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South African Journal of Surgery
versão On-line ISSN 2078-5151
versão impressa ISSN 0038-2361
S. Afr. j. surg. vol.51 no.2 Cape Town Jan. 2013
EDITORIAL
Inherited colorectal cancer: A plea for a national registry
E D T CoetzeeI; S R ThomsonII
Colorectal Surgery Unit, Department of Surgery, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa
Division of Gastroenterology, University of Cape Town and Groote Schuur Hospital, Cape Town, South Africa
Colorectal cancer (CRC) is the third most common cancer and cause of cancer-related death worldwide.[1] The majority of individuals who develop CRC have sporadic disease, but up to 20% may have an inherited predisposition.121 The two most common forms of autosomal dominant inherited colorectal cancer disorders are hereditary non-polyposis colorectal cancer (HNPCC), or Lynch syndrome, and familial adenomatous polyposis (FAP).[3-8] The interesting publication by Vergouwe et al.19 in the February issue of SAJS highlights the high incidence of inherited CRC in a low-incidence area in South Africa. The authors postulate that inherited CRCs may constitute a significant portion of the total disease burden of CRC in South Africa. To put the implications of this article in context, it is important to understand the advances in understanding of the genetics and their implication for early detection and treatment of patients and their families with these hereditary conditions. Lynch syndrome is the commoner of the two, accounting for 2 - 7% of inherited colorectal cancers, with FAP accounting for less than 1%.[6,1]
FAP is an autosomal dominant disorder with 100% penetrance, caused by mutations in the adenomatous polyposis coli gene located on chromosome 5q21-q22.[11] Mutations are detected in over 80% of individuals with FAP and most others are detected phenotypically. Prophylactic colectomy is indicated for individuals with the disease, and they should be enrolled for surveillance for extracolonic manifestations, especially duodenal polyps.[12,13] Family members with mutations should be screened after proband testing, using family trees and genetic testing. Prophylactic surgery and surveillance for these individuals result in decreased mortality from FAP.[14]
Terminology in HNPCC can be confusing. The term Lynch syndrome should be reserved for individuals in whom a germline mutation in a mismatch repair (MMR) gene has been identified. Familial colorectal cancer syndrome X should be the preferred term when referring to a family meeting the Amsterdam criteria, but without an identifiable mutation.[15] HNPCC is often used as an umbrella term including both these groups, although calls have been made to retire the term.[10]
The importance of identifying individuals with germline mutations lies in enrolling them in screening programmes to allow for detection of polyps and early cancer. Intensive screening for colorectal cancer by colonoscopy as well as prophylactic gynaecological surgery reduces the incidence of Lynch syndrome-related tumours and mortality.[16,17]
The diagnosis of Lynch syndrome has evolved over the last two decades to include family history, tumour histopathological characteristics, immunohistochemistry and testing for microsatellite instability (MSI), as well as germline genetic testing, as modalities for making the diagnosis. The Amsterdam criteria were proposed in 1990[18] and revised in 1997 to identify families at risk of HNPCC.[19] These criteria were proposed before laboratory methods were in clinical use. The Amsterdam II criteria have a sensitivity of 78% in detecting individuals with Lynch syndrome.[20] Improved understanding of the clinical and histological manifestations of Lynch syndrome led the National Cancer Institute to create the Bethesda guidelines in 1996, to identify colorectal cancers that should undergo testing for MSI. These guidelines were revised in 2004.[21,22] Individuals meeting the Amsterdam or Bethesda criteria, but without any other laboratory features of Lynch syndrome, should be labelled as familial colorectal cancer syndrome X and be enrolled in the appropriate screening programme. The risk of developing colorectal cancer in these individuals is lower than in families diagnosed with Lynch syndrome, and they are not at increased risk of extra-colonic malignancies.[23]
MSI testing is currently used as the 'gold standard' in many centres to exclude individuals lacking MSI, who are highly unlikely to have Lynch syndrome. Tumours testing MSI high (MSH-H) are then further tested with immunohistochemistry, and patients with tumours that display loss of one of the MMR proteins should then be offered genetic testing. In Lynch syndrome, there is an inherited mutation in the gene coding for one of the MMR genes MLH1, MSH2, MSH6 and PMS2. Tumours of patients with these mutations have a functional loss of one of these MMR proteins or gene products, and more than 90% of these tumours will lack expression of the involved protein.[24-26] MSI testing, however, is labour intensive and time consuming and requires a skilled molecular geneticist.
