Hereditary nonpolyposis colorectal cancer pathophysiology: Difference between revisions
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{{Hereditary nonpolyposis colorectal cancer}} | {{Hereditary nonpolyposis colorectal cancer}} | ||
{{CMG}} | {{CMG}}{{AE}}{{MV}} {{Akram}} | ||
==Overview== | ==Overview== | ||
Hereditary nonpolyposis colorectal cancer is an [[autosomal dominant]] [[genetic]] [[disease]] characterized by an early onset of [[colon cancer]], [[endometrial cancer]], and other [[malignant]] [[tumors]]. Development of hereditary nonpolyposis colorectal cancer is the result of multiple [[genetic mutation]]s. The [[Gene|genes]] involved in the [[pathogenesis]] of hereditary nonpolyposis colorectal cancer include: [[MSH2|MSH-2]], [[MLH1|MLH-1]], [[MSH6|MSH-6]], [[PMS2|PMS-2]] , [[PMS1|PMS-1]], [[TGFBR2|TGF-BR2]], and [[MLH3|MLH-3]]. This [[syndrome]] occurs most commonly in the [[proximal]] [[colon]] (60% to 80%). [[Endometrial cancer]] is the most common [[Sentinel event|sentinel]] [[cancer]] among [[female]] [[patients]] with hereditary nonpolyposis colorectal cancer. | |||
==Pathogenesis== | |||
*Hereditary nonpolyposis colorectal cancer results from a defect in the [[DNA mismatch repair]] mechanism that leads to [[microsatellite instability|microsatellite instability (MSI)]], which is a hallmark of the [[disease]]. | |||
* Most cases result in changes in the lengths of [[Tandem repeat|dinucleotide repeats]] of the [[nucleobase]]s [[cytosine]] and [[adenine]].<ref>{{cite journal | vauthors = Oki E, Oda S, Maehara Y, Sugimachi K | title = Mutated gene-specific phenotypes of dinucleotide repeat instability in human colorectal carcinoma cell lines deficient in DNA mismatch repair | journal = Oncogene | volume = 18 | issue = 12 | pages = 2143–7 | date = Mar 1999 | pmid = 10321739 | pmc = | doi = 10.1038/sj.onc.1202583 }}</ref> | |||
*[[Microsatellite instability|Microsatellite instability (MSI)]] is a [[surrogate marker]] for [[DNA mismatch repair]] [[gene]] dysfunction.<ref>Lynch syndrome.Ganfyd.http://www.ganfyd.org/index.php?title=Lynch_syndrome Accessed on December 01, 2015</ref><ref name="pmid10348829">{{cite journal |vauthors=Vasen HF, Watson P, Mecklin JP, Lynch HT |title=New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC |journal=Gastroenterology |volume=116 |issue=6 |pages=1453–6 |year=1999 |pmid=10348829 |doi= |url=}}</ref> | |||
*In hereditary nonpolyposis colorectal cancer, [[Colon (anatomy)|colon]] [[Cancer|malignancies]] usually occur from a single or multiple [[Adenoma|adenomas]], and mostly in the [[Anatomical terms of location|proximal]] [[Colon (anatomy)|colon]]. | |||
==Genetics== | |||
*Hereditary nonpolyposis colorectal cancer is inherited in an [[autosomal dominant]] manner. | |||
*Development of hereditary nonpolyposis colorectal cancer is the result of multiple [[genetic mutation]]s.<ref name="pmid26474631">{{cite journal |vauthors=Si JW, Wang L, Ba XJ, Zhang X, Dong Y, Zhang JX, Li WT, Li T |title=[Clinicopathological screening of Lynch syndrome: a report of 2 cases and literature review] |language=Chinese |journal=Beijing Da Xue Xue Bao |volume=47 |issue=5 |pages=858–64 |year=2015 |pmid=26474631 |doi= |url=}}</ref> | |||
* Most [[Mutation|mutations]] (90%) that cause hereditary nonpolyposis colorectal cancer are found in the [[MLH1]] or [[MSH2]] [[genes]].<ref>Lynch Syndrome. Canadian Cancer Society http://www.cancer.ca/en/cancer-information/cancer-101/what-is-a-risk-factor/genetic-risk/lynch-syndrome/?region=ab#ixzz3t69IQ9M7 Accessed on December 01 2015 </ref> | |||
*[[MSH6]] and [[PMS2]] account for the other 10% of mutations.<ref>Lynch Syndrome. Canadian Cancer Society http://www.cancer.ca/en/cancer-information/cancer-101/what-is-a-risk-factor/genetic-risk/lynch-syndrome/?region=ab#ixzz3t69IQ9M7 Accessed on December 01 2015 </ref> | |||
