Uterine cancer pathophysiology: Difference between revisions
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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 [[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> | 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 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. | 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. | 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.<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> | ||
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.<ref name=ComprehensiveGyn32/> Within ten years, 8–30% of atypical endometrial hyperplasias develop into cancer, whereas 1–3% of non-atypical hyperplasias do so.<ref name=Cochrane0613>{{cite journal|last1=Luo|first1=L|last2=Luo|first2=B|last3=Zheng|first3=Y|last4=Zhang|first4=H|last5=Li|first5=J|last6=Sidell|first6=N|title=Levonorgestrel-releasing intrauterine system for atypical endometrial hyperplasia.|journal=The Cochrane database of systematic reviews|date=5 June 2013|volume=6|pages=CD009458|pmid=23737032|doi=10.1002/14651858.CD009458.pub2}}</ref> An atypical hyperplasia is one with visible abnormalities in the [[cell nucleus|nuclei]]. Pre-cancerous endometrial hyperplasias are also referred to as endometrial intraepithelial neoplasia.<ref name=Hoffman820>{{cite book |editor-last1=Hoffman |editor-first1=BL |editor-last2=Schorge |editor-first2=JO |editor-last3=Schaffer |editor-first3=JI |editor-last4=Halvorson |editor-first4=LM |editor-last5=Bradshaw |editor-first5=KD |editor-last6=Cunningham |editor-first6=FG |year=2012 |chapter=Endometrial Cancer |url=http://www.accessmedicine.com/content.aspx?aID=56712550 |title=Williams Gynecology |edition=2nd |publisher=[[McGraw-Hill]] |isbn=978-0-07-171672-7|pages = 820}}</ref> Mutations in the [[KRAS]] gene can cause endometrial hyperplasia and therefore Type I endometrial cancer. Endometrial hyperplasia typically occurs after the age of 40. Endometrial glandular dysplasia occurs with an overexpression of p53, and develops into a serous carcinoma.<ref name=bmj>{{cite journal |last1=Saso |first1=S |last2=Chatterjee |first2=J |last3=Georgiou |first3=E |last4=Ditri |first4=AM |last5=Smith |first5=JR |last6=Ghaem-Maghami |first6=S |year=2011 |title=Endometrial cancer |journal=BMJ |volume=343 |issue= |pages=d3954–d3954 |doi=10.1136/bmj.d3954 |pmid=21734165}}</ref> | 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.<ref name=ComprehensiveGyn32/> Within ten years, 8–30% of atypical endometrial hyperplasias develop into cancer, whereas 1–3% of non-atypical hyperplasias do so.<ref name=Cochrane0613>{{cite journal|last1=Luo|first1=L|last2=Luo|first2=B|last3=Zheng|first3=Y|last4=Zhang|first4=H|last5=Li|first5=J|last6=Sidell|first6=N|title=Levonorgestrel-releasing intrauterine system for atypical endometrial hyperplasia.|journal=The Cochrane database of systematic reviews|date=5 June 2013|volume=6|pages=CD009458|pmid=23737032|doi=10.1002/14651858.CD009458.pub2}}</ref> An atypical hyperplasia is one with visible abnormalities in the [[cell nucleus|nuclei]]. Pre-cancerous endometrial hyperplasias are also referred to as endometrial intraepithelial neoplasia.<ref name=Hoffman820>{{cite book |editor-last1=Hoffman |editor-first1=BL |editor-last2=Schorge |editor-first2=JO |editor-last3=Schaffer |editor-first3=JI |editor-last4=Halvorson |editor-first4=LM |editor-last5=Bradshaw |editor-first5=KD |editor-last6=Cunningham |editor-first6=FG |year=2012 |chapter=Endometrial Cancer |url=http://www.accessmedicine.com/content.aspx?aID=56712550 |title=Williams Gynecology |edition=2nd |publisher=[[McGraw-Hill]] |isbn=978-0-07-171672-7|pages = 820}}</ref> Mutations in the [[KRAS]] gene can cause endometrial hyperplasia and therefore Type I endometrial cancer. Endometrial hyperplasia typically occurs after the age of 40. Endometrial glandular dysplasia occurs with an overexpression of p53, and develops into a serous carcinoma.<ref name=bmj>{{cite journal |last1=Saso |first1=S |last2=Chatterjee |first2=J |last3=Georgiou |first3=E |last4=Ditri |first4=AM |last5=Smith |first5=JR |last6=Ghaem-Maghami |first6=S |year=2011 |title=Endometrial cancer |journal=BMJ |volume=343 |issue= |pages=d3954–d3954 |doi=10.1136/bmj.d3954 |pmid=21734165}}</ref> |
Revision as of 15:00, 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.[2] Usually, when cells grow old or get damaged, they die, and new cells take their place.[2] Cancer starts when new cells form unneeded, and old or damaged cells do not die as they should.[2] The buildup of extra cells often forms a mass of tissue called a growth or tumor.[2] These abnormal cancer cells have many genetic abnormalities that cause them to grow excessively.[3]
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.[4] Loss of PTEN function leads to up-regulation of the PI3k/Akt/mTOR pathway, which causes cell growth.[5] 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.[4] 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.[5]
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. Beta-catenin mutations are commonly found in endometrial cancers with squamous cells.[5] FGFR2 mutations are found in approximately 10% of endometrial cancers, and their prognostic significance is unclear.[4] 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.[6]
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.[7] Mutations in tumor suppressor genes are common in Type II endometrial cancer. PIK3CA is commonly mutated in both Type I and Type II cancers.[8] In women with Lynch syndrome-associated endometrial cancer, microsatellite instability is common.[5]
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.[9] Within ten years, 8–30% of atypical endometrial hyperplasias develop into cancer, whereas 1–3% of non-atypical hyperplasias do so.[10] An atypical hyperplasia is one with visible abnormalities in the nuclei. Pre-cancerous endometrial hyperplasias are also referred to as endometrial intraepithelial neoplasia.[11] Mutations in the KRAS gene can cause endometrial hyperplasia and therefore Type I endometrial cancer. Endometrial hyperplasia typically occurs after the age of 40. Endometrial glandular dysplasia occurs with an overexpression of p53, and develops into a serous carcinoma.[12]
References
- ↑ International Agency for Research on Cancer (2014). World Cancer Report 2014. World Health Organization. Chapter 5.12. ISBN 978-92-832-0429-9.
- ↑ 2.0 2.1 2.2 2.3 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.
- ↑ 4.0 4.1 4.2 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.
- ↑ 5.0 5.1 5.2 5.3 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
- ↑ International Agency for Research on Cancer (2014). World Cancer Report 2014. World Health Organization. Chapter 5.12. ISBN 978-92-832-0429-9.
- ↑
- ↑
- ↑ 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.