Immunohistochemistry is a cost-effective substitute for MSI testing as the first screening tool for Lynch syndrome[27] and is currently used in our unit to detect tumours with possible MMR deficiency. When immunohistochemistry shows absence of an MMR gene product, the patient is offered germline genetic testing for that specific gene. If immunohistochemistry shows presence of all gene products but there is a strong clinical suspicion, MSI testing should be offered.
The Vergouwe study showed that in a low-prevalence area for CRC, inherited cancers form a bigger proportion of the total burden of disease and hence represent a target for focused screening and surveillance.[9] In developed countries and locally, this strategy has been shown to be cost-effective and reduces mortality.[16,28] There are very few, if any, other hereditary cancer registries in southern Africa and the African continent like the Lynch syndrome registry from the Western and Northern Cape, which provided the impetus for the Vergouwe study.[9] One way to start such a registry is to identify patients at risk by using the inexpensive immunohistochemistry technique used by Vergouwe et al., which detects absence of the hMLH1 gene product on all resected colorectal cancers.[91 Those identified in such a manner should undergo genetic counselling,[5,6] and targeted screening of the appropriate family members should be offered. Genetic nurse- counsellors are a cost-effective alternative to clinical geneticists and are invaluable in the formulation and maintenance of family trees, which is an important part of a cancer registry.[29]
There is a need for colorectal surgeons and their association to establish such a registry and to implement focused surveillance programmes, which ultimately will save lives.
REFERENCES
1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012;62(1):10-29. [http://dx.doi.org/10.3322/caac.20138] [ Links ]
2. Jass JR. What's new in hereditary colorectal cancer? Arch Pathol Lab Med 2005;129(11):1380-1384. [http://dx.doi.org/10.1043/1543-2165(2005)129] [ Links ]
3. Heald B, Church J, Plesec T, Burke CA. Detecting and managing hereditary colorectal cancer syndromes in your practice. Cleve Clin J Med 2012;79(11):787-796. [http://dx.doi.org/10.3949/ccjm.79a.11165] [ Links ]
4. Hampel H. Genetic testing for hereditary colorectal cancer. Surg Oncol Clin N Am 2009;18(4):687-703. [http://dx.doi.org/10.1016/j.soc.2009.08.001] [ Links ]
5. Lynch HT, Boland CR, Rodriguez-Bigas MA, Amos C, Lynch JF, Lynch PM. Who should be sent for genetic testing in hereditary colorectal cancer syndromes? J Clin Oncol 2007;25(23):3534-3542. [http://dx.doi.org/10.1200/JCO.2006.10.3119] [ Links ]
6. Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med 2003;348(10):919-932. [http://dx.doi.org/10.1056/NEJMra012242] [ Links ]
7. Lynch HT, Lynch JF, Lynch PM, Attard T. Hereditary colorectal cancer syndromes: Molecular genetics, genetic counseling, diagnosis and management. Fam Cancer 2008;7(1):27-39. [http://dx.doi.org/10.1007/s10689-007-9165-5] [ Links ]
8. Petersen GM, Brensinger JD, Johnson KA, Giardiello FM. Genetic testing and counseling for hereditary forms of colorectal cancer. Cancer 1999;86(11 suppl):2540-2550. [http://dx.doi.org/10.1002/(SICI)1097-0142(19991201)86:11+<2540::AID-CNCR11>3.0.CO;2-8] [ Links ]
9. Vergouwe F, Boutall A, Stupart D, et al. Mismatch repair deficiency in colorectal cancer patients in a low-incidence area. S Afr J Surg 2013;51(1):16-21. [http:// dx.doi.org/10.7196/SAJS.1314] [ Links ]
10. Vasen HF, Mecklin JP, Khan PM, Lynch HT. The international collaborative group on hereditary non-polyposis colorectal cancer (ICG-HNPCC). Dis Colon Rectum 1991;34(5):424-425. [http://dx.doi.org/10.1007/BF02053699] [ Links ]
11. Wu JS, Paul P, McGannon EA, Church JM. APC genotype, polyp number, and surgical options in familial adenomatous polyposis. Ann Surg 1998(1);227(1):57-62. [http://dx.doi.org/10.1097/00000658-199801000-00009] [ Links ]
