risk. The strongest positive association between BMI and cancer risk was found among patients in North America.{{cite web|title=Cancer risk linked to obesity by Chinese researchers|url=http://webmd.cn/en/obesity-cancer-risk/|publisher=WebMD China|date=April 29, 2018}}

The mechanisms by which obesity may increase the risk of cancer are not well understood, but it is believed that the combined effects of the adipose tissue environment and the endocrine alterations that accompany it among obese people both interact to promote tumor initiation and progression.{{cite journal|last1=Park|first1=J|last2=Morley|first2=TS|last3=Kim|first3=M|last4=Clegg|first4=DJ|last5=Scherer|first5=PE|title=Obesity and cancer--mechanisms underlying tumour progression and recurrence.|journal=Nature Reviews Endocrinology|date=August 2014|volume=10|issue=8|pages=455–65|doi=10.1038/nrendo.2014.94|pmid=24935119|pmc=4374431}} Adipose tissue also creates an inflammatory environment that enhances the ability of tumor cells to metastatize.{{cite journal|last1=Gilbert|first1=Candace A.|last2=Slingerland|first2=Joyce M.|title=Cytokines, Obesity, and Cancer: New Insights on Mechanisms Linking Obesity to Cancer Risk and Progression|journal=Annual Review of Medicine|date=14 January 2013|volume=64|issue=1|pages=45–57|doi=10.1146/annurev-med-121211-091527|pmid=23121183}}

The U.S. National Cancer Institute indicates that one of the main ways in which obesity can cause cancer is by promoting chronic low-level inflammation, which can, over time, cause DNA damage that leads to cancer.{{Cite web|url=https://www.cancer.gov/about-cancer/causes-prevention/risk/obesity/obesity-fact-sheet|title = Obesity and Cancer Fact Sheet - National Cancer Institute|date = 30 November 2020}} Articles supporting this view were reviewed by Cerda et al.{{cite book |vauthors=Cerdá C, Sánchez C, Climent B, Vázquez A, Iradi A, El Amrani F, Bediaga A, Sáez GT |chapter=Oxidative Stress and DNA Damage in Obesity-Related Tumorigenesis |title=Oxidative Stress and Inflammation in Non-communicable Diseases - Molecular Mechanisms and Perspectives in Therapeutics |volume=824 |pages=5–17 |year=2014 |pmid=25038989 |doi=10.1007/978-3-319-07320-0_2 |series=Advances in Experimental Medicine and Biology |isbn=978-3-319-07319-4 }} There are also a number of hormonal, metabolic and other changes caused by obesity that may affect carcinogenesis. A review by Tahergorabi et al. summarizes articles indicating that obesity induces changes in angiogenesis, inflammation, interaction of proinflammatory cytokines, endocrine hormones, adipokines including leptin and adiponectin, insulin, growth factors, estrogen, progesterone and cell metabolism.{{cite journal |vauthors=Tahergorabi Z, Khazaei M, Moodi M, Chamani E |title=From obesity to cancer: a review on proposed mechanisms |journal=Cell Biochem. Funct. |volume=34 |issue=8 |pages=533–545 |year=2016 |pmid=27859423 |doi=10.1002/cbf.3229 |s2cid=205552262 }}

DNA damage appears to be the primary cause of cancer (see Carcinogenesis).{{cite journal | vauthors = Kastan MB | title = DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture | journal = Molecular Cancer Research | volume = 6 | issue = 4 | pages = 517–24 | date = April 2008 | pmid = 18403632 | doi = 10.1158/1541-7786.MCR-08-0020 | doi-access = free }} It is not clear which factor(s) altered by obesity are major source(s) of the DNA damages causing increased cancer risk in obese individuals. However, both reduced DNA repair and increased DNA damage are observed in obese individuals.

