Hereditary nonpolyposis colorectal cancer pathophysiology
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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]
Overview
HNPCC is an autosomal dominant genetic disease characterized by the early onset of colon cancer, endometrial cancer, and other malignant tumors caused by genetic mutations, that lead to an accumulation of DNA mismatches in MMR gene.[1] Development of HNPCC is the result of multiple genetic mutations. Genes involved in the pathogenesis of HNPCC include; MSH-2, MLH-1, MSH-6, PMS-2 ,PMS-1, TGF-BR2, and MLH-3. This syndrome occurs mostly in the proximal colon (60% to 80%) and endometrial cancer is the most common sentinel cancer among female patients with HNPCC.[1]
Pathogenesis
HNPCC defects in DNA mismatch repair leading to microsatellite instability, also known as MSI-H, which is a hallmark of HNPCC. Three major groups of MSI-H cancers can be recognized by histopathological criteria:
- (1) right-sided poorly differentiated cancers
- (2) right-sided mucinous cancers
- (3) adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
MSI is identifiable in cancer specimens in the pathology laboratory. In hereditary nonpolyposis colorectal cancer, colon malignancies usually occur from a single or a few adenomas, and mostly occurs in the proximal colon.
Genetics
The hallmark of HNPCC is defective DNA mismatch repair, which leads to microsatellite instability, also known as MSI-H. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine.[2] HNPCC is inherited in an autosomal dominant manner. Therefore, most people with HNPCC inherit the condition from a parent. Families found to have a deleterious mutation in an HNPCC gene should be considered to have HNPCC regardless of the extent of the family history. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all patients with an HNPCC gene mutation have a parent who had cancer. Some patients develop HNPCC de-novo in a new generation, without inheriting the gene. These patients are often only identified after developing an early-life colon cancer. Parents with HNPCC have a 50% chance to pass the gene on to each child. MSH2 mutations have an increased risk of urothelial carcinoma relative to MLH1 and MSH6 mutations.[3]
Development of HNPCC is the result of multiple genetic mutations.[1] Genes involved in the pathogenesis of HNPCC include:
| OMIM name | Genes implicated in HNPCC | Frequency of mutations in HNPCC families | Locus | First publication |
|---|---|---|---|---|
| HNPCC1 (120435) | MSH2 | approximately 60% | 2p22 | Fishel 1993[4] |
| HNPCC2 (609310) | MLH1 | approximately 30% | 3p21 | Papadopoulos 1994[5] |
| HNPCC5 | MSH6 | 7-10% | 2p16 | Miyaki 1997[6] |
| HNPCC4 | PMS2 | relatively infrequent | 7p22 [7] | Nicolaides 1994 |
| HNPCC3 | PMS1 | case report[8] | 2q31-q33 | Nicolaides 1994 |
| HNPCC6 | TGFBR2 | case report[9] | 3p22 | |
| HNPCC7 | MLH3 | disputed[10] | 14q24.3 |
Associated Conditions
- Colorectal carcinoma
- Endometrial carcinoma
- Non-endometrioid endometrial carcinoma[11][12]
- Endometrioid endometrial carcinoma[13]
- Stomach carcinoma,[14] intestinal-type.[15]
- Biliary tree carcinoma[14]
- Pancreatic carcinoma[14]
- Urinary system carcinoma[14]
Gross Pathology
On gross pathology, there are no characteristic findings of HNPCC.[1]
Microscopic Pathology
On microscopic histopathological analysis, HNPCC is more likely to be poorly differentiated, abundant in extracellular mucin, and distinguished by a lymphoid (peritumoral lymphocytes) host response to the tumor.[1]
Gallery
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Micrograph of a sebaceous adenoma, as may be seen in Muir-Torre syndrome.
References
- ↑ 1.0 1.1 1.2 1.3 1.4 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.
- ↑ 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.
- ↑ 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) - ↑ Fishel R, Lescoe MK, Rao MR, Copeland NG, Jenkins NA, Garber J, Kane M, Kolodner R (Dec 1993). "The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer". Cell. 75 (5): 1027–38. doi:10.1016/0092-8674(93)90546-3. PMID 8252616.
- ↑ Papadopoulos N, Nicolaides NC, Wei YF, Ruben SM, Carter KC, Rosen CA, Haseltine WA, Fleischmann RD, Fraser CM, Adams MD (Mar 1994). "Mutation of a mutL homolog in hereditary colon cancer". Science. 263 (5153): 1625–9. doi:10.1126/science.8128251. PMID 8128251.
- ↑ Miyaki M, Konishi M, Tanaka K, Kikuchi-Yanoshita R, Muraoka M, Yasuno M, Igari T, Koike M, Chiba M, Mori T (Nov 1997). "Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer". Nature Genetics. 17 (3): 271–2. doi:10.1038/ng1197-271. PMID 9354786.
- ↑ Nicolaides NC, Papadopoulos N, Liu B, Wei YF, Carter KC, Ruben SM, Rosen CA, Haseltine WA, Fleischmann RD, Fraser CM (Sep 1994). "Mutations of two PMS homologues in hereditary nonpolyposis colon cancer". Nature. 371 (6492): 75–80. doi:10.1038/371075a0. PMID 8072530.
- ↑ Nicolaides NC, Papadopoulos N, Liu B, Wei YF, Carter KC, Ruben SM, Rosen CA, Haseltine WA, Fleischmann RD, Fraser CM (Sep 1994). "Mutations of two PMS homologues in hereditary nonpolyposis colon cancer". Nature. 371 (6492): 75–80. doi:10.1038/371075a0. PMID 8072530.
- ↑ Lu SL, Kawabata M, Imamura T, Akiyama Y, Nomizu T, Miyazono K, Yuasa Y (May 1998). "HNPCC associated with germline mutation in the TGF-beta type II receptor gene". Nature Genetics. 19 (1): 17–8. doi:10.1038/ng0598-17. PMID 9590282.
- ↑ Ou J, Rasmussen M, Westers H, Andersen SD, Jager PO, Kooi KA, Niessen RC, Eggen BJ, Nielsen FC, Kleibeuker JH, Sijmons RH, Rasmussen LJ, Hofstra RM (Apr 2009). "Biochemical characterization of MLH3 missense mutations does not reveal an apparent role of MLH3 in Lynch syndrome". Genes, Chromosomes & Cancer. 48 (4): 340–50. doi:10.1002/gcc.20644. PMID 19156873.
- ↑ 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) - ↑ 14.0 14.1 14.2 14.3 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)