Obesity and cancer

The association between obesity, as defined by a body mass index of 30 or higher, and risk of a variety of types of cancer has received a considerable amount of attention in recent years.[1] Obesity has been associated with an increased risk of esophageal cancer, pancreatic cancer, colorectal cancer, breast cancer (among postmenopausal women), endometrial cancer, kidney cancer, thyroid cancer, liver cancer and gallbladder cancer.[2] Obesity may also lead to increased cancer-related mortality.[1] Obesity has also been described as the fat tissue disease version of cancer, where common features between the two diseases were suggested for the first time.[3]

## Contents

* 1 Importance of obesity in causing cancer
* 2 Mechanisms
* 2.1 Reduced DNA repair
* 2.2 Increased DNA damage
* 3 Association by cancer site
* 3.1 Bladder cancer
* 3.2 Breast cancer
* 3.3 Colorectal cancer
* 3.4 Lung cancer
* 3.5 Liver cancer
* 3.6 Renal cell cancer
* 3.7 Thyroid cancer
* 4 References

## Importance of obesity in causing cancer[edit | edit source]

The approximate relative levels of the preventable causes of cancer in the United States, taken from the article Cancer prevention.

About 75-80% of all cancers in the United States are preventable, if risk factors are avoided[4] (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.[5][6][7]

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.[8]

## Mechanisms[edit | edit source]

The mechanisms by which obesity may increase the risk of cancer are not well understood,[1] 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.[9] Adipose tissue also creates an inflammatory environment that enhances the ability of tumor cells to metastatize.[10]

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.[11] Articles supporting this view were reviewed by Cerda et al.[12] There are also a number of hormonal, metabolic and other changes caused by obesity that may affect carcinogenesis.[11] 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.[13]

DNA damage appears to be the primary cause of cancer (see Carcinogenesis).[14] 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.

### Reduced DNA repair[edit | edit source]

As first noted in 2005,[15] there is evidence that overweight/obesity is associated with reduced DNA repair capacity. This was shown, in particular, in women with breast cancer.[16]

Lymphocytes from postmenopausal obese women also have reduced DNA repair capacity compared to non-obese postmenopausal women.[17]

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.

### Increased DNA damage[edit | edit source]

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.[18] The gamma-H2AX assay generally reflects the presence of double-strand breaks in DNA, though the assay may indicate other DNA damages as well.[19] 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.[18] 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.[20]

In a study by Donmez-Altuntas et al.,[21] 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.,[22] 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.[17]

## Association by cancer site[edit | edit source]

### Bladder cancer[edit | edit source]

Obesity is associated with an increased risk of bladder cancer.[23]

### Breast cancer[edit | edit source]

Obesity has been found to decrease the risk of breast cancer among African and Caucasian women, but increase it among Asian women.[24] Obesity is also associated with decreased survival among women with breast cancer, regardless of whether the cancer is pre- or post-menopausal.[25]

### Colorectal cancer[edit | edit source]

Both general and central obesity are associated with an increased risk of colorectal cancer (CRC).[26] The relative risk among obese people relative to those of normal weight has been reported to be 1.334.[27] 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.[28][29] Increased BMI also increases all-cause mortality and mortality from CRC specifically among people diagnosed with CRC.[30]

### Lung cancer[edit | edit source]

Obesity has been found to protect against lung cancer, especially among those who smoke or have smoked cigarettes.[31]

### Liver cancer[edit | edit source]

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.

### Renal cell cancer[edit | edit source]

Obesity is a risk factor for renal cell cancer.[32]

### Thyroid cancer[edit | edit source]

Obese people are at a higher risk of thyroid cancer than are their normal weight counterparts.[33]

