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| __NOTOC__ | | __NOTOC__ |
| {{Endometrial cancer}} | | {{Endometrial cancer}} |
| {{CMG}} | | {{CMG}}{{AE}}{{MD}} |
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| ==Overview==
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| 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).
| | 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. |
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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.
| | Endometrial cancer arises following multiple genetic mutations. The following genes are involved in the development of endometrial cancer: |
| ===Sporadic endometrial cancer=== | | {| <!--Placing these in a table with no border will keep them together/aligned in any browser--> |
| * The majority of cases of endometrial cancer are due to sporadic genetic mutations (90%).
| | |- |
| * More than one genetic mutation is usually required for the development of endometrial cancer (multiple hits).
| | | |
| * 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).
| | {| class="wikitable sortable" |
| | | |+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> |
| ===Familial endometrial cancer===
| | |- |
| Endometrial cancer may be caused by hereditary diseases (10%) and is associated with mutations of the ''[[P16 (gene)|P16/CDKN2A]]'' gene:
| | !Gene mutated |
| *Familial atypical multiple mole endometrial cancer syndrome (FAMMM syndrome)
| | !Mutation type |
| *endometrial cancer-astrocytoma syndrome
| | !Type I prevalence |
| | | !Type II prevalence |
| | | |- |
| * 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]]''.
| | |''[[ARID1A]]'' |
| * 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>
| | |[[point mutation]] |
| * 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>
| | |40% |
| * ''[[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>
| | |unknown |
| * ''[[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>
| | | ''CTNNB1'' |
| * 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>
| | |point mutation |
| * 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>
| | |14–44% |
| * 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>
| | |unknown |
| * 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>
| | |''[[FGFR2]]'' |
| | |point mutation |
| | |16% |
| | |unknown |
| | |- |
| | |''[[KRAS]]'' |
| | |point mutation |
| | |10–20% |
| | |unknown |
| | |- |
| | | ''PIK3R1'' |
| | |point mutation |
| | |43% |
| | |unknown |
| | |- |
| | |''[[TP53]]'' |
| | |point mutation |
| | |10–20% |
| | |90% |
| | |- |
| | |''[[PTEN (gene)|PTEN]]'' |
| | |point mutation |
| | |37–61% |
| | |unknown |
| | |- |
| | |''[[MLH1]]'' |
| | |[[gene silencing|epigenetic silencing]] |
| | |30% |
| | |unknown |
| | |- |
| | | ''RASSF1A'' |
| | |epigenetic silencing |
| | |48% |
| | |unknown |
| | |- |
| | | ''SPRY2'' |
| | |epigenetic silencing |
| | |20% |
| | |unknown |
| | |- |
| | | ''PPP2R1A'' |
| | |point mutation |
| | |unknown |
| | |17–41% |
| | |- |
| | | ''CDH1 (gene)|CDH1'' |
| | |[[loss of heterozygosity]] |
| | |unknown |
| | |80–90% |
| | |- |
| | |''[[p16 (gene)|CDKN2A]]'' |
| | |loss of heterozygosity and/or<br />epigenetic silencing |
| | |20% |
| | |40% |
| | |- |
| | | ''PIK3CA'' ([[oncogene]]) |
| | |point mutation or amplification (molecular biology)|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% |
| | |} |
| | |} |
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| ==References== | | ==References== |
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| | [[Category:Oncology]] |
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| | [[Category:Gynecology]] |
| | [[Category:Surgery]] |