Uterine cancer pathophysiology: Difference between revisions
Line 23: | Line 23: | ||
|unknown | |unknown | ||
|- | |- | ||
| | | CTNNB1 | ||
|point mutation | |point mutation | ||
|14–44% | |14–44% | ||
Line 38: | Line 38: | ||
|unknown | |unknown | ||
|- | |- | ||
| | | PIK3R1 | ||
|point mutation | |point mutation | ||
|43% | |43% | ||
Line 58: | Line 58: | ||
|unknown | |unknown | ||
|- | |- | ||
| | | RASSF1A | ||
|epigenetic silencing | |epigenetic silencing | ||
|48% | |48% | ||
|unknown | |unknown | ||
|- | |- | ||
| | | SPRY2 | ||
|epigenetic silencing | |epigenetic silencing | ||
|20% | |20% | ||
|unknown | |unknown | ||
|- | |- | ||
| | | PPP2R1A | ||
|point mutation | |point mutation | ||
|unknown | |unknown | ||
|17–41% | |17–41% | ||
|- | |- | ||
| | | CDH1 (gene)|CDH1 | ||
|[[loss of heterozygosity]] | |[[loss of heterozygosity]] | ||
|unknown | |unknown | ||
Line 83: | Line 83: | ||
|40% | |40% | ||
|- | |- | ||
| | | PIK3CA ([[oncogene]]) | ||
|point mutation or | |point mutation or amplification (molecular biology)|amplification | ||
|24–39% | |24–39% | ||
|20–30% | |20–30% | ||
|- | |- | ||
| | | PIK3R1 (oncogene) | ||
|point mutation | |point mutation | ||
|unknown | |unknown | ||
|12% | |12% | ||
|- | |- | ||
| | |STK15 (oncogene) | ||
|amplification | |amplification | ||
|unknown | |unknown | ||
Line 103: | Line 103: | ||
|55% | |55% | ||
|- | |- | ||
| | | ERBB2 (oncogene) | ||
|amplification | |amplification | ||
|unknown | |unknown | ||
Line 116: | Line 116: | ||
Endometrial cancer forms when there are errors in normal endometrial [[cell cycle|cell growth]].<ref name="pmid22513918">{{cite journal| author=Kong A, Johnson N, Kitchener HC, Lawrie TA| title=Adjuvant radiotherapy for stage I endometrial cancer. | journal=Cochrane Database Syst Rev | year= 2012 | volume= 4 | issue= | pages= CD003916 | pmid=22513918 | doi=10.1002/14651858.CD003916.pub4 | pmc=PMC4164955 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22513918 }} </ref> Usually, when cells grow old or get damaged, they [[apoptosis|die]], and new cells take their place.<ref name="pmid22513918">{{cite journal| author=Kong A, Johnson N, Kitchener HC, Lawrie TA| title=Adjuvant radiotherapy for stage I endometrial cancer. | journal=Cochrane Database Syst Rev | year= 2012 | volume= 4 | issue= | pages= CD003916 | pmid=22513918 | doi=10.1002/14651858.CD003916.pub4 | pmc=PMC4164955 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22513918 }} </ref> Cancer starts when new cells form unneeded, and old or damaged cells do not die as they should.<ref name="pmid22513918">{{cite journal| author=Kong A, Johnson N, Kitchener HC, Lawrie TA| title=Adjuvant radiotherapy for stage I endometrial cancer. | journal=Cochrane Database Syst Rev | year= 2012 | volume= 4 | issue= | pages= CD003916 | pmid=22513918 | doi=10.1002/14651858.CD003916.pub4 | pmc=PMC4164955 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22513918 }} </ref> The buildup of extra cells often forms a mass of tissue called a growth or tumor.<ref name="pmid22513918">{{cite journal| author=Kong A, Johnson N, Kitchener HC, Lawrie TA| title=Adjuvant radiotherapy for stage I endometrial cancer. | journal=Cochrane Database Syst Rev | year= 2012 | volume= 4 | issue= | pages= CD003916 | pmid=22513918 | doi=10.1002/14651858.CD003916.pub4 | pmc=PMC4164955 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22513918 }} </ref> These abnormal cancer cells have many [[genetic mutation|genetic abnormalities]] that cause them to grow excessively.<ref>What You Need To Know: Endometrial Cancer".NCI. National Cancer Institute. Retrieved 6 August 2014.</ref> | Endometrial cancer forms when there are errors in normal endometrial [[cell cycle|cell growth]].<ref name="pmid22513918">{{cite journal| author=Kong A, Johnson N, Kitchener HC, Lawrie TA| title=Adjuvant radiotherapy for stage I endometrial cancer. | journal=Cochrane Database Syst Rev | year= 2012 | volume= 4 | issue= | pages= CD003916 | pmid=22513918 | doi=10.1002/14651858.CD003916.pub4 | pmc=PMC4164955 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22513918 }} </ref> Usually, when cells grow old or get damaged, they [[apoptosis|die]], and new cells take their place.