As first noted in 2005,{{cite journal |vauthors=Berwick M, Vineis P |title=Measuring DNA repair capacity: small steps |journal=J. Natl. Cancer Inst. |volume=97 |issue=2 |pages=84–5 |year=2005 |pmid=15657333 |doi=10.1093/jnci/dji038 |doi-access=free }} there is evidence that overweight/obesity is associated with reduced DNA repair capacity. This was shown, in particular, in women with breast cancer.{{cite journal |vauthors=Kennedy DO, Agrawal M, Shen J, Terry MB, Zhang FF, Senie RT, Motykiewicz G, Santella RM |title=DNA repair capacity of lymphoblastoid cell lines from sisters discordant for breast cancer |journal=J. Natl. Cancer Inst. |volume=97 |issue=2 |pages=127–32 |year=2005 |pmid=15657342 |doi=10.1093/jnci/dji013 |doi-access=free }}

Lymphocytes from postmenopausal obese women also have reduced DNA repair capacity compared to non-obese postmenopausal women.{{cite journal |vauthors=Tafurt-Cardona Y, Jaramillo-Ruiz LD, Muñoz-Ordóñez W, Muñoz-Benítez SL, Sierra-Torres CH |title=[High frequency of chromosome aberrations observed in lymphocytes in postmenopausal obese women] |language=es|journal=Biomedica |volume=32 |issue=3 |pages=344–54 |year=2012 |pmid=23715183 |doi= 10.7705/biomedica.v32i3.412|doi-access=free }}

If DNA repair is reduced by obesity, this would allow DNA damages to accumulate. Excess DNA damages, when present in replicating cells, can cause an increase in oncogenic mutations through error-prone translesion synthesis during replication.

An 8-fold and 5.6-fold increase in nuclear damage was observed in lymphocytes of obese and overweight children respectively, compared to children of normal weight, evaluated by the gamma-H2AX focus assay.{{cite journal |vauthors=Scarpato R, Verola C, Fabiani B, Bianchi V, Saggese G, Federico G |title=Nuclear damage in peripheral lymphocytes of obese and overweight Italian children as evaluated by the gamma-H2AX focus assay and micronucleus test |journal=FASEB J. |volume=25 |issue=2 |pages=685–93 |year=2011 |pmid=21068397 |doi=10.1096/fj.10-168427 |doi-access=free |s2cid=205366977 }} The gamma-H2AX assay generally reflects the presence of double-strand breaks in DNA, though the assay may indicate other DNA damages as well.{{cite journal |vauthors=Rothkamm K, Barnard S, Moquet J, Ellender M, Rana Z, Burdak-Rothkamm S |title=DNA damage foci: Meaning and significance |journal=Environ. Mol. Mutagen. |volume=56 |issue=6 |pages=491–504 |year=2015 |pmid=25773265 |doi=10.1002/em.21944 |s2cid=32371215 |doi-access=free |bibcode=2015EnvMM..56..491R }} Similarly, there was a 2.7-fold and 2.5-fold increase in micronuclei in lymphocytes of obese and overweight children respectively, compared to children of normal weight. Micronuclei are usually a sign of genotoxic events and chromosomal instability (see Micronucleus).

8-dihydro-2'-deoxyguanosine (8-oxodG) concentration in peripheral blood lymphocytes is an index of nuclear DNA damage. 8-oxodG damages are mutagenic. The level of 8-oxodG was measured in 58 overweight and obese adult patients as well as in 20 normal weight individuals. The level of 8-oxodG correlated positively with body mass, BMI, hip circumference and triglyceride concentration.{{cite journal |vauthors=Karbownik-Lewinska M, Szosland J, Kokoszko-Bilska A, Stępniak J, Zasada K, Gesing A, Lewinski A |title=Direct contribution of obesity to oxidative damage to macromolecules |journal=Neuro Endocrinol. Lett. |volume=33 |issue=4 |pages=453–61 |year=2012 |pmid=22936256 }}

In a study by Donmez-Altuntas et al.,{{cite journal |vauthors=Donmez-Altuntas H, Sahin F, Bayram F, Bitgen N, Mert M, Guclu K, Hamurcu Z, Arıbas S, Gundogan K, Diri H |title=Evaluation of chromosomal damage, cytostasis, cytotoxicity, oxidative DNA damage and their association with body-mass index in obese subjects |journal=Mutat. Res. Genet. Toxicol. Environ. Mutagenesis |volume=771 |pages=30–6 |year=2014 |pmid=25308439 |doi=10.1016/j.mrgentox.2014.06.006 |bibcode=2014MRGTE.771...30D }} 83 obese, 21 over-weight and 21 normal-weight subjects were tested. Frequencies of DNA damages as measured by frequencies of micronuclei, nucleoplasmic bridges and nuclear buds were found to be significantly higher in lymphocytes of obese subjects than in normal-weight and over-weight subjects (p<0.01 and p<0.05) respectively.

