Hereditary nonpolyposis colorectal cancer: Difference between revisions
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Patients with MSH6 mutations are more likely to be Amsterdam criteria II-negative.<ref name="pmid18625694">{{cite journal |author=Ramsoekh D, Wagner A, van Leerdam ME, ''et al.'' |title=A high incidence of MSH6 mutations in Amsterdam criteria II-negative families tested in a diagnostic setting |journal=Gut |volume=57 |issue=11 |pages=1539–44 |year=2008 |month=November |pmid=18625694 |doi=10.1136/gut.2008.156695 |url=http://gut.bmj.com/cgi/pmidlookup?view=long&pmid=18625694}}</ref> |
Patients with MSH6 mutations are more likely to be Amsterdam criteria II-negative.<ref name="pmid18625694">{{cite journal |author=Ramsoekh D, Wagner A, van Leerdam ME, ''et al.'' |title=A high incidence of MSH6 mutations in Amsterdam criteria II-negative families tested in a diagnostic setting |journal=Gut |volume=57 |issue=11 |pages=1539–44 |year=2008 |month=November |pmid=18625694 |doi=10.1136/gut.2008.156695 |url=http://gut.bmj.com/cgi/pmidlookup?view=long&pmid=18625694}}</ref> The presentation with MSH6 is slightly different than with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition.<ref name="pmid19804606">{{cite journal |author=Suchy J, Lubinski J |title=MSH6 syndrome |journal=Hered Cancer Clin Pract |volume=6 |issue=2 |pages=103–104 |year=2008 |pmid=19804606 |pmc=2735474 |doi=10.1186/1897-4287-6-2-103 |url=}}</ref> |
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Up to 39% of families with mutations in an HNPCC gene do not meet the [[Amsterdam criteria]].{{fact}} Therefore, 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. This also means that the Amsterdam criteria fail to identify many patients at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. |
Up to 39% of families with mutations in an HNPCC gene do not meet the [[Amsterdam criteria]].{{fact}} Therefore, 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. This also means that the Amsterdam criteria fail to identify many patients at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. |
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Revision as of 03:31, 8 November 2009
| Hereditary nonpolyposis colorectal cancer | |
|---|---|
| Specialty | Oncology  |
 | It has been suggested that this page be moved to Lynch syndrome. (Discuss) |
Hereditary nonpolyposis colorectal cancer (HNPCC) is a colon cancer, characterised by a risk of other cancers of the endometrium, ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited mutations that impair DNA mismatch repair.
Terminology
According to some sources, HNPCC is also called Lynch syndrome, after Henry T. Lynch (professor of medicine at Creighton University Medical Center),[1] who characterized it in 1966.[2] It is divided into Lynch syndrome I (familial colon cancer) and Lynch syndrome II (colorectal cancer and another type of cancer, usually, but not limited to, the gastrointestinal system or the reproductive system).
Other sources reserve the term "Lynch syndrome" when there is a known DNA mismatch repair defect, and use the term "Familial colorectal cancer type X" when the Amsterdam criteria are met but there is no known DNA mismatch repair defect.[3] The latter type has a lower incidence of cancer.[4] About 35% of patients meeting Amsterdam criteria do not have a DNA-mismatch-repair gene mutation.[5]
Epidemiology
In the United States, about 160,000 new cases of colorectal cancer are diagnosed each year. Hereditary nonpolyposis colorectal cancer is responsible for approximately 2 percent to 7 percent of all diagnosed cases of colorectal cancer. The average age of diagnosis of cancer in patients with this syndrome is 44 years old, as compared to 64 years old in people without the syndrome. [6]
Cause
HNPCC defects in DNA mismatch repair lead to microsatellite instability, also known as MSI-H, which is a hallmark of HNPCC. MSI is identifiable in cancer specimens in the pathology laboratory. [7]
Genetics
HNPCC is known to be associated with mutations in genes involved in the DNA mismatch repair pathway
| Genes implicated in HNPCC | Frequency of mutations in HNPCC families | Locus | First publication
. |
|---|---|---|---|
| MLH1 | Together with MSH2, 90% | 3p21 | Papadopoulos et al., 1994[8] |
| MSH2 | Together with MLH1, 90% | 2p21 | Fishel et al., 1993[9] |
| MSH6 | 7-10% | 2p16 | |
| PMS1 | <5% | 2q31-q33 | |
| PMS2 | <5% | 7p22 |
Patients with MSH6 mutations are more likely to be Amsterdam criteria II-negative.[10] The presentation with MSH6 is slightly different than with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition.[11]
Up to 39% of families with mutations in an HNPCC gene do not meet the Amsterdam criteria.[citation needed] Therefore, 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. This also means that the Amsterdam criteria fail to identify many patients at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article.
HNPCC is inherited in an autosomal dominant manner. Most people with HNPCC inherit the condition from a parent. 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.
Classification
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)
Risk of colon cancer
Individuals with HNPCC have about an 80% lifetime risk for colon cancer. Two-thirds of these cancers occur in the proximal colon. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. Also, women with HNPCC have a 30-50% lifetime risk of endometrial cancer. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal-type adenocarcinoma being the most commonly reported pathology. HNPCC-associated ovarian cancers have an average age of diagnosis of 42.5 years-old; approximately 30% are diagnosed before age 40 years. Other HNPCC-related cancers have been reported with specific features: the urinary tract cancers are transitional carcinoma of the ureter and renal pelvis; small bowel cancers occur most commonly in the duodenum and jejunum; the central nervous system tumor most often seen is glioblastoma.
