Editing Cervical cancer (section)

==Causes==
[[File:Figure 28 02 08.JPG|thumb|In most cases, cells infected with the HPV heal on their own. In some cases, however, the virus continues to spread and becomes an invasive cancer.]]
[[File:Figure 28 02 06.JPG|thumb|Cervix in relation to upper part of vagina and posterior portion of uterus, showing difference in covering epithelium of inner structures]]
Infection with some types of HPV is the greatest risk factor for cervical cancer, followed by smoking.<ref name="GadducciBarsotti2011">{{cite journal |vauthors= Gadducci A, Barsotti C, Cosio S, Domenici L, Riccardo Genazzani A |title=Smoking habit, immune suppression, oral contraceptive use, and hormone replacement therapy use and cervical carcinogenesis: a review of the literature |journal=Gynecological Endocrinology |volume=27 |issue=8 |pages=597–604 |date=August 2011 |pmid=21438669 |doi=10.3109/09513590.2011.558953 |s2cid=25447563 }}</ref> [[HIV]] infection is also a risk factor.<ref name="GadducciBarsotti2011"/> Not all of the causes of cervical cancer are known, however, and several other contributing factors have been implicated.<ref>{{cite book |title=Gynaecology by Ten Teachers | vauthors = Campbell S, Monga A |edition=18th |year=2006 |publisher=Hodder Education |isbn=978-0-340-81662-2 |url-access=registration |url=https://archive.org/details/gynaecology0000unse }}</ref><ref>{{cite web|url=https://www.medicinenet.com/cervical_cancer/article.htm#cervical_cancer_facts|title=Cervical Cancer Symptoms, Signs, Causes, Stages & Treatment|website=medicinenet.com}}</ref>

===Human papillomavirus===
[[Human papillomavirus infection|Infection with HPV]] is generally believed to be required for cervical cancer to occur.<ref name=pmid16362994>{{cite journal | vauthors = Snijders PJ, Steenbergen RD, Heideman DA, Meijer CJ | title = HPV-mediated cervical carcinogenesis: concepts and clinical implications | journal = The Journal of Pathology | volume = 208 | issue = 2 | pages = 152–164 | date = January 2006 | pmid = 16362994 | doi = 10.1002/path.1866 | s2cid = 25400770 | doi-access = free }}</ref> HPV types 16 and 18 are the cause of 75% of cervical cancer cases globally, while 31 and 45 are the causes of another 10%.<ref>{{cite book| veditors = Dillman RK, Oldham RO |title=Principles of cancer biotherapy |year=2009 |publisher=Springer |location=Dordrecht|isbn=978-90-481-2289-9|page=149|url=https://books.google.com/books?id=emGC_fRJH_IC&pg=PA149|edition=5th |url-status=live|archive-url=https://web.archive.org/web/20151029195259/https://books.google.com/books?id=emGC_fRJH_IC&pg=PA149|archive-date=29 October 2015}}</ref>

Women who have multiple sexual partners, or have partners who have multiple sexual partners, regardless of sex are at higher risk of cervical cancer.<ref name="ACS What Causes">{{cite web|url=http://www.cancer.org/docroot/CRI/content/CRI_2_2_2X_What_causes_cancer_of_the_cervix_Can_it_be_prevented_8.asp?sitearea= |title=What Causes Cancer of the Cervix? |access-date=2 December 2007 |date=30 November 2006 |publisher=[[American Cancer Society]] |archive-url = https://web.archive.org/web/20071013160516/http://cancer.org/docroot/CRI/content/CRI_2_2_2X_What_causes_cancer_of_the_cervix_Can_it_be_prevented_8.asp?sitearea= <!-- Bot retrieved archive --> |archive-date = 13 October 2007}}</ref><ref name=pmid11392939>{{cite journal | vauthors = Marrazzo JM, Koutsky LA, Kiviat NB, Kuypers JM, Stine K | title = Papanicolaou test screening and prevalence of genital human papillomavirus among women who have sex with women | journal = American Journal of Public Health | volume = 91 | issue = 6 | pages = 947–952 | date = June 2001 | pmid = 11392939 | pmc = 1446473 | doi = 10.2105/AJPH.91.6.947 }}</ref>

