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Hereditary cancer: guidelines in clinical practice. Colorectal cancer genetics
Annals of Oncology 15 (Supplement 4): iv127 – iv131, 2004 doi:10.1093/annonc/mdh916
Hereditary cancer: guidelines in clinical practice. Colorectal cancer genetics H. J. Ja¨rvinen Helsinki University Central Hospital, Department of Surgery, Division of Gastroenterology, Helsinki, Finland
Colorectal cancer is one of the three most common cancer types in Europe and North America. While lifestyle and environmental factors contribute to the pathogenesis of sporadic cases, between 5% and 15% of patients develop colorectal cancer on the basis of an underlying genetic predisposition, often caused by a mutation in a single gene [1]. Because the predisposition is due to an inherited germline mutation the onset of cancer occurs at a much earlier age than in sporadic cancer and, importantly, identification of the hereditary trait in a patient offers an excellent chance for prevention or early detection of cancer in other family members by appropriate genetic workup, endoscopic surveillance of asymptomatic family members and, in some cases, by prophylactic surgery. There are two main clinical types of genetically determined predisposition to colorectal cancer: (i) intestinal polyposis syndromes; and (ii) hereditary non-polyposis colorectal cancer (HNPCC). The polyposis syndromes can be further divided into three different clinical entities: (i) familial adenomatous polyposis (FAP); (ii) juvenile polyposis (JP); and (iii) Peutz–Jeghers polyposis (P-JP). The cancer risk in polyposis syndromes results from the development of multiple adenomatous polyps in the colon and rectum and their malignant transformation through the adenoma –carcinoma sequence [2]. Even though the polyps in JP and P-JP are histopathologically defined as hamartomas, adenomatous change has been shown to develop in some of these originally non-neoplastic polyps, leading to increased cancer risk [3, 4]. The HNPCC syndrome is characterised by the development of colorectal cancer without preceding multiple adenomas but, in fact, solitary or few adenomas are the precursor lesions in this condition. It is presumed that the underlying DNA mismatch-repair gene defect accelerates the malignant transformation of sporadic adenomas in HNPCC [5]. The genes and mutations in inherited predisposition to colorectal cancer have been largely unravelled over the last 15 years [1, 6]. Most syndromes follow an autosomal dominant inheritance pattern, which means that each child of an affected parent will have a 50:50 chance of inheriting the predisposition. Recently, a new recessive predisposition type, MYH polyposis, was detected, explaining a portion of FAP-like cases of polyposis where no underlying mutation of the APC gene could be found [7, 8]. A summary of the q 2004 European Society for Medical Oncology
presently known genetically determined predispositions to colorectal cancer is shown in Table 1. There are many reasons to predict that more genes and predispositions will be defined in the future, in particular among those families exhibiting a dominant inheritance pattern but no demonstrable mutation in the known genes, and possibly also among less prominent types of familial aggregation of colorectal cancer. The following review presents the different genetic syndromes predisposing to colorectal cancer, the principles of treatment in each condition and, importantly, guidelines for the identification of these syndromes. It also considers the prevention and early detection of cancer in the family members of affected patients by genetic testing, endoscopic surveillance and prophylactic surgery.
Polyposis syndromes Familial adenomatous polyposis FAP [Mendelian inheritance in man (MIM) no. 175100] is classically characterised by at least 100 adenomatous polyps in the colon and rectum [9], but an attenuated form with a fewer number of adenomas has been described. Turcot syndrome is a variant associated with a brain tumour, medulloblastoma (MIM no. 276300). The estimated incidence of FAP is about one per 10 000 newborns or one to two per 1 million persons per year [10]. Between one-third and a half of new cases are individual patients representing new mutations of the APC gene; in others several family members are affected. Mutations of this gene, located on the long arm of chromosome 5 (5q21–22), cause the disease [11]. An APC mutation can be detected in two-thirds or more of the families affected with FAP [12]. In the remaining families, mutations of the MYH gene may explain a portion of cases [8], especially in those with attenuated disease, but more genetic aetiologies will undoubtedly be found. The clinical diagnosis of FAP needs endoscopic demonstration of at least 100 histologically confirmed colorectal adenomas. The context of a known family history helps in the diagnosis, especially in the attenuated disease form. Final diagnosis is achieved by discovery of a mutation in the APC gene. Additional factors for the diagnosis may be the demonstration of epidermoid cysts, osteomas of the jaws, desmoid tumours, gastric fundic gland polyps or congenital hypertrophy of the retinal epithelium [13].
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Introduction
iv128 Table 1. Genetic conditions predisposing to colorectal cancer, the underlying genes, the estimated cumulative lifetime cancer risk and the burden of all new colorectal cancer cases (minimum) Condition
Gene/chromosome
Lifetime cancer risk (%)
Proportion of all new cases (%)
FAP
APC/5q
100
0.1–0.5
JP
SMAD4/18q BMPR1A/10q LKB1/19p
MYHP
MYH/1p
HNPCC
MLH1/3p
<0.1
10
<0.1
?
