Abstract
Colorectal cancer remains a major health problem. Few therapies are effective apart from surgery, and survival has increased little in recent years. This is despite the fact that screening by colonoscopy can potentially remove nearly all colorectal tumours before they become malignant. Molecular genetics has identified some inherited mutations (such as at APC and the mismatch repair loci) that predispose to colon cancer and some somatic mutations (such as at APC and p53) that cause sporadic colon tumourr. We review the likely role of these and other genes in colorectal tumorigenesis. We also highlight areas of relative ignorance in colon cancer and emphasis that many important genes, especially those that cause invasion and metastasis, remain to be identified. Colorectal cancer is, however, a well characterised tumour, as regards both its natural history and its histopathology; there are consequently good prospects for advances in colon cancer genetics, with probable benefits for its treatment. We anticipate: (a) that new genes predisposing to colon tumours, including those conferring relatively minor risks, will be characterised; (b) genes and proteins important in invasion and metastasis will be identified; (c) the network of protein interactions in which molecules such as APC are involved will be elucidated; (d) large-scale studies of somatic mutations in tumours will provide accurate predictions of prognosis and suggest optimal therapeutic regimens; and (e) new potential targets for therapy will be identified. Whilst molecular genetics is by no means sufficient for progress in preventing and treating colon cancer, it is a necessary and central part of such advances.
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References
HMSO. Cancer Statisties. Registrations. England and Wales. London: HMSO, 1989
HMSO. Mortality Statistics. Cause. England and Wales. London: HMSO, 1992
Beart RW, Steele GJ, Menck HR et al.: Management and survival of patients with adenocarcinoma of the colon and rectum: a national survey of the Commission on Cancer. J Amer Coll Surg 181: 225–236, 1995
Dukes CE, Bussey HJR: The spread of cancer and its effect on prognosis. Cancer 12: 309–320, 1958
Jass JR, Love SB, Northover JMA: A new prognostic classification of rectal cancer. Lancet ii: 1303–1306, 1987
Morson B, Dawson I (eds): Morson and Dawson's gastrointestinal pathology. (Third ed.) Oxford: Blackwell Sci entific Publications, 1990.
Powell SM, Zilz N, Beazer-Barclay Y et al.: APC mutations occur carly during colorectal tumorigenesis. Nature 359: 235–237, 1992
Groden J, Thliveris A, Samowitz W et al.: Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66: 589–600, 1991
Kinzler KW, Nilbert MC, Su LK et al.: Identification of FAP locus genes from chromosome 5q21. Science 253: 661–665, 1991
Miyoshi Y, Nagase H, Ando H et al.: Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. Hum Mol Genet 1: 229–233, 1992
Solomon E, Voss R, Hall V et al.: Chromosome 5 allele loss in human colorectal carcinomas. Nature 328: 616–619, 1987
Miyaki M, Konishi M, Kikuchi-Yanoshita R et al.: Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumours. Cancer Res 54: 3011–3020, 1994
Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 61: 759–767, 1990
Bodmer WF, Bailey CJ, Bodmer J et al.: Localization of the gene familial adenomatous polyposis on chromosome 5. Nature 328: 614–616, 1987
Howe GR, Benito E, Castelleto R et al.: Dietary intake of fiber and decreased risk of cancers of the colon and rectum; evidence from the combined analysis of 13 case-control studies. J Natl Cancer Inst 84(24): 1887–1896, 1992
Joslyn G, Richardson DS, White R, Alber T: Dimer formation by an N-terminal coiled coil in the APC protein. Proc Natl Acad Sci USA 90: 11109–11113, 1993
Baeg GH, Matsumine A, Kuroda T et al.: The tumour suppressor gene product APC blocks cell cycle progression from G0/G1 to S phase. EMBO J 14: 5618–5625, 1995
Su LK, Vogelstein B, Kinzler KW: Association of the APC tumor suppressor protein with catenins. Science 262: 1734–1737, 1993
Rubinfeld B, Souza B, Albert I et al.: Assocation of the APC gene product with beta-catenin. Science 262: 1731–1734, 1993
Browne S, Williams A, Hague A, Butt A et al.: Loss of ape protein expressed by human colonic epithelial-cells and the appearance of a specific low molecular weight form is associated with apoptosis in vitro. Int J Cancer 59: 56–64, 1994
Burchill SA: The tumour suppressor APC product is associated with cell adhesion. Bioassays 16: 225–227, 1994
Munemitsu S, Souza B, Miller O et al.: The APC gene product associates with microtubules in vivo and promotes their assembly in vitro. Cancer Res 54: 3676–3681, 1994