## References[edit | edit source]

1. ↑ 1.0 1.1 1.2 Vucenik, I; Stains, JP (October 2012). "Obesity and cancer risk: evidence, mechanisms, and recommendations". Annals of the New York Academy of Sciences. 1271 (1): 37–43. Bibcode:2012NYASA1271...37V. doi:10.1111/j.1749-6632.2012.06750.x. PMC 3476838. PMID 23050962.
2. ↑ "Obesity and Cancer Risk". National Cancer Institute. Archived from the original on 4 July 2015. Retrieved 28 August 2015.
3. ↑ Boubertakh, Besma; Silvestri, Cristoforo; Di Marzo, Vincenzo (9 June 2022). "Obesity: The Fat Tissue Disease Version of Cancer". Cells. 11 (12): 1872. doi:10.3390/cells11121872. PMID 35741001.
4. ↑ Doll R, Peto R (1981). "The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today". J. Natl. Cancer Inst. 66 (6): 1191–308. doi:10.1093/jnci/66.6.1192. PMID 7017215.
5. ↑ Song M, Giovannucci E (2016). "Estimating the Influence of Obesity on Cancer Risk: Stratification by Smoking Is Critical". J. Clin. Oncol. 34 (27): 3237–9. doi:10.1200/JCO.2016.67.6916. PMID 27458311.
6. ↑ Anand P, Kunnumakkara AB, Kunnumakara AB, Sundaram C, Harikumar KB, Tharakan ST, Lai OS, Sung B, Aggarwal BB (2008). "Cancer is a preventable disease that requires major lifestyle changes". Pharm. Res. 25 (9): 2097–116. doi:10.1007/s11095-008-9661-9. PMC 2515569. PMID 18626751.
7. ↑ "Cancer preventability estimates for body fatness | World Cancer Research Fund International". www.wcrf.org. Archived from the original on 2015-02-17.
8. ↑ "Cancer risk linked to obesity by Chinese researchers". WebMD China. April 29, 2018.`{{cite web}}`: CS1 maint: url-status (link)
9. ↑ Park, J; Morley, TS; Kim, M; Clegg, DJ; Scherer, PE (August 2014). "Obesity and cancer--mechanisms underlying tumour progression and recurrence". Nature Reviews Endocrinology. 10 (8): 455–65. doi:10.1038/nrendo.2014.94. PMC 4374431. PMID 24935119.
10. ↑ Gilbert, Candace A.; Slingerland, Joyce M. (14 January 2013). "Cytokines, Obesity, and Cancer: New Insights on Mechanisms Linking Obesity to Cancer Risk and Progression". Annual Review of Medicine. 64 (1): 45–57. doi:10.1146/annurev-med-121211-091527. PMID 23121183.
11. ↑ 11.0 11.1 "Obesity and Cancer Fact Sheet - National Cancer Institute". 30 November 2020. Archived from the original on 5 July 2018. Retrieved 19 January 2023.
12. ↑ Cerdá C, Sánchez C, Climent B, Vázquez A, Iradi A, El Amrani F, Bediaga A, Sáez GT (2014). "Oxidative stress and DNA damage in obesity-related tumorigenesis". Oxidative Stress and Inflammation in Non-communicable Diseases - Molecular Mechanisms and Perspectives in Therapeutics. Adv. Exp. Med. Biol. Advances in Experimental Medicine and Biology. Vol. 824\. pp. 5–17. doi:10.1007/978-3-319-07320-0_2. ISBN 978-3-319-07319-4. PMID 25038989.
13. ↑ Tahergorabi Z, Khazaei M, Moodi M, Chamani E (2016). "From obesity to cancer: a review on proposed mechanisms". Cell Biochem. Funct. 34 (8): 533–545. doi:10.1002/cbf.3229. PMID 27859423. S2CID 205552262.
14. ↑ Kastan MB (April 2008). "DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture". Molecular Cancer Research. 6 (4): 517–24. doi:10.1158/1541-7786.MCR-08-0020. PMID 18403632.
15. ↑ Berwick M, Vineis P (2005). "Measuring DNA repair capacity: small steps". J. Natl. Cancer Inst. 97 (2): 84–5. doi:10.1093/jnci/dji038. PMID 15657333.
16. ↑ Kennedy DO, Agrawal M, Shen J, Terry MB, Zhang FF, Senie RT, Motykiewicz G, Santella RM (2005). "DNA repair capacity of lymphoblastoid cell lines from sisters discordant for breast cancer". J. Natl. Cancer Inst. 97 (2): 127–32. doi:10.1093/jnci/dji013. PMID 15657342.
17. ↑ 17.0 17.1 Tafurt-Cardona Y, Jaramillo-Ruiz LD, Muñoz-Ordóñez W, Muñoz-Benítez SL, Sierra-Torres CH (2012). "[High frequency of chromosome aberrations observed in lymphocytes in postmenopausal obese women]". Biomedica (in español). 32 (3): 344–54. doi:10.7705/biomedica.v32i3.412. PMID 23715183.
18. ↑ 18.0 18.1 Scarpato R, Verola C, Fabiani B, Bianchi V, Saggese G, Federico G (2011). "Nuclear damage in peripheral lymphocytes of obese and overweight Italian children as evaluated by the gamma-H2AX focus assay and micronucleus test". FASEB J. 25 (2): 685–93. doi:10.1096/fj.10-168427. PMID 21068397. S2CID 205366977.
19. ↑ Rothkamm K, Barnard S, Moquet J, Ellender M, Rana Z, Burdak-Rothkamm S (2015). "DNA damage foci: Meaning and significance". Environ. Mol. Mutagen. 56 (6): 491–504. doi:10.1002/em.21944. PMID 25773265. S2CID 32371215.