12. Vasen HF, Bulow S, Myrhoj T, et al. Decision analysis in the management of duodenal adenomatosis in familial adenomatous polyposis. Gut 1997;40(6):716-719. [http://dx.doi.org/10.1136/gut.40.6.716] [ Links ]
13. Groves CJ, Saunders BP, Spigelman AD, Phillips RK. Duodenal cancer in patients with familial adenomatous polyposis (FAP): Results of a 10 year prospective study. Gut 2002;50(5):636-641. [http://dx.doi.org/10.1136/gut.50.5.636] [ Links ]
14. Macrae F, du Sart D, Nasioulas S. Familial adenomatous polyposis. Best Pract Res Clin Gastroenterol 2009;23(2):197-207. [http://dx.doi.org/10.1016/j.bpg.2009.02.010] [ Links ]
15. Jass JR. Hereditary non-polyposis colorectal cancer: The rise and fall of a confusing term. World J Gastroenterol 2006;12(31):4943-4950. [ Links ]
16. Stoffel EM, Chittenden A. Genetic testing for hereditary colorectal cancer: Challenges in identifying, counseling, and managing high-risk patients. Gastroenterology 2010;139(5):1436-1441. [http://dx.doi.org/10.1053/j.gastro.2010.09.018] [ Links ]
17. Bonadona V, Bonaiti B, Olschwang S, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 2011;305(22):2304-2310. [http://dx.doi.org/10.1001/jama.2011.743] [ Links ]
18. 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(6):1453-1456. [http://dx.doi.org/10.1016/S0016-5085(99)70510-X] [ Links ]
19. Rodriguez-Bigas MA, Boland CR, Hamilton SR, et al. A National Cancer Institute workshop on hereditary nonpolyposis colorectal cancer syndrome: Meeting highlights and Bethesda guidelines. J Natl Cancer Inst 1997;89(23):1758-1762.[http://dx.doi.org/10.1093/jnci/89.23.1758] [ Links ]
20. de Leon MP, Pedroni M, Benatti P, et al. Hereditary colorectal cancer in the general population: From cancer registration to molecular diagnosis. Gut 1999;45(1):32-38. [http://dx.doi.org/10.1136/gut.45.1.32] [ Links ]
21. Boland CR, Thibodeau SN, Hamilton SR, et al. A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: Development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 1998;58:5248-5257. [ Links ]
22. Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 2004;96(4):261-268. [http://dx.doi.org/10.1093/jnci/djh034] [ Links ]
23. Lindor NM, Rabe K, Petersen GM, et al. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: Familial colorectal cancer type X. JAMA 2005;293(16):1979-1985. [http://dx.doi.org/10.1001/jama.293.16.1979] [ Links ]
24. Dietmaier W, Wallinger S, Bocker T, Kullmann F, Fishel R, Ruschoff J. Diagnostic microsatellite instability: Definition and correlation with mismatch repair protein expression. Cancer Res 1997;57(21):4749-4756. [ Links ]
25. Thibodeau SN, French AJ, Roche PC, et al. Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes. Cancer Res 1996;56(21):4836-4840. [ Links ]
26. Peltomaki P, Vasen HF. Mutations predisposing to hereditary nonpolyposis colorectal cancer: Database and results of a collaborative study. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer. Gastroenterology 1997;113(4):1146-1158. [http://dx.doi.org/10.1053/gast.1997.v113.pm9322509] [ Links ]
27. Shia J. Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome: Part I. The utility of immunohistochemistry. J Mol Diagn 2008;10(4):293-300. [http://dx.doi.org/10.2353/jmoldx.2008.080031] [ Links ]
28. Stupart DA, Goldberg PA, Algar U, Ramesar R. Surveillance colonoscopy improves survival in a cohort of subjects with a single mismatch repair gene mutation. Colorectal Dis 2009;11(2):126-130. [http://dx.doi.org/10.1111/j.1463-1318.2008.01702.x] [ Links ]
29. Torrance N, Mollison J, Wordsworth S, et al. Genetic nurse counsellors can be an acceptable and cost-effective alternative to clinical geneticists for breast cancer risk genetic counselling: Evidence from two parallel randomised controlled equivalence trials. Br J Cancer 2006;95(4):435-444. [http://dx.doi.org/10.1038/sj.bjc.6603248] [ Links ]
Corresponding author:
S R Thomson
(sandie.thomson@uct.ac.za)