<0.1 80
3.0
MSH2/2p MSH6/2p (PMS1, PMS2, MLH3/2q, 7q, 14q) FAP, familial adenomatous polyposis; JP, juvenile polyposis; P-JP, Pertz–Jeghers polyposis; MYHP, MYH polyposis; HNPCC, hereditary non-polyposis colorectal cancer; ?, not known.
The most important clinical feature of FAP is the development of cancer in one or more of the multiple colorectal adenomas at the mean age of 40 years [13]. Adenomas appear at puberty and they gradually cause symptoms of diarrhoea, rectal bleeding and features of anaemia. At diagnosis, 60% of symptomatic FAP patients will have colorectal cancer. On the other hand, if endoscopic screening is offered to the at-risk family members of an affected patient, the diagnosis can be established before the development of cancer. In practice, fibreoptic sigmoidoscopy should be offered from the age of 12 –15 years for all children of an FAP parent. If an APC mutation of the particular family has been identified, endoscopy can be replaced by mutation testing, if accepted by at-risk individuals. Consequently, only mutation-positive individuals need endoscopic surveillance to evaluate adenoma development and to estimate the timing of prophylactic surgery. The treatment for FAP is prophylactic colectomy, which should be performed at the age of 20 –25 years [14]. Colectomy with ileorectal anastomosis and life-long surveillance of the rectal stump is still appropriate, but leaves a definite rectal cancer risk up to 15% or more within 20– 25 years [15]. Therefore, many authors favour proctocolectomy with ileal pouch–anal anastomosis in most patients, despite the risk of a less perfect anal function. Morbidity may also be caused by duodenal cancer, for which reason periodic duodenoscopy is recommended, and by poorly treatable desmoid tumours. In general, early diagnosis and proper prophylactic treatment of FAP results in an excellent survival outcome comparable to that of the general population [16].
Juvenile polyposis JP (MIM no. 174900, 17505) resembles FAP and presents with multiple colorectal polyps but also with polyps in the
Peutz – Jeghers polyposis The typical features of P-JP (MIM no. 175200) are hamartomatous intestinal polyps and mucocutaneous melanin pigmentation. The polyps predominantly affect the small intestine but occur also in the stomach and large bowel. The syndrome is caused by mutations of the LKB1 gene on chromosome 19p [21]. It is rare and occurs in about one per 100 000 newborns. The hamartomatous polyps have a peculiar branching of the muscularis mucosae up to the tips of the villi and, despite their originally non-neoplastic nature, they may develop adenomatous dysplasia and cancer [3]. Consequently, there is an 80–500-fold excess of gastrointestinal cancer in the P-JP syndrome [22]. The increased cancer risk associated with P-J polyps has led to the recommendation of endoscopic polypectomies at 2-year intervals via upper gastointestinal endoscopy and colonoscopy [23]. The small bowel can in addition be evaluated by capsule endoscopy. During operations because of small bowel obstruction due to intussusception, the entire small intestine should be cleared of polyps by enterotomies.
MYH polyposis This novel, recessively inherited, cancer syndrome is still poorly defined. About 50% of patients present as multiple adenomatous polyposis or an FAP-like condition, while 50% have a small number of adenomas in association with colorectal cancer [8, 24]. MYH polyposis should be considered in FAP without a demonstrable mutation in the APC gene. In one study in patients with colorectal cancer, the proportion with mutations of MYH was about four in 1000 patients, suggesting that the frequency of MYH polyposis might be near to that of FAP [24]. The criteria for MYH polyposis await further clarification. However, endoscopic surveillance of the remaining colon after colectomy seems appropriate, and total colectomy instead of hemicolectomy or segmental resection should be
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P-JP
50
stomach and small intestine [17]. The polyps are hamartomatous, cystic polyps exhibiting hyperplastic stroma and inflammation. Large polyps are often lobulated and show adenomatous dysplasia giving rise to an increased lifetime cancer risk of up to 50% [4]. The number of juvenile polyps is moderate, with 50 –200 polyps in the colon, while many patients have only a few polyps. The syndrome is about 10 times less common than FAP, with an estimated frequency of one per 100 000 newborns. It is caused by mutations of at least two separate genes: SMAD4/DPC4 on chromosome 18q and BMPR1A/ALK3 on chromosome 10q [18, 19]. The treatment of JP consists of repeated endoscopic removal of all polyps detected in the colon or upper gastrointestinal tract at 2-year intervals. In patients with a high number of polyps in the colon, colectomy with ileorectal anastomosis is appropriate [20]. The treatment is aimed at decreasing the cancer risk and preventing symptoms such as bleeding, anaemia and diarrhoea.
iv129 strongly considered in patients where genetic diagnosis has been achieved.
Hereditary non-polyposis colorectal cancer
Table 2. The Amsterdam criteria for the clinical definition of hereditary non-polyposis colorectal cancer 1.
Three (or more) patients with colorectal cancer in a family; one patient is a first-degree relative of the other twoa
2.
Colorectal cancera occurs in at least two generations
3.
At least one cancer patient is diagnosed before the age of 50 years
4.
Familial adenomatous polyposis excluded
a
One or more of the cancers may be endometrial, small intestinal or urothelial cancer.