20. ↑ Karbownik-Lewinska M, Szosland J, Kokoszko-Bilska A, Stępniak J, Zasada K, Gesing A, Lewinski A (2012). "Direct contribution of obesity to oxidative damage to macromolecules". Neuro Endocrinol. Lett. 33 (4): 453–61. PMID 22936256.
21. ↑ Donmez-Altuntas H, Sahin F, Bayram F, Bitgen N, Mert M, Guclu K, Hamurcu Z, Arıbas S, Gundogan K, Diri H (2014). "Evaluation of chromosomal damage, cytostasis, cytotoxicity, oxidative DNA damage and their association with body-mass index in obese subjects". Mutat. Res. Genet. Toxicol. Environ. Mutagenesis. 771: 30–6. doi:10.1016/j.mrgentox.2014.06.006. PMID 25308439.
22. ↑ Hofer T, Karlsson HL, Möller L (2006). "DNA oxidative damage and strand breaks in young healthy individuals: a gender difference and the role of life style factors". Free Radic. Res. 40 (7): 707–14. doi:10.1080/10715760500525807. PMID 16983997. S2CID 12156155.
23. ↑ Sun, JW; Zhao, LG; Yang, Y; Ma, X; Wang, YY; Xiang, YB (2015). "Obesity and risk of bladder cancer: a dose-response meta-analysis of 15 cohort studies". PLOS ONE. 10 (3): e0119313. Bibcode:2015PLoSO..1019313S. doi:10.1371/journal.pone.0119313. PMC 4372289. PMID 25803438.
24. ↑ Amadou, A; Ferrari, P; Muwonge, R; Moskal, A; Biessy, C; Romieu, I; Hainaut, P (August 2013). "Overweight, obesity and risk of premenopausal breast cancer according to ethnicity: a systematic review and dose-response meta-analysis". Obesity Reviews. 14 (8): 665–78. doi:10.1111/obr.12028. PMID 23615120. S2CID 206227792.
25. ↑ Chan, DS; Vieira, AR; Aune, D; Bandera, EV; Greenwood, DC; McTiernan, A; Navarro Rosenblatt, D; Thune, I; Vieira, R; Norat, T (October 2014). "Body mass index and survival in women with breast cancer-systematic literature review and meta-analysis of 82 follow-up studies". Annals of Oncology. 25 (10): 1901–14. doi:10.1093/annonc/mdu042. PMC 4176449. PMID 24769692.
26. ↑ Chaplin, Alice; Rodriguez, Ramon Maria; Segura-Sampedro, Juan José; Ochogavía-Seguí, Aina; Romaguera, Dora; Barceló-Coblijn, Gwendolyn (January 2022). "Insights behind the Relationship between Colorectal Cancer and Obesity: Is Visceral Adipose Tissue the Missing Link?". International Journal of Molecular Sciences. 23 (21): 13128. doi:10.3390/ijms232113128. ISSN 1422-0067. Archived from the original on 2023-02-02. Retrieved 2023-01-19.
27. ↑ Ma, Y; Yang, Y; Wang, F; Zhang, P; Shi, C; Zou, Y; Qin, H (2013). "Obesity and risk of colorectal cancer: a systematic review of prospective studies". PLOS ONE. 8 (1): e53916. Bibcode:2013PLoSO...853916M. doi:10.1371/journal.pone.0053916. PMC 3547959. PMID 23349764.
28. ↑ Okabayashi, K; Ashrafian, H; Hasegawa, H; Yoo, JH; Patel, VM; Harling, L; Rowland, SP; Ali, M; Kitagawa, Y; Darzi, A; Athanasiou, T (August 2012). "Body mass index category as a risk factor for colorectal adenomas: a systematic review and meta-analysis". The American Journal of Gastroenterology. 107 (8): 1175–85, quiz 1186. doi:10.1038/ajg.2012.180. PMID 22733302. S2CID 11115062.
29. ↑ Hong, S; Cai, Q; Chen, D; Zhu, W; Huang, W; Li, Z (November 2012). "Abdominal obesity and the risk of colorectal adenoma: a meta-analysis of observational studies". European Journal of Cancer Prevention. 21 (6): 523–31. doi:10.1097/CEJ.0b013e328351c775. PMID 22343656. S2CID 19635978.
30. ↑ Lee, J; Meyerhardt, JA; Giovannucci, E; Jeon, JY (2015). "Association between body mass index and prognosis of colorectal cancer: a meta-analysis of prospective cohort studies". PLOS ONE. 10 (3): e0120706. Bibcode:2015PLoSO..1020706L. doi:10.1371/journal.pone.0120706. PMC 4374868. PMID 25811460.
31. ↑ Yang, Y; Dong, J; Sun, K; Zhao, L; Zhao, F; Wang, L; Jiao, Y (1 March 2013). "Obesity and incidence of lung cancer: a meta-analysis". International Journal of Cancer. 132 (5): 1162–9. doi:10.1002/ijc.27719. PMID 22777722.
32. ↑ Wang, F; Xu, Y (1 October 2014). "Body mass index and risk of renal cell cancer: a dose-response meta-analysis of published cohort studies". International Journal of Cancer. 135 (7): 1673–86. doi:10.1002/ijc.28813. PMID 24615287.
33. ↑ Schmid, D; Ricci, C; Behrens, G; Leitzmann, MF (December 2015). "Adiposity and risk of thyroid cancer: not just a systematic review and meta-analysis". Obesity Reviews. 16 (12): 1042–54. doi:10.1111/obr.12321. PMID 26365757. S2CID 22522317.