Over 200 types of HPV known,<ref name=":4">{{Cite web |date=2019-03-01 |title=HPV and Cancer - NCI |url=https://www.cancer.gov/about-cancer/causes-prevention/risk/infectious-agents/hpv-and-cancer |access-date=2024-02-13 |website=www.cancer.gov |language=en}}</ref> 12 are classified as high-risk types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59),<ref name=":4" /> three as probable high-risk (26, 53, and 66), and 12 as low-risk (6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, and CP6108).<ref name=pmid12571259>{{cite journal |vauthors = Muñoz N, Bosch FX, de Sanjosé S, Herrero R, Castellsagué X, Shah KV, Snijders PJ, Meijer CJ |display-authors = 6 |title = Epidemiologic classification of human papillomavirus types associated with cervical cancer |journal = The New England Journal of Medicine |volume = 348 |issue = 6 |pages = 518–527 |date = February 2003 |pmid = 12571259 |doi = 10.1056/NEJMoa021641 |hdl-access = free |hdl = 2445/122831 |s2cid = 1451343 |url = https://revistasojs.ucaldas.edu.co/index.php/hacialapromociondelasalud/article/view/2173 }}</ref> Most cases of squamous cell carcinomas of the cervix are due to HPV type 16 and most cases of adenocarcinoma are due to HPV type 18.<ref name="Tewari 2025" /> High risk HPV viral subtypes can integrate their DNA into the host genome and induce [[transcription (biology)|transcription]] of the viral cancer causing proteins E6 and E7.<ref name="Tewari 2025" /><ref name="Peng 2024">{{cite journal |last1=Peng |first1=Qiu |last2=Wang |first2=Lujuan |last3=Zuo |first3=Liang |last4=Gao |first4=Shuichao |last5=Jiang |first5=Xianjie |last6=Han |first6=Yaqian |last7=Lin |first7=Jinguan |last8=Peng |first8=Mingjing |last9=Wu |first9=Nayiyuan |last10=Tang |first10=Yanyan |last11=Tian |first11=Hao |last12=Zhou |first12=Yujuan |last13=Liao |first13=Qianjin |title=HPV E6/E7: insights into their regulatory role and mechanism in signaling pathways in HPV-associated tumor |journal=Cancer Gene Therapy |date=January 2024 |volume=31 |issue=1 |pages=9–17 |doi=10.1038/s41417-023-00682-3}}</ref> E6 degrades the tumor suppressing protein [[p53]] and E7 degrades and inactivates the tumor suppressing protein [[pRb]]. The loss of p53 and pRb leads to increased blood vessel growth feeding tumors (via [[vascular endothelial growth factor]](VEGF) over-expression), loss of tumor cell suppression and [[cell cycle]] regulation disruptions all of which can lead to cervical cancer.<ref name="Tewari 2025" />

[[Genital wart]]s, which are a form of [[benign tumor]] of [[epithelium|epithelial]] cells, are also caused by various strains of HPV. However, these serotypes are usually not related to cervical cancer. Having multiple strains at the same time is common, including those that can cause cervical cancer along with those that cause warts.

=== Smoking ===
[[File:RICO tobacco litigation corrective statement, Whitehall, PA (cropped).jpg|thumb|A [[United States v. Philip Morris|court-ordered]] corrective statement: "Smoking also causes reduced fertility, low birth weight in newborns, and cancer of the cervix" (United States, 2024).]]

[[Tobacco smoking|Cigarette smoking]], both active and passive, increases the risk of cervical cancer. Among HPV-infected women, current and former smokers have roughly two to three times the incidence of invasive cancer. Passive smoking is also associated with increased risk but to a lesser extent.<ref name="NIHNCIHPV2015">{{cite web | publisher = National Cancer Institute, National Institutes of Health | work = PDQ |  url = http://cancer.gov/cancertopics/pdq/prevention/cervical/HealthProfessional | title = Cervical Cancer Prevention | date = 26 December 2022 | location = Bethesda, MD }}</ref>