*[[Endometrial cancer]] is the most common distant [[cancer]] among female [[Patient|patients]] with hereditary nonpolyposis colorectal cancer. | |||
*[[MSH2]] [[Mutation|mutations]] have an increased risk of [[Transitional cell carcinoma|urothelial carcinoma]] relative to [[MLH1]] and [[MSH6]] [[Mutation|mutations]].<ref name="pmid20591884">{{Cite journal | last1 = van der Post | first1 = RS. | last2 = Kiemeney | first2 = LA. | last3 = Ligtenberg | first3 = MJ. | last4 = Witjes | first4 = JA. | last5 = Hulsbergen-van de Kaa | first5 = CA. | last6 = Bodmer | first6 = D. | last7 = Schaap | first7 = L. | last8 = Kets | first8 = CM. | last9 = van Krieken | first9 = JH. | title = Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers. | journal = J Med Genet | volume = 47 | issue = 7 | pages = 464-70 | month = Jul | year = 2010 | doi = 10.1136/jmg.2010.076992 | PMID = 20591884 }}</ref> | |||
====== The table below lists the [[Gene|genes]] involved in the [[pathogenesis]] of hereditary nonpolyposis colorectal cancer: ====== | |||
{| style="border: 0px; font-size: 90%; margin: 3px; width: 800px" align="center" | |||
| valign="top" | | |||
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! style="background: #4479BA; width: 50px;" |{{fontcolor|#FFF|Genes implicated in hereditary nonpolyposis colorectal cancer}} | |||
! style="background: #4479BA; width: 100px;" |{{fontcolor|#FFF|Frequency of mutations in hereditary nonpolyposis colorectal cancer families}} | |||
! style="background: #4479BA; width: 50px;" |{{fontcolor|#FFF|Locus}} | |||
|- | |||
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold; text-align:center;" |[[MSH2]] | |||
| style="padding: 5px 5px; background: #F5F5F5;" |Approximately 60% | |||
| style="padding: 5px 5px; background: #F5F5F5;" |2p22 | |||
|- | |||
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold; text-align:center;" |[[MLH1]] | |||
| style="padding: 5px 5px; background: #F5F5F5;" | Approximately 30% | |||
| style="padding: 5px 5px; background: #F5F5F5;" |3p21 | |||
|- | |||
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold; text-align:center;" |[[MSH6]] | |||
| style="padding: 5px 5px; background: #F5F5F5;" | 7 - 10% | |||
| style="padding: 5px 5px; background: #F5F5F5;" |2p16 | |||
|- | |||
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold; text-align:center;" |[[PMS2]] | |||
| style="padding: 5px 5px; background: #F5F5F5;" |Relatively infrequent | |||
| style="padding: 5px 5px; background: #F5F5F5;" |7p22 | |||
|- | |||
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold; text-align:center;" |[[PMS1]] | |||
| style="padding: 5px 5px; background: #F5F5F5;" |Case report | |||
| style="padding: 5px 5px; background: #F5F5F5;" |2q31-q33 | |||
|- | |||
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold; text-align:center;" |[[TGFBR2]] | |||
| style="padding: 5px 5px; background: #F5F5F5;" |Case report | |||
| style="padding: 5px 5px; background: #F5F5F5;" |3p22 | |||
|- | |||
| style="padding: 5px 5px; background: #DCDCDC; font-weight: bold; text-align:center;" |[[MLH3]] | |||
| style="padding: 5px 5px; background: #F5F5F5;" |Disputed | |||
| style="padding: 5px 5px; background: #F5F5F5;" |14q24.3 | |||
|- | |||
|} | |||
==Associated Conditions== | |||
*[[Colorectal carcinoma]] | |||
*[[Endometrial carcinoma]] | |||