<ref name="pmid22513918">{{cite journal| author=Kong A, Johnson N, Kitchener HC, Lawrie TA| title=Adjuvant radiotherapy for stage I endometrial cancer. | journal=Cochrane Database Syst Rev | year= 2012 | volume= 4 | issue= | pages= CD003916 | pmid=22513918 | doi=10.1002/14651858.CD003916.pub4 | pmc=PMC4164955 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22513918 }} </ref> Cancer starts when new cells form unneeded, and old or damaged cells do not die as they should.<ref name="pmid22513918">{{cite journal| author=Kong A, Johnson N, Kitchener HC, Lawrie TA| title=Adjuvant radiotherapy for stage I endometrial cancer. | journal=Cochrane Database Syst Rev | year= 2012 | volume= 4 | issue= | pages= CD003916 | pmid=22513918 | doi=10.1002/14651858.CD003916.pub4 | pmc=PMC4164955 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22513918 }} </ref> The buildup of extra cells often forms a mass of tissue called a growth or tumor.<ref name="pmid22513918">{{cite journal| author=Kong A, Johnson N, Kitchener HC, Lawrie TA| title=Adjuvant radiotherapy for stage I endometrial cancer. | journal=Cochrane Database Syst Rev | year= 2012 | volume= 4 | issue= | pages= CD003916 | pmid=22513918 | doi=10.1002/14651858.CD003916.pub4 | pmc=PMC4164955 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22513918 }} </ref> These abnormal cancer cells have many [[genetic mutation|genetic abnormalities]] that cause them to grow excessively.<ref>What You Need To Know: Endometrial Cancer".NCI. National Cancer Institute. Retrieved 6 August 2014.</ref> | ||
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 [[p53]] or [[PTEN (gene)|PTEN]]. In 20% of [[endometrial hyperplasia]]s and 50% of | 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 [[p53]] 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 p53 pathway can either be suppressed or highly activated in endometrial cancer. When a mutant version of p53 is overexpressed, the cancer tends to be particularly aggressive.<ref name=ComprehensiveGyn26/> P53 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 | 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.<ref name=ComprehensiveGyn26/> 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 name="WCR2014Epi"/><ref name=Suh/> Mutations in tumor suppressor genes are common in Type II endometrial cancer.<ref name="WCR2014Epi"/> PIK3CA is commonly mutated in both Type I and Type II cancers.<ref name=Suh/> 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> | 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 name="WCR2014Epi"/><ref name=Suh/> Mutations in tumor suppressor genes are common in Type II endometrial cancer.<ref name="WCR2014Epi"/> PIK3CA is commonly mutated in both Type I and Type II cancers.<ref name=Suh/> 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> |
Revision as of 14:33, 31 August 2015
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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Overview
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Pathophysiology
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Endometrial cancer forms when there are errors in normal endometrial cell growth.[3] Usually, when cells grow old or get damaged, they die, and new cells take their place.[3] Cancer starts when new cells form unneeded, and old or damaged cells do not die as they should.[3] The buildup of extra cells often forms a mass of tissue called a growth or tumor.[3] These abnormal cancer cells have many genetic abnormalities that cause them to grow excessively.[4]
