Kolorektales Karzinom bei V. a. Lynch-Syndrom: ein interdisziplinärer Algorithmus

Zusammenfassung

Mit etwa 3–5 % aller kolorektalen Karzinome (KRK) ist das Lynch-Syndrom das häufigste hereditäre Prädispositions-Syndrom, bei dem neben kolorektalen Karzinomen gehäuft Endometrium-, Magen-, Ovarial- und Urothelkarzinome, aber auch verschiedene andere Karzinome auftreten. Im klinischen Alltag wird das Lynch-Syndrom oft nicht erkannt und bei Verdacht auf das Vorliegen eines Lynch-Syndroms gibt es viele Unsicherheiten hinsichtlich des korrekten diagnostischen und therapeutischen Vorgehens. Darüber hinaus wird die Beratung in Bezug auf die verschiedenen Therapieoptionen und -empfehlungen – vor allem hinsichtlich einer erweiterten Resektion und der Chemotherapie – als schwierig angesehen. Anhand der Literatur werden Strategien zur Identifikation von Lynch-Syndrom-Patienten vorgestellt und kritisch diskutiert. Ziel ist es, einen interdisziplinär konsentierten Algorithmus zum diagnostischen Vorgehen bei Verdacht auf Lynch-Syndrom aufzuzeigen. Die sich daraus ergebenden Konsequenzen für das operative Vorgehen bei Vorliegen eines Lynch-Syndrom-assoziierten KRK werden diskutiert. Der Verdacht auf ein Lynch-Syndrom kann durch die Erhebung der Familienanamnese und die Anwendung der revidierten Bethesda- und Amsterdam-II-Kriterien gestellt werden. Daran schließen sich immunohistochemische Untersuchungen der Mismatch-Reparatur-Gene, eine BRAF-Untersuchung im Falle eines immunohistochemischen Expressionsverlustes von MLH1, ggf. zusätzlich eine Bestimmung der Mikrosatelliteninstabilität (MSI) und zuletzt der Mutationsnachweis durch Gensequenzierung an. Die Möglichkeiten, Patienten mit Lynch-Syndrom durch pathologische Untersuchungen zu identifizieren, sind exzellent. Diese Untersuchungen sollten allerdings bereits präoperativ zum Zeitpunkt der endoskopischen Diagnosestellung eingeleitet werden, um so die Möglichkeit einer prophylaktisch erweiterten chirurgischen Resektion mit dem Patienten und ggf. eine leitliniengerechte, rein prophylaktische Chirurgie des Uterus und evtl. der Ovarien mit den (postmenopausalen) Patientinnen zusätzlich individuell zu besprechen. In der klinischen Praxis scheitert die Identifikation der Betroffenen allerdings häufig an Basisproblemen wie der Erhebung der Familienanamnese und einer nicht vorhandenen „Awareness“ hinsichtlich des Krankheitsbildes. Wenn daran gedacht wird, erfolgen die empfohlenen MSI-Untersuchungen postoperativ in dem Tumorresektat und Patienten werden in die Überlegungen einer erweiterten prophylaktischen Chirurgie nicht mit einbezogen. Die klinische Erfahrung zeigt, dass die postoperative Analyse von Tumorresektaten hinsichtlich Mikrosatelliteninstabilität – auch bei Erfüllung der Bethesda-Kriterien – häufig nicht erfolgt und bei verdächtigem Befund die empfohlene humangenetische Beratung entweder nicht empfohlen oder nicht umgesetzt wird. Hierdurch wird die Chance einer lebenslangen jährlichen Vorsorge der betroffenen Indexperson verpasst und durchschnittlich 3 Mutationsträger pro Familie verpassen die Möglichkeit, aktiv gegen ihr deutlich erhöhtes Karzinomrisiko vorzugehen.