Genetic testing In families with polyposis syndromes, prophylactic endoscopy at a young age is a good method for diagnosis, while in families with HNPCC examinations should be repeated over their lifetimes because of lack of multiple polyps, even though half of them do not need such surveillance. Predictive genetic testing of family members of a patient affected with a dominant-inherited susceptibility syndrome offers a simple means for risk evaluation. Before testing, the molecular diagnosis of the particular mutation in the family must be determined. This is possible in 50% to 75% of families with polyposis syndromes and in 80% of HNPCC families [6]. The first step towards genetic testing is a reliable clinical and histopathological diagnosis. This makes it possible to direct the search for the pathogenic mutation in the appropriate gene(s). In HNPCC the presence of microsatellite instability supports the presence of a mismatch-repair defect. Furthermore, mismatch-repair gene proteins can be stained with immunohistochemical techniques in tumour tissue [33]. The final identification is done by sequencing a particular gene. After a reliable identification of the pathogenic mutation, the predictive testing of at-risk family members is highly accurate. Accordingly, mutation-positive subjects can be advised on appropriate prophylactic measures, such as endoscopy and surgery in FAP or colonoscopic surveillance in HNPCC. Mutation-negative subjects need no further increased evaluation and the same applies to their children. Omission of endoscopic surveillance of half of the offspring correspondingly cuts the costs of screening. This may cover the extra
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HNPCC (MIM no. 120435, 120436), or Lynch syndrome, is an autosomal-dominant cancer predisposition syndrome with no clear clinical signs preceding cancer except for solitary adenomas. The predominant tumours are colorectal and endometrial cancer, with estimated lifetime risks of 80% and 60%, respectively. Increased risk has been observed for gastric, ovarian, urothelial, bile duct, kidney and small intestinal cancers and brain tumours, resulting in a lifetime risk between 2% and 13% [25]. Mutations in one of several DNA mismatch-repair genes cause the predisposition [1]. Mutations in the MHS2 and MLH1 genes are responsible for >90% of HNPCC families with a known mutation, while some 5% are due to mutations in MSH6. The role of mutations in PMS1, PMS2 and MSH3 in HNPCC is minimal [1, 26]. HNPCC is the most common hereditary colorectal cancer syndrome, explaining up to 3% of all colorectal cancers [27]. Clinical features suggesting HNPCC include cancer at young age, proximal site of the colon and synchronous (or metachronous) second tumours [28]. The DNA content of the tumour is diploid [29] and microsatellite instability is characteristic in HNPCC [30]. In addition, histology often reveals a high mucin content, poor differentiation and Crohn’s diseaselike inflammatory reaction around the tumour [31]. These clinical or pathological features are not specific. The family history is essential and is the basis for the clinical Amsterdam criteria (Table 2). In the latest revision of the Amsterdam criteria, one or more of the index tumours may include endometrial, small intestinal or urothelial cancer instead of colorectal cancer [32]. However, the final diagnosis is only possible after detection of a pathogenic germline mutation in one of the DNA mismatch-repair genes. This also allows predictive genetic testing of family members of the affected patients. Thereafter, clinical surveillance can be limited to mutation-positive individuals, while mutation-negative family members need no follow-up. The search for a germline mutation precedes, at present, the determination of microsatellite instability and the immunohistochemical study of the expression of the DNA mismatchrepair genes in tumour tissue [33]. In cancer patients with HNPCC, a total abdominal colectomy with ileosigmoidal anastomosis is preferable to
hemicolectomy because of the high risk of metachronous second tumours [34]. In addition, the remaining colon and rectum should be subsequently examined every 2 –3 years. Furthermore, in women, prophylactic hysterectomy should be considered or surveillance by endometrial aspiration biopsy should be performed every 2–3 years. For asymptomatic mutation carriers, a cancer surveillance and prevention programme should be proposed. Colonoscopic screening with polypectomies reduces colorectal cancer incidence by >60%, prevents cancer deaths and improves overall life-expectancy [35]. Screening for endometrial and ovarian cancer is commonly recommended, with endometrial aspiration biopsy and ultrasonography every 2 –3 years starting from age 30–35 years, even though formal evidence proving benefit is lacking [36]. Prophylactic hysterectomy, salpingo-oophorectomy and colectomy is an alternative option. Chemoprevention of colorectal cancer with cyclo-oxygenase-2 inhibitors such as aspirin is under evaluation. Similarly, the role of oral contraceptives in reducing the risk of endometrial and ovarian cancer in the context of HNPCC is worthy of further study. There remains an excess risk of tumour types for which preventive programmes are of unproven benefit, such as gastric cancer [37], bile duct and urothelial cancers or brain tumours.