Hofer et al.,{{cite journal |vauthors=Hofer T, Karlsson HL, Möller L |title=DNA oxidative damage and strand breaks in young healthy individuals: a gender difference and the role of life style factors |journal=Free Radic. Res. |volume=40 |issue=7 |pages=707–14 |year=2006 |pmid=16983997 |doi= 10.1080/10715760500525807|s2cid=12156155 }} used the enzyme formamidopyrimidine DNA glycosylase (FPG) and gel electrophoresis to measure levels of DNA damage (oxidized purines). They found two factors that can affect DNA damage in a young healthy population. These were fruit intake (high intake; lower DNA damage) and BMI (high BMI; higher DNA damage).

In the study by Tafurt-Cardona et al., described above, where they found reduced DNA repair in obese postmenopausal women, they also found increased DNA damages, as measured by frequencies of chromosome aberrations, in the obese postmenopausal women.

Obesity is associated with an increased risk of bladder cancer.{{cite journal|last1=Sun|first1=JW|last2=Zhao|first2=LG|last3=Yang|first3=Y|last4=Ma|first4=X|last5=Wang|first5=YY|last6=Xiang|first6=YB|title=Obesity and risk of bladder cancer: a dose-response meta-analysis of 15 cohort studies.|journal=PLOS ONE|date=2015|volume=10|issue=3|pages=e0119313|pmid=25803438|doi=10.1371/journal.pone.0119313|pmc=4372289|bibcode=2015PLoSO..1019313S|doi-access=free}}

Obesity has been found to decrease the risk of breast cancer among African and Caucasian women, but increase it among Asian women.{{cite journal|last1=Amadou|first1=A|last2=Ferrari|first2=P|last3=Muwonge|first3=R|last4=Moskal|first4=A|last5=Biessy|first5=C|last6=Romieu|first6=I|last7=Hainaut|first7=P|title=Overweight, obesity and risk of premenopausal breast cancer according to ethnicity: a systematic review and dose-response meta-analysis.|journal=Obesity Reviews|date=August 2013|volume=14|issue=8|pages=665–78|pmid=23615120|doi=10.1111/obr.12028|s2cid=206227792}} Obesity is also associated with decreased survival among women with breast cancer, regardless of whether the cancer is pre- or post-menopausal.{{cite journal|last1=Chan|first1=DS|last2=Vieira|first2=AR|last3=Aune|first3=D|last4=Bandera|first4=EV|last5=Greenwood|first5=DC|last6=McTiernan|first6=A|last7=Navarro Rosenblatt|first7=D|last8=Thune|first8=I|last9=Vieira|first9=R|last10=Norat|first10=T|title=Body mass index and survival in women with breast cancer-systematic literature review and meta-analysis of 82 follow-up studies.|journal=Annals of Oncology|date=October 2014|volume=25|issue=10|pages=1901–14|pmid=24769692|doi=10.1093/annonc/mdu042|pmc=4176449}}