Abstract

Lynch syndrome is the most frequent hereditary cancer syndrome, accounting for approximately 3–5 % of all colorectal cancers. In addition, it is the most frequent predisposing hereditary cause of endometrial cancer and is also associated with gastric cancer, ovarian cancer, cancer of the urinary tract as well as several other cancers. In clinical practise Lynch syndrome is frequently not detected and many clinicians admit uncertainties regarding diagnostic procedures. Also, counselling of patients is considered difficult regarding therapeutic – especially prophylactic surgical and chemopreventive options and recommendations. Based on a review of available literature we discuss optimized strategies for improved detection of suspected Lynch syndrome patients. The aim of this review is to establish a clinical algorithm of how to proceed on a diagnostic level and to discuss surgical options at the time of a colorectal cancer. In order to identify patients with Lynch syndrome, family history should be ascertained and evaluated in regards to fulfilment of the Amsterdam-II- and/or the revised Bethesda criteria. Subsequently immunohistochemical staining for the mismatch-repair-genes, BRAF testing for MLH1 loss of expression, as well as testing for microsatellite instability in some, followed by genetic counselling and mutation analysis when indicated, is recommended. Pathological identification of suspected Lynch syndrome is readily feasible and straightforward. However, the need of performing these analyses in the tumor biopsy at the time of (gastroenterological) diagnosis of CRC neoplasia is essential, in order to offer patients the option of a prophylactically extended surgery and – as recommended in the German S3 guidelines – to discuss the option of a merely prophylactical hysterectomy and oophorectomy (if postmenopausal) in women. Close cooperation between gastroenterologists, pathologists and surgeons is warranted, so that patients may benefit from options of extended or prophylactically extended surgery at the time of diagnosis of a colorectal primary. Patients nowadays must be involved in informed decision-making regarding prophylactic or extended prophylactic surgery at the time of a colorectal primary. To date, however, limitations in daily clinical practise, the failure to assess family history and the lack of awareness of this important hereditary syndrome is the major asset leading to severe underdiagnosis and putting to risk the indexpatients themselves and their families to (metachronous) CRC and the associated extracolonic cancers. If at all tumors of patients fulfilling Bethesda criteria will be analysed for MSI in the surgical specimen and therefore Lynch syndrome patients are not given the opportunity to opt for extended surgery. In clinical experience the postoperative MSI-analysis is inconsistently performed – even if the Bethesda criteria are fulfilled – and in case of suspected Lynch syndrome genetically counselling is not consistently recommended. Therefore affected cancer patients are left unaware of their increased genetic risk and in average 3 high-risk gene carriers per family miss the opportunity to actively engage in the recommended screening program.

Schlüsselwörter

kolorektales Karzinom - Lynch-Syndrom - HNPCC - Mikrosatelliteninstabilität - Immunohistochemie - prophylaktische und prophylaktisch erweiterte Chirurgie

Key words

colorectal cancer - Lynch syndrome - HNPCC - microsatellite instability - immunohistochemistry - prophylactic and prophylactically extended surgery