iv130
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syndrome): report of a case and review of the literature. Cancer 1982; 49: 971– 983. 4. Jass JR, Williams CB, Bussey HJR, Morson BC. Juvenile polyposis—a precancerous condition. Histopathology 1988; 13: 619–630. 5. Jass JR, Stewart SM, Stewart J, Lane MR. Hereditary non-polyposis colorectal cancer—morphologies, genes and mutations. Mutat Res 1994; 310: 125 –133. 6. Ja¨rvinen HJ. Genetic testing for polyposis: practical and ethical aspects. Gut 2003; 52 (Suppl II): ii19–ii22. 7. Al-Tassan N, Chmiel NH, Maynard J et al. Inherited variants of MYH associated with somatic G:C–T:A mutations in colorectal tumors. Nat Genet 2002; 30: 227 –232. 8. Sieber OM, Lipton L, Crabtree M et al. Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med 2003; 348: 791 –799. 9. Bussey HJR. Familial polyposis coli. Family studies, histopathology, differential diagnosis and results of treatment. Baltimore, MD: The Johns Hopkins University Press 1975. 10. Bu¨low S, Holm NV, Hauge M. The incidence and prevalence of familial adenomatous polyposis in Denmark. Scand J Soc Med 1986; 14: 67–74. 11. Groden J, Thliveris A, Samowitz W et al. Identification and characterization of the familial adenomatous polyposis gene. Cell 1991; 66: 589–600. 12. Moisio A-L, Ja¨rvinen H, Peltoma¨ki P. Genetic and clinical characterisation of familial adenomatous polyposis: a population based study. Gut 2002; 50: 845– 850. 13. Talbot IC, Burt R, Ja¨rvinen H, Thomas G. Familial adenomatous polyposis. In Hamilton SR, Aaltonen LA (eds): WHO Classification of Tumours: Pathology and Genetics of Tumours of the Digestive System. Lyon: IARC Press 2000; 120–125. 14. Ja¨rvinen HJ. Time and type of prophylactic surgery for familial adenomatosis coli. Ann Surg 1985; 202: 93–97. 15. Bu¨low C, Vasen HFA, Ja¨rvinen H et al. Ileorectal anastomosis is appropriate for a subset of patients with familial adenomatous polyposis. Gastroenterology 2000; 119: 1454– 1460. 16. Heiskanen I, Luostarinen T, Ja¨rvinen HJ. Impact of screening examinations on survival in familial adenomatous polyposis. Scand J Gastorenterol 2000; 35: 1284–1287. 17. McColl I, Bussey HJR, Veale AM, Morson BC. Juvenile polyposis coli. Proc R Soc Med 1964; 57: 896–897. 18. Howe JR, Roth S, Ringold JC et al. Mutations in the SMAD4/DCP4 gene in juvenile polyposis. Science 1998; 280: 1086–1088. 19. Howe JR, Blair JA, Sayed MG et al. Germline mutations of BMPR1A in juvenile polyposis. Nat Genet 2001; 28: 184 –187. 20. Ja¨rvinen H. Juvenile gastrointestinal polyposis. Probl Gen Surg 1993; 10: 749–757. 21. Hemminki A, Markie D, Tomlinson IPM et al. A serine/threonine kinase gene defective in Peutz–Jeghers syndrome. Nature 1998; 391: 184–187. 22. Giardiello FM, Brensinger JD, Tersmette AC et al. Very high risk of cancer in familial Peutz–Jeghers syndrome. Gastroenterology 2000; 119: 1447–1453. 23. Phillips RKS, Spigelman AD, Thomson JPS. Familial adenomatous polyposis and other polyposis syndromes. London: Edward Arnold 1994; 188–202. 24. Enholm S, Hienonen T, Suomalainen A et al. Proportion and phenotype of MYH associated colorectal neoplasia in a population based series of Finnish colorectal cancer patients. Am J Pathol 2003; 163: 827–832. 25. Aarnio M, Sankila R, Pukkala E et al. Cancer risk in mutation carriers of DNA-mismatch repair genes. Int J Cancer 1999; 81: 214–218.
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costs of mutation testing and the search for the pathogenic mutation. Genetic testing also results in an increased accuracy of diagnosis leading to a reduction in anxiety in family members with a negative test result. Furthermore, mutation data may have some clinical significance in explaining the phenotypic variation of FAP in different families [38], even though the clinical application of this knowledge is limited. An important aspect of genetic testing is adequate genetic counselling before testing. Knowledge of a cancer predisposition syndrome in a family provokes significant anxiety, which tends to increase in the case of a positive test result. In a study of at-risk family members of HNPCC patients, the immediate anxiety scores of mutation-positive subjects increased and those of mutation-negative subjects decreased; but the difference, however, in anxiety scores disappeared within 1 month [39]. Despite careful individual counselling, the mutation-positive subjects commonly tended to misunderstand or forget the significance of the test result and the consequent risks [40]. Individual counselling and ensuring informed written consent before testing is necessary because of the possible deleterious effects of testing besides anxiety. For example, eligibility for insurance or employment may be affected, even though there is common agreement that genetic testing should not cause discrimination and test results are confidential. The practices of insurance companies and employers in non-European countries may differ from those in the European Union. The identification of a family with an inherited cancer predisposition syndrome verified by genetic diagnostics causes worry about the organisation of permanent surveillance and proper prophylactic treatment throughout life, including screening and testing of all family members. This task is often beyond the scope of an individual clinician, especially if the family is large and scattered around the country or even abroad. National or regional polyposis and HNPCC registries give the best guarantees of continued care of surveillance, genealogical studies, genetic counselling and testing. Research cooperation is still needed and ongoing in most of the registries covering almost the whole of Europe [41]. In updating their patient follow-up data, the registries need informed consent of the family members as stated in the Personal Data Act by the European Union. In many registries, including the Finnish Polyposis and HNPCC Registry, achieving permanent status and financial independence awaits resolution. These problems will hopefully be solved in the near future considering the excellent results in cancer prevention provided by cancer genetics care [16, 35].