Screening
Genetic testing for mutations in DNA mismatch repair genes is expensive and time-consuming, so researchers have proposed techniques for identifying cancer patients who are most likely to be HNPCC carriers as ideal candidates for genetic testing. The Amsterdam Criteria (see below) are useful, but do not identify up to 30% of potential Lynch syndrome carriers[citation needed]. In colon cancer patients, pathologists can measure microsatellite instability in colon tumor specimens, which is a surrogate marker for DNA mismatch repair gene dysfunction. If there is microsatellite instability identified, there is a higher likelihood for a Lynch syndrome diagnosis. Recently, researchers combined microsatellite instability (MSI) profiling and immunohistochemistry testing for DNA mismatch repair gene expression and identified an extra 32% of Lynch syndrome carriers who would have been missed on MSI profiling alone.[citation needed] Currently, this combined immunohistochemistry and MSI profiling strategy is the most advanced way of identifying candidates for genetic testing for the Lynch syndrome.
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer.
Amsterdam criteria
The following are the Amsterdam criteria in identifying high-risk candidates for molecular genetic testing:[12]
Amsterdam Criteria:
- Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
- Two successive affected generations
- One or more colon cancers diagnosed under age 50 years
- Familial adenomatous polyposis (FAP) has been excluded
Amsterdam Criteria II:
- Three or more family members with HNPCC-related cancers, one of whom is a first degree relative of the other two
- Two successive affected generations
- One or more of the HNPCC-related cancers diagnosed under age 50 years
- Familial adenomatous polyposis (FAP) has been excluded
Diagnosis
The Amsterdam clinical criteria identifies candidates for genetic testing, and genetic testing can make a diagnosis of Lynch syndrome. Genetic testing is commercially available and consists of a blood test.
Therapy
Surgery remains the front-line therapy for HNPCC. There is an ongoing controversy over the benefit of 5-fluorouracil-based adjuvant therapies for HNPCC-related colorectal tumours, particularly those in stages I and II.[13]
After reporting a null finding from their randomized controlled trial of aspirin (ASA) to prevent against the colorectal neoplasia of Lynch Syndrome,[14] Burn and colleagues have recently reported new data, representing a longer follow-up period than reported in the initial NEJM paper. These new data demonstrates a reduced incidence in Lynch Syndrome patients who were exposed to at least four years of high-dose aspirin, with a satisfactory risk profile.[15] These results have been widely covered in the media; future studies will look at modifying (lowering) the dose (to reduce risk associated with the high dosage of ASA. Individuals with Lynch Syndrome may wish to discuss the application of these results with their medical care team.
References
- ^ School of Medicine :: Hereditary Cancer Center :: Creighton University
- ^ Lynch HT, Shaw MW, Magnuson CW, Larsen AL, Krush AJ (1966). "Hereditary factors in cancer. Study of two large midwestern kindreds". Arch. Intern. Med. 117 (2): 206–12. PMID 5901552.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Lindor NM (2009). "Familial colorectal cancer type X: the other half of hereditary nonpolyposis colon cancer syndrome". Surg. Oncol. Clin. N. Am. 18 (4): 637–45. doi:10.1016/j.soc.2009.07.003. PMID 19793571.
{{cite journal}}: Unknown parameter|month=ignored (help) - ^ Lindor NM, Rabe K, Petersen GM; et al. (2005). "Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X". JAMA. 293 (16): 1979–85. doi:10.1001/jama.293.16.1979. PMID 15855431.
{{cite journal}}: Explicit use of et al. in:|author=(help); Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Scott RJ, McPhillips M, Meldrum CJ; et al. (2001). "Hereditary nonpolyposis colorectal cancer in 95 families: differences and similarities between mutation-positive and mutation-negative kindreds". Am. J. Hum. Genet. 68 (1): 118–127. PMC 1234904. PMID 11112663.
{{cite journal}}: Explicit use of et al. in:|author=(help); Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Cancer Information, Research, and Treatment for all Types of Cancer | OncoLink
- ^ Pathology of Hereditary Nonpolyposis Colorectal Cancer - JASS 910 (1): 62 - Annals of the New York Academy of Sciences
- ^ Papadopoulos N, Nicolaides N, Wei Y, Ruben S, Carter K, Rosen C, Haseltine W, Fleischmann R, Fraser C, Adams M (1994). "Mutation of a mutL homolog in hereditary colon cancer". Science. 263 (5153): 1625–9. doi:10.1126/science.8128251. PMID 8128251.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Fishel R, Lescoe M, Rao M, Copeland N, Jenkins N, Garber J, Kane M, Kolodner R (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.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Ramsoekh D, Wagner A, van Leerdam ME; et al. (2008). "A high incidence of MSH6 mutations in Amsterdam criteria II-negative families tested in a diagnostic setting". Gut. 57 (11): 1539–44. doi:10.1136/gut.2008.156695. PMID 18625694.
{{cite journal}}: Explicit use of et al. in:|author=(help); Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Suchy J, Lubinski J (2008). "MSH6 syndrome". Hered Cancer Clin Pract. 6 (2): 103–104. doi:10.1186/1897-4287-6-2-103. PMC 2735474. PMID 19804606.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 1999;116:1453-6. PMID 10348829.
- ^ Boland CR, Koi M, Chang DK, Carethers JM. The biochemical basis of microsatellite instability and abnormal immunohistochemistry and clinical behavior in Lynch Syndrome: from bench to bedside. Familial Cancer epub 2007; DOI 10.1007/s10689-007-9145-9
- ^ Burn J, Bishop DT, Mecklin JP; et al. (2008). "Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome". N. Engl. J. Med. 359 (24): 2567–78. doi:10.1056/NEJMoa0801297. PMID 19073976.
{{cite journal}}: Explicit use of et al. in:|author=(help); Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ "Aspirin Confers Long-Term Protective Effect in Lynch Syndrome Patients". Retrieved 2009-11-07.