• Literatur

• 1 Krebs in Deutschland 2005/2006. Häufigkeiten und Trends. 7. Ausgabe. Berlin: Robert Koch-Institut (Hrsg.) und die Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V. (Hrsg.); 2010
• 2 Lichtenstein P, Holm NV, Verkasalo PK et al. Environmental and heritable factors in the causation of cancer–analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 2000; 343: 78-85
• 3 Jasperson KW, Tuohy TM, Neklason DW et al. Hereditary and familial colon cancer. Gastroenterology 2010; 138: 2044-2058
• 4 Johns LE, Houlston RS. A systematic review and meta-analysis of familial colorectal cancer risk. Am J Gastroenterol 2001; 96: 2992-3003
• 5 Rüschoff J, Roggendorf B, Brasch F et al. [Molecular pathology in hereditary colorectal cancer. Recommendations of the Collaborative German Study Group on hereditary colorectal cancer funded by the German Cancer Aid (Deutsche Krebshilfe)]. Pathologe 2004; 25: 178-192
• 6 Hampel H, Frankel WL, Martin E et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 2005; 352: 1851-1860
• 7 Lynch HT, Shaw MW, Magnuson CW et al. Hereditary factors in cancer. Study of two large midwestern kindreds. Arch Intern Med 1966; 117: 206-212
• 8 Cristofaro G, Lynch HT, Caruso ML et al. New phenotypic aspects in a family with Lynch syndrome II. Cancer 1987; 60: 51-58
• 9 Law IP, Herberman RB, Oldham RK et al. Familial occurrence of colon and uterine carcinoma and of lymphoproliferative malignancies: clinical description. Cancer 1977; 39: 1224-1228
• 10 Love RR. Small bowel cancers, B-cell lymphatic leukemia, and six primary cancers with metastases and prolonged survival in the cancer family syndrome of Lynch. Cancer 1985; 55: 499-502
• 11 Lynch HT, Smyrk TC, Lynch PM et al. Adenocarcinoma of the small bowel in lynch syndrome II. Cancer 1989; 64: 2178-2183
• 12 Lynch HT, Kriegler M, Christiansen TA et al. Laryngeal carcinoma in a Lynch syndrome II kindred. Cancer 1988; 62: 1007-1013
• 13 Lynch HT, Voorhees GJ, Lanspa SJ et al. Pancreatic carcinoma and hereditary nonpolyposis colorectal cancer: a family study. Br J Cancer 1985; 52: 271-273
• 14 Lynch HT, Ens JA, Lynch JF. The Lynch syndrome II and urological malignancies. J Urol 1990; 143: 24-28
• 15 Mecklin JP, Jarvinen HJ, Virolainen M. The association between cholangiocarcinoma and hereditary nonpolyposis colorectal carcinoma. Cancer 1992; 69: 1112-1114
• 16 Mecklin JP, Jarvinen HJ. Tumor spectrum in cancer family syndrome (hereditary nonpolyposis colorectal cancer). Cancer 1991; 68: 1109-1112
• 17 Watson P, Lynch HT. The tumor spectrum in HNPCC. Anticancer Res 1994; 14: 1635-1639
• 18 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: 261-268
• 19 Lynch HT, Lynch PM, Lanspa SJ et al. Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet 2009; 76: 1-18
• 20 Möslein G. [Hereditary colorectal cancer]. Chirurg 2008; 79: 1038-1046
• 21 Francisco I, Albuquerque C, Lage P et al. Familial colorectal cancer type X syndrome: two distinct molecular entities?. Fam Cancer 2011; 10: 623-631
• 22 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
• 23 Dunlop MG, Farrington SM, Carothers AD et al. Cancer risk associated with germline DNA mismatch repair gene mutations. Hum Mol Genet 1997; 6: 105-110
• 24 Wijnen JT, Vasen HF, Khan PM et al. Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. N Engl J Med 1998; 339: 511-518
• 25 Aarnio M, Mecklin JP, Aaltonen LA et al. Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer 1995; 64: 430-433
• 26 Hampel H, Stephens JA, Pukkala E et al. Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset. Gastroenterology 2005; 129: 415-421
• 27 Vasen HF, Stormorken A, Menko FH et al. MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of hereditary nonpolyposis colorectal cancer families. J Clin Oncol 2001; 19: 4074-4080
• 28 Hendriks YM, Wagner A, Morreau H et al. Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counseling and surveillance. Gastroenterology 2004; 127: 17-25
• 29 Lynch HT, de la Chapelle A. Genetic susceptibility to non-polyposis colorectal cancer. J Med Genet 1999; 36: 801-818
• 30 Kim H, Jen J, Vogelstein B et al. Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol 1994; 145: 148-156
• 31 Jass JR, Smyrk TC, Stewart SM et al. Pathology of hereditary non-polyposis colorectal cancer. Anticancer Res 1994; 14: 1631-1634
• 32 Vasen HF, Mecklin JP, Watson P et al. Surveillance in hereditary nonpolyposis colorectal cancer: an international cooperative study of 165 families. The International Collaborative Group on HNPCC. Dis Colon Rectum 1993; 36: 1-4
• 33 Vasen HF, Blanco I, Aktan-Collan K et al. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut 2013; 62: 812-823