iv131 34. de Vos tot Nederveen Cappel, Buskens E, van Duijvendijk P et al. Decision analysis in the surgical treatment of colorectal cancer due to a mismatch repair gene defect. Gut 2003; 52: 1752–1755. 35. Ja¨rvinen HJ, Aarnio M, Mustonen H et al. Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 2000; 118: 829–834. 36. Lawes DA, SenGupta SB, Boulos PB. Pathogenesis and clinical management of hereditary non-polyposis colorectal cancer. Br J Surg 2002; 89: 1357–1369. 37. Renkonen-Sinisalo L, Sipponen P, Aarnio M et al. No support for endoscopic surveillance for gastric cancer in hereditary non-polyposis colorectal cancer. Scand J Gastroenterol 2002; 37: 574– 577. 38. Ja¨rvinen HJ, Peltoma¨ki P. The complex genotype– phenotype relationship in familial adenomatous polyposis. Eur J Gastroenterol Hepatol 2004; 16: 5–8. 39. Akta´n-Colla´n K, Haukkala A, Mecklin J-P et al. Psychological consequences of predictive genetic testing for hereditary nonpolyposis colorectal cancer (HNPCC): a prospective follow-up study. Int J Cancer 2001; 93: 608–611. 40. Akta´n-Colla´n K, Haukkala A, Mecklin J-P et al. Comprehension of cancer risk 1 and 12 months after predictive genetic testing for hereditary colon cancer. J Med Genet 2001; 38: 787– 792. 41. Spigelman AD, Thomson JPS. Introduction, history and registries. In Phillips RKS, Spigelman AD, Thomson JPS (eds): Familial Adenomatous Polyposis and Other Polyposis Syndromes. London: Edward Arnold 1994; 3–14.
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26. Liu T, Yan H, Kuismanen S et al. The role of hPMS1 and hPMS2 in predisposing to colorectal cancer. Cancer Res 2001; 61: 7798–7802. 27. Salovaara R, Loukola A, Kristo P et al. Population-based molecular detection of hereditary nonpolyposis colorectal cancer. J Clin Oncol 2000; 18: 2193– 2200. 28. Mecklin J-P, Ja¨rvinen HJ. Clinical features of colorectal carcinoma in cancer family syndrome. Dis Colon Rectum 1986; 29: 160 –164. 29. Kouri M, Laasonen A, Mecklin J-P et al. Diploid predominance in hereditary nonpolyposis colorectal carcinoma evaluated by flow cytometry. Cancer 1990; 65: 1825–1829. 30. Aaltonen LA, Peltoma¨ki P, Leach FS et al. Clues to the pathogenesis of familial colorectal cancer. Science 1993; 260: 812–816. 31. Shashidharam M, Smyrk T, Liu KM et al. Histologic comparison of hereditary nonpolyposis colorectal cancer associated with MSH2 and MLH1 and colorectal cancer from the general population. Dis Colon Rectum 1999; 42: 722 –726. 32. Vasen HFA, Watson P, Mecklin J-P et al. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC. Gastroenterology 1999; 116: 1453–1456. 33. Wahlberg SS, Schneits J, Thomas G et al. Evaluation of microsatellite instability and immunohistochemistry for the prediction of germ-line MHS2 and MLH1 mutations in hereditary nonpolyposis colon cancer. Cancer Res 2002; 62: 3485–3492.
