Molecular genetic approach for screening of hereditary non-polyposis colorectal cancer
Background: The main goal of knowledge concerning human diseases is to transfer as much as possible useful information into clinical applications. Hereditary non-polyposis colorectal cancer (HNPCC) is the most common autosomal dominant inherited predisposition for colorectal cancer, accounting for 1–2% of all bowel cancer. The only way to diagnose HNPCC is by a family history consistent with the disease defined by International Collaborative Group on HNPCC (Amsterdam criteria I and II). The main molecular cause of HNPCC is a constitutional mutation in one of the mismatch repair (MMR) genes. Since HNPCC mutations have been detected also in families that did not fulfil the Amsterdam criteria, molecular genetic characteristics of HNPCC cancers have been proposed as valuable first step in HNPCC identification. Microsatellite instability is present in about 90% of cancers of HNPCC patients. However, of all MSI colorectal cancers 80– 90% are sporadic. Several molecular mechanisms have been uncovered that enable distinguishing to some extent between sporadic and HNPCC cancers with MSI including hypermethylation of hMLH1 promoter and frequent mutations in BAX and TGFBR2 in sporadic CRC with MSI-H.
Conclusions: The determination of MSI status and careful separation of MSI positive colorectal cancer into sporadic MSIL, sporadic MSI-H, and HNPCC MSI-H followed by mutation detection in MMR genes is important for prevention, screening and management of colorectal cancer. In some studies we and others have already shown that large-scale molecular genetic analysis for HNPCC can be done and is sensitive enough to approve population screening. Population screening includes also colonoscopy which is restricted only to the obligate carriers of the mutation. This enables that the disease is detected in earlier stages which would greatly decrease medical treatment costs and most importantly decrease mortality. In Slovenia we have started population screening based on moleculargenetic and high-risk clinical bases.
Vogelstein B, Fearon ER, Kern SE, Hamilton SR, Preisinger AC, Nakamura Y, et al. Allelotype of colorectal carcinomas. Science 1989; 244: 207–11.
Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon (see comments). Science 1993; 260: 816–9.
Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, et al. Genetic alterations during colorectal-tumor development. N Engl J Med 1988; 319: 525–32.
Aaltonen LA, Peltomaki P, Leach FS, Sistonen P, Pylkkanen L, Mecklin JP, et al. Clues to the pathogenesis of familial colorectal cancer (see comments). Science 1993; 260: 812–86.
Rampino N, Yamamoto H, Ionov Y, Li Y, Sawai H, Reed JC, et al. Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science 1997; 275: 967–9.
Eshleman JR, Lang EZ, Bowerfind GK, Parsons R, Vogelstein B, Willson JK, et al. Increased mutation rate at the hprt locus accompanies microsatellite instability in colon cancer. Oncogene 1995; 10: 33–7.
Duval A, Gayet J, Zhou XP, Iacopetta B, Thomas G, Hamelin R. Frequent frameshift mutations of the TCF-4 gene in colorectal cancers with microsatellite instability. Cancer Res 1999; 59: 4213–5.
Potocnik U, Glavac D, Ravnik-Glavac M. Identification of novel genes with somatic frameshift mutations within coding mononucleotide repeats in colorectal tumors with high microsatellite instability. Genes Chromosomes Cancer 2003; 36: 48–56.
Tomlinson I, Ilyas M, Johnson V, Davies A, Clark G, Talbot I, et al. A comparison of the genetic pathways involved in the pathogenesis of three types of colorectal cancer. J Pathol 1998; 184: 148–52.
Shitoh K, Konishi F, Miyaki M, Iijima T, Furukawa T, Tsukamoto T, et al. Pathogenesis of non-familial colorectal carcinomas with high microsatellite instability. J Clin Pathol 2000; 53: 841–5.
Peltomaki P, Lothe RA, Aaltonen LA, Pylkkanen L, Nystrom-Lahti M, Seruca R, et al. Microsatellite instability is associated with tumors that characterize the hereditary non-polyposis colorectal carcinoma syndrome. Cancer Res 1993; 53: 5853–5.