In 10–20% of endometrial cancers, mostly Grade 3 (the highest histologic grade), mutations are found in a tumor suppressor gene, commonly p53 or PTEN. In 20% of endometrial hyperplasias and 50% of endometrioid cancers, PTEN suffers a loss-of-function mutation or a null mutation, making it less effective or completely ineffective.[5] Loss of PTEN function leads to up-regulation of the PI3k/Akt/mTOR pathway, which causes cell growth.[6] The p53 pathway can either be suppressed or highly activated in endometrial cancer. When a mutant version of p53 is overexpressed, the cancer tends to be particularly aggressive.[5] P53 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.[6]
PTEN and 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 gene) mutations are found in 14–44% of endometrial cancers and may indicate a good prognosis, but the data is unclear.[5] Beta-catenin mutations are commonly found in endometrial cancers with squamous cells.[6] FGFR2 mutations are found in approximately 10% of endometrial cancers, and their prognostic significance is unclear.[5] 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.[7]
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. Epigenetic silencing and point mutations of several genes are commonly found in Type I endometrial cancer.[1][2] Mutations in tumor suppressor genes are common in Type II endometrial cancer.[1] PIK3CA is commonly mutated in both Type I and Type II cancers.[2] In women with Lynch syndrome-associated endometrial cancer, microsatellite instability is common.[6]
Development of an endometrial hyperplasia (overgrowth of endometrial cells) is a significant risk factor because hyperplasias can and often do develop into adenocarcinoma, though cancer can develop without the presence of a hyperplasia.[8] Within ten years, 8–30% of atypical endometrial hyperplasias develop into cancer, whereas 1–3% of non-atypical hyperplasias do so.[9] An atypical hyperplasia is one with visible abnormalities in the nuclei. Pre-cancerous endometrial hyperplasias are also referred to as endometrial intraepithelial neoplasia.[10] Mutations in the KRAS gene can cause endometrial hyperplasia and therefore Type I endometrial cancer.[5] Endometrial hyperplasia typically occurs after the age of 40.[11] Endometrial glandular dysplasia occurs with an overexpression of p53, and develops into a serous carcinoma.[12]
References
- ↑ 1.0 1.1 1.2
- ↑ 2.0 2.1 2.2
- ↑ 3.0 3.1 3.2 3.3 Kong A, Johnson N, Kitchener HC, Lawrie TA (2012). "Adjuvant radiotherapy for stage I endometrial cancer". Cochrane Database Syst Rev. 4: CD003916. doi:10.1002/14651858.CD003916.pub4. PMC 4164955. PMID 22513918.
- ↑ What You Need To Know: Endometrial Cancer".NCI. National Cancer Institute. Retrieved 6 August 2014.
- ↑ 5.0 5.1 5.2 5.3 5.4 Thaker, PH; Sood, AK. "Molecular Oncology in Gynecologic Cancer". In Lentz, GM; Lobo, RA; Gershenson, DM; Katz, VL. Comprehensive Gynecology (6th ed.). Mosby. ISBN 978-0-323-06986-1.
- ↑ 6.0 6.1 6.2 6.3 Colombo N, Preti E, Landoni F, Carinelli S, Colombo A, Marini C; et al. (2013). "Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up". Ann Oncol. 24 Suppl 6: vi33–8. doi:10.1093/annonc/mdt353. PMID 24078661.
- ↑ Mani, RS (September 2014). "The emerging role of speckle-type POZ protein (SPOP) in cancer development". Drug Discovery Today. 19 (9): 1498–1502. doi:10.1016/j.drudis.2014.07.009. PMID 25058385.
A recent exome-sequencing study revealed that 8% of serious endometrial cancers and 9% of clear cell endometrial cancers have SPOP mutations
- ↑
- ↑ Luo, L; Luo, B; Zheng, Y; Zhang, H; Li, J; Sidell, N (5 June 2013). "Levonorgestrel-releasing intrauterine system for atypical endometrial hyperplasia". The Cochrane database of systematic reviews. 6: CD009458. doi:10.1002/14651858.CD009458.pub2. PMID 23737032.
- ↑ Hoffman, BL; Schorge, JO; Schaffer, JI; Halvorson, LM; Bradshaw, KD; Cunningham, FG, eds. (2012). "Endometrial Cancer". Williams Gynecology (2nd ed.). McGraw-Hill. p. 820. ISBN 978-0-07-171672-7.
- ↑
- ↑ Saso, S; Chatterjee, J; Georgiou, E; Ditri, AM; Smith, JR; Ghaem-Maghami, S (2011). "Endometrial cancer". BMJ. 343: d3954–d3954. doi:10.1136/bmj.d3954. PMID 21734165.