Smoking has also been linked to the development of cervical cancer.<ref name=LuhnWalker2013>{{cite journal |vauthors = Luhn P, Walker J, Schiffman M, Zuna RE, Dunn ST, Gold MA, Smith K, Mathews C, Allen RA, Zhang R, Wang S, Wentzensen N |display-authors = 6 |title = The role of co-factors in the progression from human papillomavirus infection to cervical cancer |journal = Gynecologic Oncology |volume = 128 |issue = 2 |pages = 265–270 |date = February 2013 |pmid = 23146688 |pmc = 4627848 |doi = 10.1016/j.ygyno.2012.11.003 }}</ref><ref name=RemschmidtKaufmann2013>{{cite journal | vauthors = Remschmidt C, Kaufmann AM, Hagemann I, Vartazarova E, Wichmann O, Deleré Y | title = Risk factors for cervical human papillomavirus infection and high-grade intraepithelial lesion in women aged 20 to 31 years in Germany | journal = International Journal of Gynecological Cancer | volume = 23 | issue = 3 | pages = 519–526 | date = March 2013 | pmid = 23360813 | doi = 10.1097/IGC.0b013e318285a4b2 | s2cid = 205679729 | doi-access = free }}</ref><ref name=GadducciBarsotti2011/> Smoking can increase the risk in women a few different ways, which can be by direct and indirect methods of inducing cervical cancer.<ref name=LuhnWalker2013/><ref name=GadducciBarsotti2011/><ref name=AgorastosMiliaras2005>{{cite journal | vauthors = Agorastos T, Miliaras D, Lambropoulos AF, Chrisafi S, Kotsis A, Manthos A, Bontis J | title = Detection and typing of human papillomavirus DNA in uterine cervices with coexistent grade I and grade III intraepithelial neoplasia: biologic progression or independent lesions? | journal = European Journal of Obstetrics, Gynecology, and Reproductive Biology | volume = 121 | issue = 1 | pages = 99–103 | date = July 2005 | pmid = 15949888 | doi = 10.1016/j.ejogrb.2004.11.024 }}</ref> A direct way of contracting this cancer is a smoker has a higher chance of [[cervical intraepithelial neoplasia]] (CIN3) occurring, which has the potential of forming cervical cancer.<ref name=LuhnWalker2013/> When CIN3 lesions lead to cancer, most of them have the assistance of the HPV virus, but that is not always the case, which is why it can be considered a direct link to cervical cancer.<ref name=AgorastosMiliaras2005/> Heavy smoking and long-term smoking seem to have more of a risk of getting the CIN3 lesions than lighter smoking or not smoking at all.<ref name=JensenSchmiedel2012>{{cite journal | vauthors = Jensen KE, Schmiedel S, Frederiksen K, Norrild B, Iftner T, Kjær SK | title = Risk for cervical intraepithelial neoplasia grade 3 or worse in relation to smoking among women with persistent human papillomavirus infection | journal = Cancer Epidemiology, Biomarkers & Prevention | volume = 21 | issue = 11 | pages = 1949–1955 | date = November 2012 | pmid = 23019238 | pmc = 3970163 | doi = 10.1158/1055-9965.EPI-12-0663 }}</ref> Although smoking has been linked to cervical cancer, it aids in the development of HPV, which is the leading cause of this type of cancer.<ref name=GadducciBarsotti2011/> Also, not only does it aid in the development of HPV, but also if the woman is already HPV-positive, she is at an even greater likelihood of contracting cervical cancer.<ref name=JensenSchmiedel2012/>

===Oral contraceptives===
Long-term use of [[Oral contraceptive pill|oral contraceptives]] is associated with increased risk of cervical cancer in women who have had [[Human papillomavirus infection|HPV]]. Women who have used oral contraceptives for 5 to 9 years have about three times the incidence of invasive cancer, and those who used them for 10 years or longer have about four times the risk.<ref name=NIHNCIHPV2015/><ref>{{cite journal | vauthors = Asthana S, Busa V, Labani S | title = Oral contraceptives use and risk of cervical cancer-A systematic review & meta-analysis | journal = European Journal of Obstetrics, Gynecology, and Reproductive Biology | volume = 247 | pages = 163–175 | date = April 2020 | pmid = 32114321 | doi = 10.1016/j.ejogrb.2020.02.014 | s2cid = 211728228 }}</ref>

===Multiple pregnancies===
Having many pregnancies is associated with an increased risk of cervical cancer. Among HPV-infected women, those who have had seven or more full-term pregnancies have around four times the risk of cancer compared with women with no pregnancies, and two to three times the risk of women who have had one or two full-term pregnancies.<ref name=NIHNCIHPV2015/>