Thibodeau SN, French AJ, Cunningham JM, Tester D, Burgart LJ, Roche PC, et al. Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1. Cancer Res 1998; 58: 1713–8.
Jass JR, Do KA, Simms LA, Iino H, Wynter C, Pillay SP, et al. Morphology of sporadic colorectal cancer with DNA replication errors. Gut 1998; 42: 673– 9.
Lindor NM, Burgart LJ, Leontovich O, Goldberg RM, Cunningham JM, Sargent DJ, et al. Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol 2002; 20: 1043–8.
Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, 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: 5248–57.
Mecklin JP, Jarvinen HJ, Hakkiluoto A, Hallikas H, Hiltunen KM, Harkonen N, et al. Frequency of hereditary nonpolyposis colorectal cancer. A prospective multicenter study in Finland. Dis Colon Rectum 1995; 38: 588–93.
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: 424–5.
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.
Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 1993; 363: 558–61.
Papadopoulos N, Nicolaides NC, Wei YF, Ruben SM, Carter KC, Rosen CA, et al. Mutation of a mutL homolog in hereditary colon cancer. Science 1994; 263: 1625–9.
Bronner CE, Baker SM, Morrison PT, Warren G, Smith LG, Lescoe MK, et al. Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature 1994; 368: 258–61.
Fishel R, Lescoe MK, Rao MR, Copeland NG, Jenkins NA, Garber J, et al. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer (published erratum appears in Cell 1994; 77: 167). Cell 1993; 75: 1027–38.
Leach FS, Nicolaides NC, Papadopoulos N, Liu B, Jen J, Parsons R, et al. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 1993; 75: 1215–25.
Nicolaides NC, Papadopoulos N, Liu B, Wei YF, Carter KC, Ruben SM, et al. Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 1994; 371: 75–80.
Papadopoulos N, Nicolaides NC, Liu B, Parsons R, Lengauer C, Palombo F, et al. Mutations of GTBP in genetically unstable cells (see comments). Science 1995; 268: 1915–7.
Peltomaki P, de la Chapelle A. Mutations predisposing to hereditary nonpolyposis colorectal cancer. Adv Cancer Res 1997; 71: 93–119.
Liu B, Farrington SM, Petersen GM, Hamilton SR, Parsons R, Papadopoulos N, et al. Genetic instability occurs in the majority of young patients with colorectal cancer (see comments). Nat Med 1995; 1: 348–52.
Parsons R, Li GM, Longley MJ, Fang WH, Papadopoulos N, Jen J, et al. Hypermutability and mismatch repair deficiency in RER+ tumor cells. Cell 1993; 75: 1227–36.
Holinski-Feder E, Muller-Koch Y, Friedl W, Moeslein G, Keller G, Plaschke J, et al. DHPLC mutation analysis of the hereditary nonpolyposis colon cancer (HNPCC) genes hMLH1 and hMSH2. J Biochem Biophys Methods 2001; 47: 21–32.
Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 1996; 93: 9821–6.
Hackman P, Tannergard P, Osei-Mensa S, Chen J, Kane MF, Kolodner R, et al. A human compound heterozygote for two MLH1 missense mutations (letter). Nat Genet 1997; 17: 135–6.
Cunningham JM, Christensen ER, Tester DJ, Kim CY, Roche PC, Burgart LJ, et al. Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res 1998; 58: 3455–60.
Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa JP, et al. Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA 1998; 95: 6870–5.
Veigl ML, Kasturi L, Olechnowicz J, Ma AH, Lutterbaugh JD, Periyasamy S, et al. Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc Natl Acad Sci USA 1998; 95: 8698–702.
Potočnik U, Glavač D, Golouh R, Ravnik-Glavač M. Causes of microsatellite instability in colorectal tumors: implications for hereditary non-polyposis colorectal cancer screening. Cancer Genet Cytogenet 2001; 126: 85–96.
Huang J, Papadopoulos N, McKinley AJ, Farrington SM, Curtis LJ, Wyllie AH, et al. APC mutations in colorectal tumors with mismatch repair deficiency. Proc Natl Acad Sci USA 1996; 93: 9049–54.
