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| ==Overview== | | ==Overview== |
| The cause of endometrial cancer has not been identified. | | The cause of endometrial cancer has not been identified. |
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| ==Overview== | | ==Overview== |
| Endometrial cancer arises from the epidermal melanocytes, which are neural crest cells involved in the synthesis of melanin (a brown pigment with photoprotective properties). endometrial cancer may be caused by sporadic genetic (e.g. ''[[BRAF]]'' and/or ''[[Ras|N-RAS]]'') or may be part of familial syndromes (e.g. familial atypical multiple mole endometrial cancer syndrome).
| | There are both genetic and environmental causes of endometrial carcinoma. Some of the genetic causes are Hereditary nonpolyposis colon cancer (HNPCC) syndrome.The sporadic colorectal cancers develop from environmental causes. |
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| ==Causes== | | ==Causes== |
| Endometrial cancer arises from the epidermal melanocytes, which are neural crest cells involved in the synthesis of melanin (a brown pigment with photoprotective properties). endometrial cancer may be caused by sporadic genetic mutations (e.g. ''[[BRAF]]'' and/or ''[[Ras|N-RAS]]'') or may be part of familial syndromes.
| | [[Genetic disorder]]s can also cause endometrial cancer. Overall, genetic causes contribute to 2–10% of endometrial cancer cases. |
| ===Sporadic endometrial cancer===
| | [[Lynch syndrome]], an [[autosomal dominant]] genetic disorder that mainly causes [[colorectal cancer]], also causes endometrial cancer, especially before menopause. Women with Lynch syndrome have a 40–60% risk of developing endometrial cancer, higher than their risk of developing colorectal (bowel) or ovarian cancer.<ref name=Hoffman818/> Ovarian and endometrial cancer develop simultaneously in 20% of people. Endometrial cancer nearly always develops before colon cancer, on average, 11 years before.<ref name=Ma>{{cite journal |last1=Ma |first1=J |last2=Ledbetter |first2=N |last3=Glenn |first3=L |year=2013 |title=Testing women with endometrial cancer for lynch syndrome: should we test all? |journal=Journal of the Advanced Practitioner in Oncology |volume=4 |issue=5 |pages=322–30 |doi= |pmid=25032011 |pmc=4093445}}</ref> [[Carcinogenesis]] in Lynch syndrome comes from a mutation in [[MLH1]] and/or [[MLH2]]: genes that participate in the process of [[mismatch repair]], which allows a cell to correct mistakes in the DNA.<ref name=Hoffman818/> Other genes mutated in Lynch syndrome include [[MSH2]], [[MSH6]], and [[PMS2]], which are also mismatch repair genes. Women with Lynch syndrome represent 2–3% of endometrial cancer cases; some sources place this as high as 5%.<ref name=Ma/><ref name=Colombo/> Depending on the gene mutation, women with Lynch syndrome have different risks of endometrial cancer. With MLH1 mutations, the risk is 54%; with MSH2, 21%; and with MSH6, 16%.<ref name=Burke1/> |
| * The majority of cases of endometrial cancer are due to sporadic genetic mutations (90%).
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| * More than one genetic mutation is usually required for the development of endometrial cancer (multiple hits).
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| * The most common mutations that result in the development of endometrial cancer are ''[[BRAF]]'' (approximately 50% of endometrial cancers) and ''[[Ras|N-RAS]]'' (approximately 15% of endometrial cancers).
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| ===Familial endometrial cancer===
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| Endometrial cancer may be caused by hereditary diseases (10%) and is associated with mutations of the ''[[P16 (gene)|P16/CDKN2A]]'' gene:
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| *Familial atypical multiple mole endometrial cancer syndrome (FAMMM syndrome)
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| *endometrial cancer-astrocytoma syndrome
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| * In 10–20% of endometrial cancers, mostly Grade 3 (the highest [[Grading (tumors)|histologic grade]]), [[mutation]]s are found in a [[tumor suppressor]] gene, commonly ''[[TP53]]'' or ''[[PTEN (gene)|PTEN]]''.