**Non-[[Endometrium|endometrioid]] [[endometrial carcinoma]]<ref name="pmid20396392">{{cite journal |author=Okuda T, Sekizawa A, Purwosunu Y, ''et al.'' |title=Genetics of endometrial cancers |journal=Obstet Gynecol Int |volume=2010 |issue= |pages=984013 |year=2010 |pmid=20396392 |pmc=2852605 |doi=10.1155/2010/984013 |url=}}</ref><ref name="pmid19638537">{{Cite journal | last1 = Garg | first1 = K. | last2 = Soslow | first2 = RA. | title = Lynch syndrome (hereditary non-polyposis colorectal cancer) and endometrial carcinoma. | journal = J Clin Pathol | volume = 62 | issue = 8 | pages = 679-84 | month = Aug | year = 2009 | doi = 10.1136/jcp.2009.064949 | PMID = 19638537 | url = http://jcp.bmj.com/content/62/8/679.long }}</ref> | |||
**[[Endometrium|Endometrioid]] [[Endometrial cancer|endometrial carcinoma]]<ref name="pmid11873308">{{Cite journal | last1 = Lax | first1 = SF. | title = [Dualistic model of molecular pathogenesis in endometrial carcinoma]. | journal = Zentralbl Gynakol | volume = 124 | issue = 1 | pages = 10-6 | month = Jan | year = 2002 | doi = 10.1055/s-2002-20303 | PMID = 11873308 }}</ref> | |||
*[[Stomach carcinoma|Stomach carcinoma (intestinal type)]]<ref name="OMIM120435">{{OMIM|120435}}</ref><ref name="pmid3581033">{{Cite journal | last1 = Cristofaro | first1 = G. | last2 = Lynch | first2 = HT. | last3 = Caruso | first3 = ML. | last4 = Attolini | first4 = A. | last5 = DiMatteo | first5 = G. | last6 = Giorgio | first6 = P. | last7 = Senatore | first7 = S. | last8 = Argentieri | first8 = A. | last9 = Sbano | first9 = E. | title = New phenotypic aspects in a family with Lynch syndrome II. | journal = Cancer | volume = 60 | issue = 1 | pages = 51-8 | month = Jul | year = 1987 | doi = | PMID = 3581033 }}</ref> | |||
*[[Cholangiocarcinoma|Biliary tree carcinoma]]<ref name="OMIM120435">{{OMIM|120435}}</ref> | |||
*[[Pancreatic cancer|Pancreatic carcinoma]] | |||
*[[Urinary system]] [[carcinoma]] | |||
==Gross Pathology== | |||
*On [[gross pathology]], there are no characteristic findings of hereditary nonpolyposis colorectal cancer.<ref name="pmid26474631">{{cite journal |vauthors=Si JW, Wang L, Ba XJ, Zhang X, Dong Y, Zhang JX, Li WT, Li T |title=[Clinicopathological screening of Lynch syndrome: a report of 2 cases and literature review] |language=Chinese |journal=Beijing Da Xue Xue Bao |volume=47 |issue=5 |pages=858–64 |year=2015 |pmid=26474631 |doi= |url=}}</ref> | |||
==Microscopic Pathology== | |||
*On [[microscopic]] [[Histopathology|histopathological]] [[analysis]], hereditary nonpolyposis colorectal cancer is more likely to be poorly differentiated, abundant in [[extracellular]] [[mucin]], and distinguished by a [[Lymphocyte|lymphoid]] (peritumoral [[Lymphocyte|lymphocytes]]) host response to the [[tumor]].<ref name="pmid26474631">{{cite journal |vauthors=Si JW, Wang L, Ba XJ, Zhang X, Dong Y, Zhang JX, Li WT, Li T |title=[Clinicopathological screening of Lynch syndrome: a report of 2 cases and literature review] |language=Chinese |journal=Beijing Da Xue Xue Bao |volume=47 |issue=5 |pages=858–64 |year=2015 |pmid=26474631 |doi= |url=}}</ref> | |||
* Three major groups of MSI-H [[Cancer|cancers]] can be recognized by [[Histopathology|histopathological]] criteria, which include:<ref name="pmid19659756">{{cite journal| author=Lynch HT, Lynch PM, Lanspa SJ, Snyder CL, Lynch JF, Boland CR| title=Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. | journal=Clin Genet | year= 2009 | volume= 76 | issue= 1 | pages= 1-18 | pmid=19659756 | doi=10.1111/j.1399-0004.2009.01230.x | pmc=2846640 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19659756 }} </ref><ref name="pmid29169633">{{cite journal| author=Ma H, Brosens LAA, Offerhaus GJA, Giardiello FM, de Leng WWJ, Montgomery EA| title=Pathology and genetics of hereditary colorectal cancer. | journal=Pathology | year= 2018 | volume= 50 | issue= 1 | pages= 49-59 | pmid=29169633 | doi=10.1016/j.pathol.2017.09.004 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29169633 }} </ref> | |||