Rowan AJ, Lamlum H, Ilyas M, Wheeler J, Straub J, Papadopoulou A, et al. APC mutations in sporadic colorectal tumors: A mutational »hotspot« and interdependence of the »two hits«. Proc Natl Acad Sci USA 2000; 97: 3352– 7.
Mirabelli-Primdahl L, Gryfe R, Kim H, Millar A, Luceri C, Dale D, et al. Betacatenin mutations are specific for colorectal carcinomas with microsatellite instability but occur in endometrial carcinomas irrespective of mutator pathway. Cancer Res 1999; 59: 3346–51.
Miyaki M, Iijima T, Kimura J, Yasuno M, Mori T, Hayashi Y, et al. Frequent mutation of beta-catenin and APC genes in primary colorectal tumors from patients with hereditary nonpolyposis colorectal cancer. Cancer Res 1999; 59: 4506–9.
Olschwang S, Hamelin R, Laurent-Puig P, Thuille B, De Rycke Y, Li YJ, et al. Alternative genetic pathways in colorectal carcinogenesis. Proc Natl Acad Sci USA 1997; 94: 12122–7.
Fujiwara T, Stolker JM, Watanabe T, Rashid A, Longo P, Eshleman JR, et al. Accumulated clonal genetic alterations in familial and sporadic colorectal carcinomas with widespread instability in microsatellite sequences. Am J Pathol 1998; 153: 1063–78.
Salahshor S, Kressner U, Pahlman L, Glimelius B, Lindmark G, Lindblom A. Colorectal cancer with and without microsatellite instability involves different genes. Genes Chromosomes Cancer 1999; 26: 247–52.
Konishi M, Kikuchi-Yanoshita R, Tanaka K, Muraoka M, Onda A, Okumura Y, et al. Molecular nature of colon tumors in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer (see comments). Gastroenterology 1996; 111: 307–17.
Jass JR, Biden KG, Cummings MC, Simms LA, Walsh M, Schoch E, et al. Characterisation of a subtype of colorectal cancer combining features of the suppressor and mild mutator pathways. J Clin Pathol 1999; 52: 455–60.
Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbaugh J, et al. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability (see comments). Science 1995; 268: 1336–8.
Souza RF, Appel R, Yin J, Wang S, Smolinski KN, Abraham JM, et al. Microsatellite instability in the insulin-like growth factor II receptor gene in gastrointestinal tumours (letter) (published erratum appears in Nat Genet 1996; 14: 488). Nat Genet 1996; 14: 255–7.
Yin J, Kong D, Wang S, Zou TT, Souza RF, Smolinski KN, et al. Mutation of hMSH3 and hMSH6 mismatch repair genes in genetically unstable human colorectal and gastric carcinomas. Hum Mutat 1997; 10: 474–8.
Wicking C, Simms LA, Evans T, Walsh M, Chawengsaksophak K, Beck F, et al. CDX2, a human homologue of Drosophila caudal, is mutated in both alleles in a replication error positive colorectal cancer. Oncogene 1998; 17: 657–9.
Schwartz SJ, Yamamoto H, Navarro M, Maestro M, Reventos J, Perucho M. Frameshift mutations at mononucleotide repeats in caspase-5 and other target genes in endometrial and gastrointestinal cancer of the microsatellite mutator phenotype. Cancer Res 1999; 59: 2995–3002.
Liu W, Dong X, Mai M, Seelan RS, Taniguchi K, Krishnadath KK, et al. Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating beta-catenin/TCF signalling. Nat Genet 2000; 26: 146–7.
Vilkki S, Launonen V, Karhu A, Sistonen P, Vastrik I, Aaltonen LA. Screening for microsatellite instability target genes in colorectal cancers. J Med Genet 2002; 39: 785–9.
Toyota M, Issa JP. CpG island methylator phenotypes in aging and cancer. Semin Cancer Biol 1999; 9: 349–57.
Mori Y, Yin J, Rashid A, Leggett BA, Young J, Simms L, et al. Instabilotyping: comprehensive identification of frameshift mutations caused by coding region microsatellite instability. Cancer Res 2001; 61: 6046–55.