Hereditary cancer: guidelines in clinical practice. Colorectal cancer genetics H. J. Ja¨rvinen Helsinki University Central Hospital, Department of Surgery, Division of Gastroenterology, Helsinki, Finland
Colorectal cancer is one of the three most common cancer types in Europe and North America. While lifestyle and environmental factors contribute to the pathogenesis of sporadic cases, between 5% and 15% of patients develop colorectal cancer on the basis of an underlying genetic predisposition, often caused by a mutation in a single gene [1]. Because the predisposition is due to an inherited germline mutation the onset of cancer occurs at a much earlier age than in sporadic cancer and, importantly, identification of the hereditary trait in a patient offers an excellent chance for prevention or early detection of cancer in other family members by appropriate genetic workup, endoscopic surveillance of asymptomatic family members and, in some cases, by prophylactic surgery. There are two main clinical types of genetically determined predisposition to colorectal cancer: (i) intestinal polyposis syndromes; and (ii) hereditary non-polyposis colorectal cancer (HNPCC). The polyposis syndromes can be further divided into three different clinical entities: (i) familial adenomatous polyposis (FAP); (ii) juvenile polyposis (JP); and (iii) Peutz–Jeghers polyposis (P-JP). The cancer risk in polyposis syndromes results from the development of multiple adenomatous polyps in the colon and rectum and their malignant transformation through the adenoma –carcinoma sequence [2]. Even though the polyps in JP and P-JP are histopathologically defined as hamartomas, adenomatous change has been shown to develop in some of these originally non-neoplastic polyps, leading to increased cancer risk [3, 4]. The HNPCC syndrome is characterised by the development of colorectal cancer without preceding multiple adenomas but, in fact, solitary or few adenomas are the precursor lesions in this condition. It is presumed that the underlying DNA mismatch-repair gene defect accelerates the malignant transformation of sporadic adenomas in HNPCC [5]. The genes and mutations in inherited predisposition to colorectal cancer have been largely unravelled over the last 15 years [1, 6]. Most syndromes follow an autosomal dominant inheritance pattern, which means that each child of an affected parent will have a 50:50 chance of inheriting the predisposition. Recently, a new recessive predisposition type, MYH polyposis, was detected, explaining a portion of FAP-like cases of polyposis where no underlying mutation of the APC gene could be found [7, 8]. A summary of the q 2004 European Society for Medical Oncology
presently known genetically determined predispositions to colorectal cancer is shown in Table 1. There are many reasons to predict that more genes and predispositions will be defined in the future, in particular among those families exhibiting a dominant inheritance pattern but no demonstrable mutation in the known genes, and possibly also among less prominent types of familial aggregation of colorectal cancer. The following review presents the different genetic syndromes predisposing to colorectal cancer, the principles of treatment in each condition and, importantly, guidelines for the identification of these syndromes. It also considers the prevention and early detection of cancer in the family members of affected patients by genetic testing, endoscopic surveillance and prophylactic surgery.
Polyposis syndromes Familial adenomatous polyposis FAP [Mendelian inheritance in man (MIM) no. 175100] is classically characterised by at least 100 adenomatous polyps in the colon and rectum [9], but an attenuated form with a fewer number of adenomas has been described. Turcot syndrome is a variant associated with a brain tumour, medulloblastoma (MIM no. 276300). The estimated incidence of FAP is about one per 10 000 newborns or one to two per 1 million persons per year [10]. Between one-third and a half of new cases are individual patients representing new mutations of the APC gene; in others several family members are affected. Mutations of this gene, located on the long arm of chromosome 5 (5q21–22), cause the disease [11]. An APC mutation can be detected in two-thirds or more of the families affected with FAP [12]. In the remaining families, mutations of the MYH gene may explain a portion of cases [8], especially in those with attenuated disease, but more genetic aetiologies will undoubtedly be found. The clinical diagnosis of FAP needs endoscopic demonstration of at least 100 histologically confirmed colorectal adenomas. The context of a known family history helps in the diagnosis, especially in the attenuated disease form. Final diagnosis is achieved by discovery of a mutation in the APC gene. Additional factors for the diagnosis may be the demonstration of epidermoid cysts, osteomas of the jaws, desmoid tumours, gastric fundic gland polyps or congenital hypertrophy of the retinal epithelium [13].
Downloaded from http://annonc.oxfordjournals.org/ at Mahidol University, Faculty of Medicine, Siriraj Hospital on March 8, 2015
Introduction
iv128 Table 1. Genetic conditions predisposing to colorectal cancer, the underlying genes, the estimated cumulative lifetime cancer risk and the burden of all new colorectal cancer cases (minimum) Condition
Gene/chromosome
Lifetime cancer risk (%)
Proportion of all new cases (%)
FAP
APC/5q
100
0.1–0.5
JP
SMAD4/18q BMPR1A/10q LKB1/19p
MYHP
MYH/1p
HNPCC
MLH1/3p
<0.1
10
<0.1
?
<0.1 80
3.0
MSH2/2p MSH6/2p (PMS1, PMS2, MLH3/2q, 7q, 14q) FAP, familial adenomatous polyposis; JP, juvenile polyposis; P-JP, Pertz–Jeghers polyposis; MYHP, MYH polyposis; HNPCC, hereditary non-polyposis colorectal cancer; ?, not known.
The most important clinical feature of FAP is the development of cancer in one or more of the multiple colorectal adenomas at the mean age of 40 years [13]. Adenomas appear at puberty and they gradually cause symptoms of diarrhoea, rectal bleeding and features of anaemia. At diagnosis, 60% of symptomatic FAP patients will have colorectal cancer. On the other hand, if endoscopic screening is offered to the at-risk family members of an affected patient, the diagnosis can be established before the development of cancer. In practice, fibreoptic sigmoidoscopy should be offered from the age of 12 –15 years for all children of an FAP parent. If an APC mutation of the particular family has been identified, endoscopy can be replaced by mutation testing, if accepted by at-risk individuals. Consequently, only mutation-positive individuals need endoscopic surveillance to evaluate adenoma development and to estimate the timing of prophylactic surgery. The treatment for FAP is prophylactic colectomy, which should be performed at the age of 20 –25 years [14]. Colectomy with ileorectal anastomosis and life-long surveillance of the rectal stump is still appropriate, but leaves a definite rectal cancer risk up to 15% or more within 20– 25 years [15]. Therefore, many authors favour proctocolectomy with ileal pouch–anal anastomosis in most patients, despite the risk of a less perfect anal function. Morbidity may also be caused by duodenal cancer, for which reason periodic duodenoscopy is recommended, and by poorly treatable desmoid tumours. In general, early diagnosis and proper prophylactic treatment of FAP results in an excellent survival outcome comparable to that of the general population [16].