• 34 Goecke T, Schulmann K, Engel C et al. Genotype-phenotype comparison of German MLH1 and MSH2 mutation carriers clinically affected with Lynch syndrome: a report by the German HNPCC Consortium. J Clin Oncol 2006; 24: 4285-4292
• 35 Barrow E, Robinson L, Alduaij W et al. Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations. Clin Genet 2009; 75: 141-149
• 36 Stoffel E, Mukherjee B, Raymond VM et al. Calculation of risk of colorectal and endometrial cancer among patients with Lynch syndrome. Gastroenterology 2009; 137: 1621-1627
• 37 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: 2304-2310
• 38 Rüschoff JBR. Hereditäre Tumoren. In: Stolte M, Rüschoff J, Klöppel G, Hrsg. Pathologie. Verdauungstrakt und Peritoneum. Berlin, Heidelberg: Springer; 2013: 727-759
• 39 Bailey-Wilson JE, Elston RC, Schuelke GS et al. Segregation analysis of hereditary nonpolyposis colorectal cancer. Genet Epidemiol 1986; 3: 27-38
• 40 Vasen HF. What is hereditary nonpolyposis colorectal cancer (HNPCC). Anticancer Res 1994; 14: 1613-1615
• 41 Wildenberg J, Meselson M. Mismatch repair in heteroduplex DNA. Proc Natl Acad Sci U S A 1975; 72: 2202-2206
• 42 Lazar V, Grandjouan S, Bognel C et al. Accumulation of multiple mutations in tumour suppressor genes during colorectal tumorigenesis in HNPCC patients. Hum Mol Genet 1994; 3: 2257-2260
• 43 de la Chapelle A. Microsatellite instability phenotype of tumors: genotyping or immunohistochemistry? The jury is still out. J Clin Oncol 2002; 20: 897-899
• 44 Lothe RA, Peltomaki P, Meling GI et al. Genomic instability in colorectal cancer: relationship to clinicopathological variables and family history. Cancer Res 1993; 53: 5849-5852
• 45 Park JG, Vasen HF, Park YJ et al. Suspected HNPCC and Amsterdam criteria II: evaluation of mutation detection rate, an international collaborative study. Int J Colorectal Dis 2002; 17: 109-114
• 46 Schulmann K, Stemmler S. Hereditäres Kolonkarzinom. Gastroenterologe 2008; 3: 112-118
• 47 Aaltonen LA. Molecular epidemiology of hereditary nonpolyposis colorectal cancer in Finland. Recent Results Cancer Res 1998; 154: 306-311
• 48 Ligtenberg MJ, Kuiper RP, Chan TL et al. Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1. Nat Genet 2009; 41: 112-117
• 49 Guarinos C, Castillejo A, Barbera VM et al. EPCAM germ line deletions as causes of Lynch syndrome in Spanish patients. J Mol Diagn 2010; 12: 765-770
• 50 Capper D, Voigt A, Bozukova G et al. BRAF V600E-specific immunohistochemistry for the exclusion of Lynch syndrome in MSI-H colorectal cancer. Int J Cancer 2013; 133: 1624-1630
• 51 Lindor NM, Burgart LJ, Leontovich O et al. Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol 2002; 20: 1043-1048
• 52 Engel C, Forberg J, Holinski-Feder E et al. Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer. Int J Cancer 2006; 118: 115-122
• 53 Canard G, Lefevre JH, Colas C et al. Screening for Lynch syndrome in colorectal cancer: are we doing enough?. Ann Surg Oncol 2012; 19: 809-816
• 54 Ogino S, Cantor M, Kawasaki T et al. CpG island methylator phenotype (CIMP) of colorectal cancer is best characterised by quantitative DNA methylation analysis and prospective cohort studies. Gut 2006; 55: 1000-1006
• 55 Sullivan RJ, Flaherty KT. BRAF in Melanoma: Pathogenesis, Diagnosis, Inhibition, and Resistance. J Skin Cancer 2011; 2011: 423239
• 56 Kim TH, Park YJ, Lim JA et al. The association of the BRAF(V600E) mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer: a meta-analysis. Cancer 2011; 118: 1764-1773
• 57 Tiacci E, Schiavoni G, Forconi F et al. Simple genetic diagnosis of hairy cell leukemia by sensitive detection of the BRAF-V600E mutation. Blood 2012; 119: 192-195
• 58 Domingo E, Laiho P, Ollikainen M et al. BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing. J Med Genet 2004; 41: 664-668
• 59 Vilkin A, Niv Y, Nagasaka T et al. Microsatellite instability, MLH1 promoter methylation, and BRAF mutation analysis in sporadic colorectal cancers of different ethnic groups in Israel. Cancer 2009; 115: 760-769
• 60 Bettstetter M, Dechant S, Ruemmele P et al. Distinction of hereditary nonpolyposis colorectal cancer and sporadic microsatellite-unstable colorectal cancer through quantification of MLH1 methylation by real-time PCR. Clin Cancer Res 2007; 13: 3221-3228
• 61 Bettstetter M, Rümmele P, Hofstädter F et al. [A new quantitative DNA-methylation analysis of MSI colorectal cancers helps to separate sporadic colorectal cancers from HNPCC-candidates]. Verh Dtsch Ges Pathol 2006; 90: 236-243
• 62 Rasuck CG, Leite SM, Komatsuzaki F et al. Association between methylation in mismatch repair genes, V600E BRAF mutation and microsatellite instability in colorectal cancer patients. Mol Biol Rep 2011; 39: 2553-2560