Rodriguez-Bigas MA, Boland CR, Hamilton SR, Henson DE, Jass JR, Khan PM, et al. A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst 1997; 89: 1758–62.
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: 4749–56.
Starostik P, Muller-Hermelink HK. Diagnosis of microsatellite instabilitypositive colorectal cancer. Expert Rev Mol Diagn 2001; 1: 71–80.
Zhou XP, Hoang JM, Cottu P, Thomas G, Hamelin R. Allelic profiles of mononucleotide repeat microsatellites in control individuals and in colorectal tumors with and without replication errors. Oncogene 1997; 15: 1713–8.
Hoang JM, Cottu PH, Thuille B, Salmon RJ, Thomas G, Hamelin R. BAT-26, an indicator of the replication error phenotype in colorectal cancers and cell lines. Cancer Res 1997; 57: 300–3.
Liu L, Markowitz S, Gerson SL. Mismatch repair mutations override alkyltransferase in conferring resistance to temozolomide but not to 1, 3-bis(2-chloroethyl)nitrosourea. Cancer Res 1996; 56: 5375–9.
Weissenbach J. A second generation linkage map of the human genome based on highly informative microsatellite loci. Gene 1993; 135: 275–8.
Spirio L, Joslyn G, Nelson L, Leppert M, White R. A CA repeat 30–70 KB downstream from the adenomatous polyposis coli (APC) gene (published erratum) appears in Nucleic Acids Res 1991; 19: 6348.
Jones MH, Nakamura Y. Detection of loss of heterozygosity at the human TP53 locus using a dinucleotide repeat polymorphism. Genes Chromosomes Cancer 1992; 5: 89–90.
Vanagaite L, James MR, Rotman G, Savitsky K, Bar-Shira A, Gilad S, et al. A high-density microsatellite map of the ataxia-telangiectasia locus. Hum Genet 1995; 95: 451–4.
Weber JL, Kwitek AE, May PE, Wallace MR, Collins FS, Ledbetter DH. Dinucleotide repeat polymorphisms at the D17S250 and D17S261 loci. Nucleic Acids Res 1990; 18: 4640.
Dib C, Faure S, Fizames C, Samson D, Drouot N, Vignal A, et al. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 1996; 380: 152–4.
Makela TP, Hellsten E, Vesa J, Alitalo K, Peltonen L. An Alu variable polyA repeat polymorphism upstream of L-myc at 1p32. Hum Mol Genet 1992; 1: 217.
Potocnik U, Glavac D, Golouh R, Ravnik-Glavac M. Evaluation of microsatellite markers for efficient assessment of high microsatellite instabile colorectal tumors. Pflugers Arch 2000; 439 Suppl 3: R47–R49.
Potocnik U. Molekularno genetska analiza dednih in sporadičnih oblik kolorektalnega raka v slovenski populaciji, Magistrsko delo. Ljubljana: Medicinska fakulteta, 1998.
Ravnik-Glavac M, Potocnik U, Glavac D. Incidence of germline hMLH1 and hMSH2 mutations (HNPCC patients) among newly diagnosed colorectal cancers in a Slovenian population. J Med Genet 2000; 37: 533–6.
Aaltonen LA, Salovaara R, Kristo P, Canzian F, Hemminki A, Peltomaki P, et al. Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. N Engl J Med 1998; 338: 1481–7.
Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 2002; 418: 934.
Peltomaki P. Deficient DNA mismatch repair: a common etiologic factor for colon cancer. Hum Mol Genet 2001; 10: 735–40.
Peltomaki P. DNA mismatch repair and cancer. Mutat Res 2001; 488: 77–85.
Wahlberg S, Liu T, Lindblom P, Lindblom A. Various mutation screening techniques in the DNA mismatch repair genes hMSH2 and hMLH1. Genet Test 1999; 3: 259–64.
Wijnen J, Vasen H, Khan PM, Menko FH, van der Klift H, van Leeuwen C, et al. Seven new mutations in hMSH2, and HNPCC gene, identified by denaturing gradient-gel electrophoresis. Am J Hum Genet 1995; 56: 1060–6.