Juvenile polyposis JP (MIM no. 174900, 17505) resembles FAP and presents with multiple colorectal polyps but also with polyps in the
Peutz – Jeghers polyposis The typical features of P-JP (MIM no. 175200) are hamartomatous intestinal polyps and mucocutaneous melanin pigmentation. The polyps predominantly affect the small intestine but occur also in the stomach and large bowel. The syndrome is caused by mutations of the LKB1 gene on chromosome 19p [21]. It is rare and occurs in about one per 100 000 newborns. The hamartomatous polyps have a peculiar branching of the muscularis mucosae up to the tips of the villi and, despite their originally non-neoplastic nature, they may develop adenomatous dysplasia and cancer [3]. Consequently, there is an 80–500-fold excess of gastrointestinal cancer in the P-JP syndrome [22]. The increased cancer risk associated with P-J polyps has led to the recommendation of endoscopic polypectomies at 2-year intervals via upper gastointestinal endoscopy and colonoscopy [23]. The small bowel can in addition be evaluated by capsule endoscopy. During operations because of small bowel obstruction due to intussusception, the entire small intestine should be cleared of polyps by enterotomies.
MYH polyposis This novel, recessively inherited, cancer syndrome is still poorly defined. About 50% of patients present as multiple adenomatous polyposis or an FAP-like condition, while 50% have a small number of adenomas in association with colorectal cancer [8, 24]. MYH polyposis should be considered in FAP without a demonstrable mutation in the APC gene. In one study in patients with colorectal cancer, the proportion with mutations of MYH was about four in 1000 patients, suggesting that the frequency of MYH polyposis might be near to that of FAP [24]. The criteria for MYH polyposis await further clarification. However, endoscopic surveillance of the remaining colon after colectomy seems appropriate, and total colectomy instead of hemicolectomy or segmental resection should be
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P-JP
50
stomach and small intestine [17]. The polyps are hamartomatous, cystic polyps exhibiting hyperplastic stroma and inflammation. Large polyps are often lobulated and show adenomatous dysplasia giving rise to an increased lifetime cancer risk of up to 50% [4]. The number of juvenile polyps is moderate, with 50 –200 polyps in the colon, while many patients have only a few polyps. The syndrome is about 10 times less common than FAP, with an estimated frequency of one per 100 000 newborns. It is caused by mutations of at least two separate genes: SMAD4/DPC4 on chromosome 18q and BMPR1A/ALK3 on chromosome 10q [18, 19]. The treatment of JP consists of repeated endoscopic removal of all polyps detected in the colon or upper gastrointestinal tract at 2-year intervals. In patients with a high number of polyps in the colon, colectomy with ileorectal anastomosis is appropriate [20]. The treatment is aimed at decreasing the cancer risk and preventing symptoms such as bleeding, anaemia and diarrhoea.
iv129 strongly considered in patients where genetic diagnosis has been achieved.
Hereditary non-polyposis colorectal cancer
Table 2. The Amsterdam criteria for the clinical definition of hereditary non-polyposis colorectal cancer 1.
Three (or more) patients with colorectal cancer in a family; one patient is a first-degree relative of the other twoa
2.
Colorectal cancera occurs in at least two generations
3.
At least one cancer patient is diagnosed before the age of 50 years
4.
Familial adenomatous polyposis excluded
a
One or more of the cancers may be endometrial, small intestinal or urothelial cancer.