**Right-sided poorly differentiated [[Cancer|cancers]] | |||
**Right-sided [[Mucin|mucinous]] [[Cancer|cancers]] | |||
**[[Adenocarcinomas]] in any location showing any measurable level of [[intraepithelial lymphocyte]] | |||
==References== | ==References== | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2] Ali Akram, M.B.B.S.[3]
Overview
Hereditary nonpolyposis colorectal cancer is an autosomal dominant genetic disease characterized by an early onset of colon cancer, endometrial cancer, and other malignant tumors. Development of hereditary nonpolyposis colorectal cancer is the result of multiple genetic mutations. The genes involved in the pathogenesis of hereditary nonpolyposis colorectal cancer include: MSH-2, MLH-1, MSH-6, PMS-2 , PMS-1, TGF-BR2, and MLH-3. This syndrome occurs most commonly in the proximal colon (60% to 80%). Endometrial cancer is the most common sentinel cancer among female patients with hereditary nonpolyposis colorectal cancer.
Pathogenesis
- Hereditary nonpolyposis colorectal cancer results from a defect in the DNA mismatch repair mechanism that leads to microsatellite instability (MSI), which is a hallmark of the disease.
- Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine.[1]
- Microsatellite instability (MSI) is a surrogate marker for DNA mismatch repair gene dysfunction.[2][3]
- In hereditary nonpolyposis colorectal cancer, colon malignancies usually occur from a single or multiple adenomas, and mostly in the proximal colon.
Genetics
- Hereditary nonpolyposis colorectal cancer is inherited in an autosomal dominant manner.
- Development of hereditary nonpolyposis colorectal cancer is the result of multiple genetic mutations.[4]
- Most mutations (90%) that cause hereditary nonpolyposis colorectal cancer are found in the MLH1 or MSH2 genes.[5]
- MSH6 and PMS2 account for the other 10% of mutations.[6]
- Endometrial cancer is the most common distant cancer among female patients with hereditary nonpolyposis colorectal cancer.
- MSH2 mutations have an increased risk of urothelial carcinoma relative to MLH1 and MSH6 mutations.[7]
The table below lists the genes involved in the pathogenesis of hereditary nonpolyposis colorectal cancer:
| Genes implicated in hereditary nonpolyposis colorectal cancer | Frequency of mutations in hereditary nonpolyposis colorectal cancer families | Locus |
|---|---|---|
| MSH2 | Approximately 60% | 2p22 |
| MLH1 | Approximately 30% | 3p21 |
| MSH6 | 7 - 10% | 2p16 |
| PMS2 | Relatively infrequent | 7p22 |
| PMS1 | Case report | 2q31-q33 |
| TGFBR2 | Case report | 3p22 |
| MLH3 | Disputed | 14q24.3 |
Associated Conditions
- Stomach carcinoma (intestinal type)[11][12]
- Biliary tree carcinoma[11]
- Pancreatic carcinoma
- Urinary system carcinoma
Gross Pathology
- On gross pathology, there are no characteristic findings of hereditary nonpolyposis colorectal cancer.[4]
Microscopic Pathology
- On microscopic histopathological analysis, hereditary nonpolyposis colorectal cancer is more likely to be poorly differentiated, abundant in extracellular mucin, and distinguished by a lymphoid (peritumoral lymphocytes) host response to the tumor.[4]
- Three major groups of MSI-H cancers can be recognized by histopathological criteria, which include:[13][14]
- Right-sided poorly differentiated cancers
- Right-sided mucinous cancers
- Adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte
References
- ↑ Oki E, Oda S, Maehara Y, Sugimachi K (Mar 1999). "Mutated gene-specific phenotypes of dinucleotide repeat instability in human colorectal carcinoma cell lines deficient in DNA mismatch repair". Oncogene. 18 (12): 2143–7. doi:10.1038/sj.onc.1202583. PMID 10321739.