Beck NE, Tomlinson IP, Homfray T, Frayling I, Hodgson SV, Harocopos C, et al. Use of SSCP analysis to identify germline mutations in HNPCC families fulfilling the Amsterdam criteria. Hum Genet 1997; 99: 219–24.
Ravnik-Glavac M, Potocnik U, Kozelj M, Krizman I, Glavac D. A novel in frame deletion of codons 188–190 in the hMSH2 gene of a Slovenian patient with hereditary non-polyposis colorectal cancer. Hum Hered 1998; 48: 285–7.
Wijnen JT, Vasen HF, Khan PM, Zwinderman AH, van der Klift H, Mulder A, et al. Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. N Engl J Med 1998; 339: 511–8.
Kohonen-Corish M, Ross VL, Doe WF, Kool DA, Edkins E, Faragher I, et al. RNA-based mutation screening in hereditary nonpolyposis colorectal cancer. Am J Hum Genet 1996; 59: 818–24.
Bateman JF, Freddi S, Lamande SR, Byers P, Nasioulas S, Douglas J, et al. Reliable and sensitive detection of premature termination mutations using a protein truncation test designed to overcome problems of nonsense-mediated mRNA instability. Hum Mutat 1999; 13: 311–7.
Charbonnier F, Raux G, Wang Q, Drouot N, Cordier F, Limacher JM, et al. Detection of exon deletions and duplications of the mismatch repair genes in hereditary nonpolyposis colorectal cancer families using multiplex polymerase chain reaction of short fluorescent fragments. Cancer Res 2000; 60: 2760–3.
Wang Y, Friedl W, Sengteller M, Jungck M, Filges I, Propping P, et al. A modified multiplex PCR assay for detection of large deletions in MSH2 and MLH1. Hum Mutat 2002; 19: 279–86.
Nakagawa H, Yan H, Lockman J, Hampel H, Kinzler KW, Vogelstein B, et al. Allele separation facilitates interpretation of potential splicing alterations and genomic rearrangements. Cancer Res 2002; 62: 4579–82.
Nystrom-Lahti M, Wu Y, Moisio AL, Hofstra RM, Osinga J, Mecklin JP, et al. DNA mismatch repair gene mutations in 55 kindreds with verified or putative hereditary non-polyposis colorectal cancer. Hum Mol Genet 1996; 5: 763–9.
Farrington SM, Lin-Goerke J, Ling J, Wang Y, Burczak JD, Robbins DJ, et al. Systematic analysis of hMSH2 and hMLH1 in young colon cancer patients and controls. Am J Hum Genet 1998; 63: 749–59.
Jarvinen HJ, Mecklin JP, Sistonen P. Screening reduces colorectal cancer rate in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 1995; 108: 1405–11.
Jarvinen HJ, Aarnio M, Mustonen H, Aktan-Collan K, Aaltonen LA, Peltomaki P, et al. Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 2000; 118: 829–34.
Ruschoff J, Wallinger S, Dietmaier W, Bocker T, Brockhoff G, Hofstadter F, et al. Aspirin suppresses the mutator phenotype associated with hereditary nonpolyposis colorectal cancer by genetic selection. Proc Natl Acad Sci USA 1998; 95: 11301–6.
Loukola A, Salovaara R, Kristo P, Moisio AL, Kaariainen H, Ahtola H, et al. Microsatellite instability in adenomas as a marker for hereditary nonpolyposis colorectal cancer. Am J Pathol 1999; 155: 1849–53.
Salovaara R, Loukola A, Kristo P, Kaariainen H, Ahtola H, Eskelinen M, et al. Population-based molecular detection of hereditary nonpolyposis colorectal cancer. J Clin Oncol 2000; 18: 2193–200.
Aktan-Collan K, Mecklin JP, de la Chapelle A, Peltomaki P, Uutela A, Kaariainen H. Evaluation of a counselling protocol for predictive genetic testing for hereditary non-polyposis colorectal cancer. J Med Genet 2000; 37: 108–13.
Lynch HT, Lynch JF. Hereditary nonpolyposis colorectal cancer. Semin Surg Oncol 2000; 18: 305–13.