Genetic testing In families with polyposis syndromes, prophylactic endoscopy at a young age is a good method for diagnosis, while in families with HNPCC examinations should be repeated over their lifetimes because of lack of multiple polyps, even though half of them do not need such surveillance. Predictive genetic testing of family members of a patient affected with a dominant-inherited susceptibility syndrome offers a simple means for risk evaluation. Before testing, the molecular diagnosis of the particular mutation in the family must be determined. This is possible in 50% to 75% of families with polyposis syndromes and in 80% of HNPCC families [6]. The first step towards genetic testing is a reliable clinical and histopathological diagnosis. This makes it possible to direct the search for the pathogenic mutation in the appropriate gene(s). In HNPCC the presence of microsatellite instability supports the presence of a mismatch-repair defect. Furthermore, mismatch-repair gene proteins can be stained with immunohistochemical techniques in tumour tissue [33]. The final identification is done by sequencing a particular gene. After a reliable identification of the pathogenic mutation, the predictive testing of at-risk family members is highly accurate. Accordingly, mutation-positive subjects can be advised on appropriate prophylactic measures, such as endoscopy and surgery in FAP or colonoscopic surveillance in HNPCC. Mutation-negative subjects need no further increased evaluation and the same applies to their children. Omission of endoscopic surveillance of half of the offspring correspondingly cuts the costs of screening. This may cover the extra
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HNPCC (MIM no. 120435, 120436), or Lynch syndrome, is an autosomal-dominant cancer predisposition syndrome with no clear clinical signs preceding cancer except for solitary adenomas. The predominant tumours are colorectal and endometrial cancer, with estimated lifetime risks of 80% and 60%, respectively. Increased risk has been observed for gastric, ovarian, urothelial, bile duct, kidney and small intestinal cancers and brain tumours, resulting in a lifetime risk between 2% and 13% [25]. Mutations in one of several DNA mismatch-repair genes cause the predisposition [1]. Mutations in the MHS2 and MLH1 genes are responsible for >90% of HNPCC families with a known mutation, while some 5% are due to mutations in MSH6. The role of mutations in PMS1, PMS2 and MSH3 in HNPCC is minimal [1, 26]. HNPCC is the most common hereditary colorectal cancer syndrome, explaining up to 3% of all colorectal cancers [27]. Clinical features suggesting HNPCC include cancer at young age, proximal site of the colon and synchronous (or metachronous) second tumours [28]. The DNA content of the tumour is diploid [29] and microsatellite instability is characteristic in HNPCC [30]. In addition, histology often reveals a high mucin content, poor differentiation and Crohn’s diseaselike inflammatory reaction around the tumour [31]. These clinical or pathological features are not specific. The family history is essential and is the basis for the clinical Amsterdam criteria (Table 2). In the latest revision of the Amsterdam criteria, one or more of the index tumours may include endometrial, small intestinal or urothelial cancer instead of colorectal cancer [32]. However, the final diagnosis is only possible after detection of a pathogenic germline mutation in one of the DNA mismatch-repair genes. This also allows predictive genetic testing of family members of the affected patients. Thereafter, clinical surveillance can be limited to mutation-positive individuals, while mutation-negative family members need no follow-up. The search for a germline mutation precedes, at present, the determination of microsatellite instability and the immunohistochemical study of the expression of the DNA mismatchrepair genes in tumour tissue [33]. In cancer patients with HNPCC, a total abdominal colectomy with ileosigmoidal anastomosis is preferable to
hemicolectomy because of the high risk of metachronous second tumours [34]. In addition, the remaining colon and rectum should be subsequently examined every 2 –3 years. Furthermore, in women, prophylactic hysterectomy should be considered or surveillance by endometrial aspiration biopsy should be performed every 2–3 years. For asymptomatic mutation carriers, a cancer surveillance and prevention programme should be proposed. Colonoscopic screening with polypectomies reduces colorectal cancer incidence by >60%, prevents cancer deaths and improves overall life-expectancy [35]. Screening for endometrial and ovarian cancer is commonly recommended, with endometrial aspiration biopsy and ultrasonography every 2 –3 years starting from age 30–35 years, even though formal evidence proving benefit is lacking [36]. Prophylactic hysterectomy, salpingo-oophorectomy and colectomy is an alternative option. Chemoprevention of colorectal cancer with cyclo-oxygenase-2 inhibitors such as aspirin is under evaluation. Similarly, the role of oral contraceptives in reducing the risk of endometrial and ovarian cancer in the context of HNPCC is worthy of further study. There remains an excess risk of tumour types for which preventive programmes are of unproven benefit, such as gastric cancer [37], bile duct and urothelial cancers or brain tumours.
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costs of mutation testing and the search for the pathogenic mutation. Genetic testing also results in an increased accuracy of diagnosis leading to a reduction in anxiety in family members with a negative test result. Furthermore, mutation data may have some clinical significance in explaining the phenotypic variation of FAP in different families [38], even though the clinical application of this knowledge is limited. An important aspect of genetic testing is adequate genetic counselling before testing. Knowledge of a cancer predisposition syndrome in a family provokes significant anxiety, which tends to increase in the case of a positive test result. In a study of at-risk family members of HNPCC patients, the immediate anxiety scores of mutation-positive subjects increased and those of mutation-negative subjects decreased; but the difference, however, in anxiety scores disappeared within 1 month [39]. Despite careful individual counselling, the mutation-positive subjects commonly tended to misunderstand or forget the significance of the test result and the consequent risks [40]. Individual counselling and ensuring informed written consent before testing is necessary because of the possible deleterious effects of testing besides anxiety. For example, eligibility for insurance or employment may be affected, even though there is common agreement that genetic testing should not cause discrimination and test results are confidential. The practices of insurance companies and employers in non-European countries may differ from those in the European Union. The identification of a family with an inherited cancer predisposition syndrome verified by genetic diagnostics causes worry about the organisation of permanent surveillance and proper prophylactic treatment throughout life, including screening and testing of all family members. This task is often beyond the scope of an individual clinician, especially if the family is large and scattered around the country or even abroad. National or regional polyposis and HNPCC registries give the best guarantees of continued care of surveillance, genealogical studies, genetic counselling and testing. Research cooperation is still needed and ongoing in most of the registries covering almost the whole of Europe [41]. In updating their patient follow-up data, the registries need informed consent of the family members as stated in the Personal Data Act by the European Union. In many registries, including the Finnish Polyposis and HNPCC Registry, achieving permanent status and financial independence awaits resolution. These problems will hopefully be solved in the near future considering the excellent results in cancer prevention provided by cancer genetics care [16, 35].
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