• 63 Aaltonen LA, Peltomaki P, Leach FS et al. Clues to the pathogenesis of familial colorectal cancer. Science 1993; 260: 812-816
• 64 Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science 1993; 260: 816-819
• 65 Ionov Y, Peinado MA, Malkhosyan S et al. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 1993; 363: 558-561
• 66 Dietmaier W, Wallinger S, Bocker T et al. Diagnostic microsatellite instability: definition and correlation with mismatch repair protein expression. Cancer Res 1997; 57: 4749-4756
• 67 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
• 68 Kievit W, Bolster MJ, van der Wilt GJ et al. Cost-effectiveness of new guidelines for adjuvant systemic therapy for patients with primary breast cancer. Ann Oncol 2005; 16: 1874-1881
• 69 Giuffre G, Muller A, Brodegger T et al. Microsatellite analysis of hereditary nonpolyposis colorectal cancer-associated colorectal adenomas by laser-assisted microdissection: correlation with mismatch repair protein expression provides new insights in early steps of tumorigenesis. J Mol Diagn 2005; 7: 160-170
• 70 Warrier SK, Trainer AH, Lynch AC et al. Preoperative diagnosis of Lynch syndrome with DNA mismatch repair immunohistochemistry on a diagnostic biopsy. Dis Colon Rectum 2011; 54: 1480-1487
• 71 Hampel H, Frankel WL, Martin E et al. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol 2008; 26: 5783-5788
• 72 Schmiegel W, Pox C, Reinacher-Schick A et al. S3 guidelines for colorectal carcinoma: results of an evidence-based consensus conference on February 6/7, 2004 and June 8/9, 2007 (for the topics IV, VI and VII). Z Gastroenterol 2010; 48: 65-136
• 73 Vasen HF, Möslein G, Alonso A et al. Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet 2007; 44: 353-362
• 74 Julie C, Tresallet C, Brouquet A et al. Identification in daily practice of patients with Lynch syndrome (hereditary nonpolyposis colorectal cancer): revised Bethesda guidelines-based approach versus molecular screening. Am J Gastroenterol 2008; 103: 2825-2835
• 75 Palomaki GE, McClain MR, Melillo S et al. EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome. Genet Med 2009; 11: 42-65
• 76 Kumarasinghe AP, de Boer B, Bateman AC et al. DNA mismatch repair -enzyme immunohistochemistry in colorectal cancer: a comparison of biopsy and resection material. Pathology 2010; 42: 414-420
• 77 Shia J, Stadler Z, Weiser MR et al. Immunohistochemical staining for DNA mismatch repair proteins in intestinal tract carcinoma: how reliable are biopsy samples?. Am J Surg Pathol 2011; 35: 447-454
• 78 Roth AD, Delorenzi M, Tejpar S et al. Integrated analysis of molecular and clinical prognostic factors in stage II/III colon cancer. J Natl Cancer Inst 2012; 104: 1635-1646
• 79 Hutchins G, Southward K, Handley K et al. Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. J Clin Oncol 2011; 29: 1261-1270
• 80 Sargent DJ, Marsoni S, Monges G et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol 2010; 28: 3219-3226
• 81 Sinicrope FA, Foster NR, Thibodeau SN et al. DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-fluorouracil-based adjuvant therapy. J Natl Cancer Inst 2011; 103: 863-875
• 82 Schulmann K, Koepnick S, Engel C et al. Adjuvant chemotherapy (ACT) in stage II colon cancer (CC) in patients with Lynch syndrome. J Clin Oncol 2012; 30 (Suppl.) Abstr. 3550
• 83 Weber T, Link KH. [Multimodal therapy for colon cancer: state of the art]. Zentralbl Chir 2011; 136: 325-333
• 84 Merok MA, Ahlquist T, Royrvik EC et al. Microsatellite instability has a positive prognostic impact on stage II colorectal cancer after complete resection: results from a large, consecutive Norwegian series. Ann Oncol 2012; 24: 1274-1282
• 85 Flejou JF, Andre T, Chibaudel B et al. Effect of adding oxaliplatin to adjuvant 5-fluorouracil/leucovorin (5FU/LV) in patients with defective mismatch repair (dMMR) colon cancer stage II und III included in the MOSAIC study. J Clin Oncol 2013; 31 (Suppl.) Abstr. 3524
• 86 Win AK, Parry S, Parry B et al. Risk of metachronous colon cancer following surgery for rectal cancer in mismatch repair gene mutation carriers. Ann Surg Oncol 2013; 20: 1829-1836
• 87 Weissman SM, Bellcross C, Bittner CC et al. Genetic counseling considerations in the evaluation of families for Lynch syndrome–a review. J Genet Couns 2011; 20: 5-19
• 88 Vasen HF, Watson P, Mecklin JP 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
• 89 Teutsch SM, Bradley LA, Palomaki GE et al. The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Initiative: methods of the EGAPP Working Group. Genet Med 2009; 11: 3-14
• 90 Burt RW, Barthel JS, Dunn KB et al. NCCN clinical practice guidelines in oncology. Colorectal cancer screening. J Natl Compr Canc Netw 2010; 8: 8-61