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| * In 20% of [[endometrial hyperplasia]]s and 50% of endometrioid cancers, ''[[PTEN]]'' suffers a loss-of-function mutation or a null mutation, making it less effective or completely ineffective.<ref name=ComprehensiveGyn26/> Loss of PTEN function leads to up-regulation of the PI3k/Akt/mTOR pathway, which causes cell growth.<ref name="pmid24078661">{{cite journal| author=Colombo N, Preti E, Landoni F, Carinelli S, Colombo A, Marini C et al.| title=Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. | journal=Ann Oncol | year= 2013 | volume= 24 Suppl 6 | issue= | pages= vi33-8 | pmid=24078661 | doi=10.1093/annonc/mdt353 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24078661 }} </ref>
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| * The ''[[TP53]]'' pathway can either be suppressed or highly activated in endometrial cancer. When a mutant version of ''[[TP53]]'' is overexpressed, the cancer tends to be particularly aggressive. [[TP53]] mutations and chromosome instability are associated with serous carcinomas, which tend to resemble ovarian and Fallopian carcinomas. Serous carcinomas are thought to develop from endometrial intraepithelial carcinoma.<ref name="pmid24078661">{{cite journal| author=Colombo N, Preti E, Landoni F, Carinelli S, Colombo A, Marini C et al.| title=Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. | journal=Ann Oncol | year= 2013 | volume= 24 Suppl 6 | issue= | pages= vi33-8 | pmid=24078661 | doi=10.1093/annonc/mdt353 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24078661 }} </ref>
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| * ''[[PTEN]]'' and ''[[p27 (gene)|p27]]'' loss of function mutations are associated with a good prognosis, particularly in obese women. The ''Her2/neu'' [[oncogene]], which indicates a poor prognosis, is expressed in 20% of endometrioid and serous carcinomas. '''CTNNB1'' (beta-catenin; a [[transcription (genetics)|transcription]] gene) mutations are found in 14–44% of endometrial cancers and may indicate a good prognosis, but the data is unclear. Beta-catenin mutations are commonly found in endometrial cancers with [[squamous cell]]s.<ref name="pmid24078661">{{cite journal| author=Colombo N, Preti E, Landoni F, Carinelli S, Colombo A, Marini C et al.| title=Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up}}. | journal=Ann Oncol | year= 2013 | volume= 24 Suppl 6 | issue= | pages= vi33-8 | pmid=24078661 | doi=10.1093/annonc/mdt353 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24078661 }</ref>
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| * ''[[FGFR2]]'' mutations are found in approximately 10% of endometrial cancers, and their prognostic significance is unclear.<ref name=ComprehensiveGyn26>{{cite book |last1=Thaker |first1=PH |last2=Sood |first2=AK |chapter=Molecular Oncology in Gynecologic Cancer |editor-last1=Lentz |editor-first1=GM |editor-last2=Lobo |editor-first2=RA |editor-last3=Gershenson |editor-first3=DM |editor-last4=Katz |editor-first4=VL|displayeditors=4 |title=Comprehensive Gynecology |edition=6th |isbn=978-0-323-06986-1 |publisher=[[Mosby (publisher)|Mosby]]}}</ref>
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| * ''[[SPOP]]'' is another tumor suppressor gene found to be mutated in some cases of endometrial cancer: 9% of clear cell endometrial carcinomas and 8% of serous endometrial carcinomas have mutations in this gene.<ref>{{cite journal|last1=Mani|first1=RS|title=The emerging role of speckle-type POZ protein (SPOP) in cancer development.|journal=Drug Discovery Today|date=September 2014|volume=19|issue=9|pages=1498–1502|doi=10.1016/j.drudis.2014.07.009|pmid=25058385|quote="A recent exome-sequencing study revealed that 8% of serious endometrial cancers and 9% of clear cell endometrial cancers have SPOP mutations"}}</ref>
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| * Type I and Type II cancers (explained below) tend to have different mutations involved. ''ARID1A'', which often carries a [[point mutation]] in Type I endometrial cancer, is also mutated in 26% of clear cell carcinomas of the endometrium, and 18% of serous carcinomas. [[Gene silencing|Epigenetic silencing]] and [[point mutations]] of several genes are commonly found in Type I endometrial cancer.<ref>International Agency for Research on Cancer (2014). World Cancer Report 2014. World Health Organization. Chapter 5.12. ISBN 978-92-832-0429-9.</ref>
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| * Mutations in tumor suppressor genes are common in Type II endometrial cancer. ''PIK3CA'' is commonly mutated in both Type I and Type II cancers. In women with Lynch syndrome-associated endometrial cancer, [[microsatellite instability]] is common.<ref name="pmid24078661">{{cite journal| author=Colombo N, Preti E, Landoni F, Carinelli S, Colombo A, Marini C et al.| title=Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. | journal=Ann Oncol | year= 2013 | volume= 24 Suppl 6 | issue= | pages= vi33-8 | pmid=24078661 | doi=10.1093/annonc/mdt353 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24078661 }} </ref>
