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{{Endometrial cancer}}
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==Overview==
==Overview==
The cause of endometrial cancer has not been identified.
Causes of endometrial cancer include genetic mutations of the ''[[KRAS]]'' gene, ''[[TP53]]'' gene, ''[[P16 (gene)|TP16]]'' gene, and/or ''[[PTEN]]'' gene. Other genetic mutations have also been described.


==Causes==
==Causes==
==Genetics==
Endometrial cancer arises following multiple genetic mutations. The following genes are involved in the development of endometrial cancer:
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|+Mutations found in Type I and Type II endometrial cancers<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>  
|+Mutations found in Type I and Type II endometrial cancers<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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* In 10–20% of endometrial cancers, mostly Grade&nbsp;3 (the highest [[Grading (tumors)|histologic grade]]), [[mutation]]s are found in a [[tumor suppressor]] gene, commonly ''[[TP53]]'' or ''[[PTEN (gene)|PTEN]]''.
* 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>
* 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>
* ''[[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>
* ''[[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>
* ''[[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>
* 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>
* 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>
* 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>
* 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>
* 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>
==Microscopic Patho
==References==
==References==
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{{reflist|2}}
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Latest revision as of 22:15, 26 November 2017

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Monalisa Dmello, M.B,B.S., M.D. [2]

Overview

Causes of endometrial cancer include genetic mutations of the KRAS gene, TP53 gene, TP16 gene, and/or PTEN gene. Other genetic mutations have also been described.

Causes

Endometrial cancer arises following multiple genetic mutations. The following genes are involved in the development of endometrial cancer:

Mutations found in Type I and Type II endometrial cancers[1]
Gene mutated Mutation type Type I prevalence Type II prevalence
ARID1A point mutation 40% unknown
CTNNB1 point mutation 14–44% unknown
FGFR2 point mutation 16% unknown
KRAS point mutation 10–20% unknown
PIK3R1 point mutation 43% unknown
TP53 point mutation 10–20% 90%
PTEN point mutation 37–61% unknown
MLH1 epigenetic silencing 30% unknown
RASSF1A epigenetic silencing 48% unknown
SPRY2 epigenetic silencing 20% unknown
PPP2R1A point mutation unknown 17–41%
CDH1 loss of heterozygosity unknown 80–90%
CDKN2A loss of heterozygosity and/or
epigenetic silencing
20% 40%
PIK3CA (oncogene) amplification 24–39% 20–30%
PIK3R1 (oncogene) point mutation unknown 12%
STK15 (oncogene) amplification unknown 60%
CCNE1 (oncogene) amplification unknown 55%
ERBB2 (oncogene) amplification unknown 30%
CCND1 (oncogene) amplification unknown 26%

References

  1. International Agency for Research on Cancer (2014). World Cancer Report 2014. World Health Organization. Chapter 5.12. ISBN 978-92-832-0429-9.


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