- ↑ Lynch syndrome.Ganfyd.http://www.ganfyd.org/index.php?title=Lynch_syndrome Accessed on December 01, 2015
- ↑ Vasen HF, Watson P, Mecklin JP, Lynch HT (1999). "New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC". Gastroenterology. 116 (6): 1453–6. PMID 10348829.
- ↑ 4.0 4.1 4.2 Si JW, Wang L, Ba XJ, Zhang X, Dong Y, Zhang JX, Li WT, Li T (2015). "[Clinicopathological screening of Lynch syndrome: a report of 2 cases and literature review]". Beijing Da Xue Xue Bao (in Chinese). 47 (5): 858–64. PMID 26474631.
- ↑ Lynch Syndrome. Canadian Cancer Society http://www.cancer.ca/en/cancer-information/cancer-101/what-is-a-risk-factor/genetic-risk/lynch-syndrome/?region=ab#ixzz3t69IQ9M7 Accessed on December 01 2015
- ↑ Lynch Syndrome. Canadian Cancer Society http://www.cancer.ca/en/cancer-information/cancer-101/what-is-a-risk-factor/genetic-risk/lynch-syndrome/?region=ab#ixzz3t69IQ9M7 Accessed on December 01 2015
- ↑ van der Post, RS.; Kiemeney, LA.; Ligtenberg, MJ.; Witjes, JA.; Hulsbergen-van de Kaa, CA.; Bodmer, D.; Schaap, L.; Kets, CM.; van Krieken, JH. (2010). "Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers". J Med Genet. 47 (7): 464–70. doi:10.1136/jmg.2010.076992. PMID 20591884. Unknown parameter
|month=ignored (help) - ↑ Okuda T, Sekizawa A, Purwosunu Y; et al. (2010). "Genetics of endometrial cancers". Obstet Gynecol Int. 2010: 984013. doi:10.1155/2010/984013. PMC 2852605. PMID 20396392.
- ↑ Garg, K.; Soslow, RA. (2009). "Lynch syndrome (hereditary non-polyposis colorectal cancer) and endometrial carcinoma". J Clin Pathol. 62 (8): 679–84. doi:10.1136/jcp.2009.064949. PMID 19638537. Unknown parameter
|month=ignored (help) - ↑ Lax, SF. (2002). "[Dualistic model of molecular pathogenesis in endometrial carcinoma]". Zentralbl Gynakol. 124 (1): 10–6. doi:10.1055/s-2002-20303. PMID 11873308. Unknown parameter
|month=ignored (help) - ↑ 11.0 11.1 Online Mendelian Inheritance in Man (OMIM) 120435
- ↑ Cristofaro, G.; Lynch, HT.; Caruso, ML.; Attolini, A.; DiMatteo, G.; Giorgio, P.; Senatore, S.; Argentieri, A.; Sbano, E. (1987). "New phenotypic aspects in a family with Lynch syndrome II". Cancer. 60 (1): 51–8. PMID 3581033. Unknown parameter
|month=ignored (help) - ↑ Lynch HT, Lynch PM, Lanspa SJ, Snyder CL, Lynch JF, Boland CR (2009). "Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications". Clin Genet. 76 (1): 1–18. doi:10.1111/j.1399-0004.2009.01230.x. PMC 2846640. PMID 19659756.
- ↑ Ma H, Brosens LAA, Offerhaus GJA, Giardiello FM, de Leng WWJ, Montgomery EA (2018). "Pathology and genetics of hereditary colorectal cancer". Pathology. 50 (1): 49–59. doi:10.1016/j.pathol.2017.09.004. PMID 29169633.