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| * The genetic mutations most commonly associated with endometrioid adenocarcinoma are in the genes ''[[PTEN]]'', a tumor suppressor; ''PIK3CA'', a [[kinase]]; ''[[KRAS]]'', a [[GTPase]] that functions in [[signal transduction]]; and ''CTNNB1'', involved in adhesion and cell signaling. The ''CTNNB1'' (beta-catenin) gene is most commonly mutated in the squamous subtype of endometrioid adenocarcinoma.<ref name=annonc>{{cite journal |last1=Colombo |first1=N |last2=Preti |first2=E |last3=Landoni |first3=F |last4=Carinelli |first4=S |last5=Colombo |first5=A |last6=Marini |first6=C |last7=Sessa |first7=C |year=2011 |title=Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up |journal=Annals of Oncology |volume=22 |issue=Supplement 6 |pages=vi35–vi39 |doi=10.1093/annonc/mdr374 |pmid=21908501}}</ref>
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| * The genetic mutations seen in serous carcinoma are chromosomal instability and mutations in ''[[TP53]]'', an important tumor suppressor gene.<ref name="pmid21975736">{{cite journal| author=Johnson N, Bryant A, Miles T, Hogberg T, Cornes P| title=Adjuvant chemotherapy for endometrial cancer after hysterectomy. | journal=Cochrane Database Syst Rev | year= 2011 | volume= | issue= 10 | pages= CD003175 | pmid=21975736 | doi=10.1002/14651858.CD003175.pub2 | pmc=PMC4164379 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21975736 }} </ref>
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| * The p53 cell signaling system is not active in endometrial clear cell carcinoma.<ref name="pmid21734165">{{cite journal| author=Saso S, Chatterjee J, Georgiou E, Ditri AM, Smith JR, Ghaem-Maghami S| title=Endometrial cancer. | journal=BMJ | year= 2011 | volume= 343 | issue= | pages= d3954 | pmid=21734165 | doi=10.1136/bmj.d3954 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21734165 }} </ref>
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| | Women with a family history of endometrial cancer are at higher risk.<ref name=NCIBooklet/> Two genes most commonly associated with some other women's cancers, [[BRCA1]] and [[BRCA2]], do not cause endometrial cancer.<!--<ref name=Hoffman818/>--> There is an apparent link with these genes but it is attributable to the use of tamoxifen, a drug that itself can cause endometrial cancer, in breast and ovarian cancers.<ref name=Hoffman818/> The inherited genetic condition [[Cowden syndrome]] can also cause endometrial cancer. Women with this disorder have a 5–10% lifetime risk of developing endometrial cancer,<ref name="WCR2014Epi"/> compared to the 2–3% risk for unaffected women.<ref name=Ma/> |
| ==References== | | ==References== |
| {{reflist|2}} | | {{reflist|2}} |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
The cause of endometrial cancer has not been identified.
Overview
There are both genetic and environmental causes of endometrial carcinoma. Some of the genetic causes are Hereditary nonpolyposis colon cancer (HNPCC) syndrome.The sporadic colorectal cancers develop from environmental causes.
Causes
Genetic disorders can also cause endometrial cancer. Overall, genetic causes contribute to 2–10% of endometrial cancer cases.
Lynch syndrome, an autosomal dominant genetic disorder that mainly causes colorectal cancer, also causes endometrial cancer, especially before menopause. Women with Lynch syndrome have a 40–60% risk of developing endometrial cancer, higher than their risk of developing colorectal (bowel) or ovarian cancer.[1] Ovarian and endometrial cancer develop simultaneously in 20% of people. Endometrial cancer nearly always develops before colon cancer, on average, 11 years before.[2] Carcinogenesis in Lynch syndrome comes from a mutation in MLH1 and/or MLH2: genes that participate in the process of mismatch repair, which allows a cell to correct mistakes in the DNA.[1] Other genes mutated in Lynch syndrome include MSH2, MSH6, and PMS2, which are also mismatch repair genes. Women with Lynch syndrome represent 2–3% of endometrial cancer cases; some sources place this as high as 5%.[2][3] Depending on the gene mutation, women with Lynch syndrome have different risks of endometrial cancer. With MLH1 mutations, the risk is 54%; with MSH2, 21%; and with MSH6, 16%.[4]
Women with a family history of endometrial cancer are at higher risk.[5] Two genes most commonly associated with some other women's cancers, BRCA1 and BRCA2, do not cause endometrial cancer. There is an apparent link with these genes but it is attributable to the use of tamoxifen, a drug that itself can cause endometrial cancer, in breast and ovarian cancers.[1] The inherited genetic condition Cowden syndrome can also cause endometrial cancer. Women with this disorder have a 5–10% lifetime risk of developing endometrial cancer,[6] compared to the 2–3% risk for unaffected women.[2]
References
Template:WikiDoc Sources