Both general and central obesity are associated with an increased risk of colorectal cancer (CRC).{{Cite journal |last1=Chaplin |first1=Alice |last2=Rodriguez |first2=Ramon Maria |last3=Segura-Sampedro |first3=Juan José |last4=Ochogavía-Seguí |first4=Aina |last5=Romaguera |first5=Dora |last6=Barceló-Coblijn |first6=Gwendolyn |date=January 2022 |title=Insights behind the Relationship between Colorectal Cancer and Obesity: Is Visceral Adipose Tissue the Missing Link? |journal=International Journal of Molecular Sciences |language=en |volume=23 |issue=21 |pages=13128 |doi=10.3390/ijms232113128 |pmid=36361914 |pmc=9655590 |issn=1422-0067 |doi-access=free }} The relative risk among obese people relative to those of normal weight has been reported to be 1.334.{{cite journal|last1=Ma|first1=Y|last2=Yang|first2=Y|last3=Wang|first3=F|last4=Zhang|first4=P|last5=Shi|first5=C|last6=Zou|first6=Y|last7=Qin|first7=H|title=Obesity and risk of colorectal cancer: a systematic review of prospective studies.|journal=PLOS ONE|date=2013|volume=8|issue=1|pages=e53916|pmid=23349764|doi=10.1371/journal.pone.0053916|pmc=3547959|bibcode=2013PLoSO...853916M|doi-access=free}} An association between increased BMI and risk of colorectal adenoma has been reported, as has a dose–response relationship between BMI and colorectal adenoma risk.{{cite journal|last1=Okabayashi|first1=K|last2=Ashrafian|first2=H|last3=Hasegawa|first3=H|last4=Yoo|first4=JH|last5=Patel|first5=VM|last6=Harling|first6=L|last7=Rowland|first7=SP|last8=Ali|first8=M|last9=Kitagawa|first9=Y|last10=Darzi|first10=A|last11=Athanasiou|first11=T|title=Body mass index category as a risk factor for colorectal adenomas: a systematic review and meta-analysis.|journal=The American Journal of Gastroenterology|date=August 2012|volume=107|issue=8|pages=1175–85; quiz 1186|doi=10.1038/ajg.2012.180|pmid=22733302|s2cid=11115062}}{{cite journal|last1=Hong|first1=S|last2=Cai|first2=Q|last3=Chen|first3=D|last4=Zhu|first4=W|last5=Huang|first5=W|last6=Li|first6=Z|title=Abdominal obesity and the risk of colorectal adenoma: a meta-analysis of observational studies.|journal=European Journal of Cancer Prevention|date=November 2012|volume=21|issue=6|pages=523–31|pmid=22343656|doi=10.1097/CEJ.0b013e328351c775|s2cid=19635978}} Increased BMI also increases all-cause mortality and mortality from CRC specifically among people diagnosed with CRC.{{cite journal|last1=Lee|first1=J|last2=Meyerhardt|first2=JA|last3=Giovannucci|first3=E|last4=Jeon|first4=JY|title=Association between body mass index and prognosis of colorectal cancer: a meta-analysis of prospective cohort studies.|journal=PLOS ONE|date=2015|volume=10|issue=3|pages=e0120706|doi=10.1371/journal.pone.0120706|pmid=25811460|pmc=4374868|bibcode=2015PLoSO..1020706L|doi-access=free}}

Obesity has been found to protect against lung cancer, especially among those who smoke or have smoked cigarettes.{{cite journal|last1=Yang|first1=Y|last2=Dong|first2=J|last3=Sun|first3=K|last4=Zhao|first4=L|last5=Zhao|first5=F|last6=Wang|first6=L|last7=Jiao|first7=Y|title=Obesity and incidence of lung cancer: a meta-analysis.|journal=International Journal of Cancer |date=1 March 2013|volume=132|issue=5|pages=1162–9|pmid=22777722|doi=10.1002/ijc.27719|doi-access=free}}

Obesity affects the liver through non-alcoholic fatty liver disease which can cause steatohepatitis which in turn, due to the inflammation caused by the hepatitis, can cause oncogenic changes in hepatocytes. Dietary or genetic obesity induces alterations of the gut microbiota that result in an increased level of deoxycholic acid, a gut bacterial metabolite considered to cause DNA damage leading to liver cancer.{{cite journal |vauthors=Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, Iwakura Y, Oshima K, Morita H, Hattori M, Honda K, Ishikawa Y, Hara E, Ohtani N |title=Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome |journal=Nature |volume=499 |issue=7456 |pages=97–101 |date=July 2013 |pmid=23803760 |doi=10.1038/nature12347 |bibcode=2013Natur.499...97Y |url=}}

Obesity is a risk factor for renal cell cancer.{{cite journal|last1=Wang|first1=F|last2=Xu|first2=Y|title=Body mass index and risk of renal cell cancer: a dose-response meta-analysis of published cohort studies.|journal=International Journal of Cancer |date=1 October 2014|volume=135|issue=7|pages=1673–86|doi=10.1002/ijc.28813|pmid=24615287|doi-access=free}}

Obese people are at a higher risk of thyroid cancer than are their normal weight counterparts.{{cite journal|last1=Schmid|first1=D|last2=Ricci|first2=C|last3=Behrens|first3=G|last4=Leitzmann|first4=MF|title=Adiposity and risk of thyroid cancer: not just a systematic review and meta-analysis.|journal=Obesity Reviews|date=December 2015|volume=16|issue=12|pages=1042–54|doi=10.1111/obr.12321|pmid=26365757|s2cid=22522317|doi-access=free}}

{{Reflist}}

{{Obesity}}

Category:Medical conditions related to obesity

Category:Cancer