Spirio L, Olschwang S, Groden J et al.: Alleles of the APC gene: an attenuated form of familial polyposis. Cell 75: 951–957, 1993
Friedl W, Meuschel S, Caspari R et al.: Attenuated familial adenomatous polyposis due to a mutation in the 3′ part of the APC gene. A clue for understanding the function of the APC protein. Hum Genet 97: 579–584, 1996
Samowitz WS, Thliveris A, Spirio LN, White R: Alternatively spliced adenomatous polyposis coli (APC) gene transcripts that delete exons mutated in attenuated APC. Oncogene 55: 3732–3734, 1995
Novelli MR, Williamson JA, Tomlinson IPM et al.: Poly clonal origin of colonic adenomas in an XO/XY patient with FAP. Science 272: 1187–1190, 1996
Su LK, Kinzler KW, Vogelstein BV et al.: Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 256: 668–670, 1992
Moser AR, Luongo C, Gould KA et al.: ApcMin: a mouse model for intestinal and mammary tumorigenesis. Eur J Cancer 31A: 1061–1064, 1995
MacPhee M, Chepenik KP, Liddell RA et al.: The secretory phospholipase A2 gene is a candidate for the Moml locus, a major modifier of ApcMin-induced intestinal neoplasia. Cell 81: 957–966, 1995
Tomlinson IPM, Nealc K, Talbot IC et al.: A modifying locus for familial adenomatous polyposis may be present on chromosome 1p35–p36. J Med Genet 33: 268–273, 1996
Riggins GJ, Markowitz S, Wilson JK et al.: Absence of secretory phospholipase A2 gene alterations in human colorectal cancer. Cancer Res 55(22): 5184–5186, 1995
Leach FS, Nicolaides NC, Papadopoulos N et al.: Mutations of a mutS homolog in heriditary nonpolyposis colorectal cancer. Cell 75: 1215–1225, 1993
Lindblom A, Tannergard P, Werelius B, Nordenskjold M: Genetic mapping of a second locus predisposing to hereditary non-polyposis colon cancer. Nat Genet 5: 279–282, 1993
Fishel R, Lescoc MK, Rao MR et al.: The human mutator gene homolog MSII2 and its association with hereditary nonpolyposis colon cancer. Cell 75: 1027–1038, 1993
Aaltonen LA, Peltomaki P, Leach FS et al.: Cues to the pathogenesis of familial colorectal cancer. Science 260: 812–816, 1993
Tomlinson IPM, Novelli MR, Bodmer WF: The mutation rate and cancer. Proc Natl Acad Sci USA 1996
Liu B, Nicolaides NC, Markowitz S et al.: Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. Nat Genet 9: 48–55, 1995
Connell WR, Talbot IC, Harpaz N et al.: Clinicopathological characteristics of colorectal carcinoma complicating ulcerative colitis. Gut 35(10): 1419–1423, 1994
Ilyas M, Tomlinson IPM: Genetic pathways in colorectal cancer. Histopathol 28: 389–399, 1996
Redston M, Papadipoulos N, Caldas C et al.: Common occurrence of APC and K-ras mutation in the spectrum of colitis-associated neoplasias. Gastroenterol 108: 383–392, 1995
Tarmin L, Yin J, Harpaz N et al.: Adenomatous polyposis coli gene mutations in ulcerative colitis-associated dysplasias and cancers versus sporadic colon neoplasms. Cancer Res 55: 2035–2038, 1995
Burmer GC, Crispin DA, Kolli VR et al.: Frequent loss of a p53 allele in carcinomas and their precursors in ulcerative colitis. Cancer Commun 3: 167–172, 1991
Brentnall TA, Crispin DA, Rabinovitch PS et al.: Mutations in the p53 gene: An early marker of neoplastic progression in ulcerative colitis. Gastroenterol 107: 369–378, 1994
Tops CM, van der Klift HM, van der Luijt RB et al.: Nonallelic heterogencity of familial adenomatous polyposis. Amer J Med Genet 47: 563–567, 1993
Whitelaw SC, Murday VA, Tomlinson IPM et al.: Clinical and molecular features of the Hereditary Mixed Polyposis Syndrome. Gastroenterol 1997, in press
Hemminki A, Tomlinson IPM, Markie D et al.: Localisation of a susceptibility focus for Peutz-Jeghers syndrome using comparative genomic hybridisation and targeted linkage analysis. Nat Genet 15: 87–90, 1997
Jacoby RF, Schlack S, Cole CE, Marshall DJ, Kuhlman G et al.: Identification of a juvenile polyposis tumor-suppressor gene locus (JP1) and demonstration of its deletion in subepithehal cells. Gastroenterol 110: A535, 1996
Thomas HJW, Whitelaw SC, Cottrell SE et al.: Genetic mapping of the Hereditary Mixed Polyposis Syndrome to chromosome 6q. Amer J Hum Genet 58: 770–776, 1996
Nelen MR, Padberg GW, Peeters EAJ et al.: Localization of the gene for Cowden disease to chromosome 10q22–23. Nat Genet 13: 114–116, 1996
Nowell PC: The clonal evaluation of tumor cell populations. Science 194: 23–28, 1976
Tomlinson IPM: Evolutionary theory and cancer. Trends Ecol Evol 8: 107–110, 1993
Shepherd JA: Regression phenomenon in familial polyposis. Proc Roy Soc Med 65: 169, 1972
Giardello FM: Snlindac and polyp regression. Cancer Met Rev 13: 279–283, 1994
Bos JL: The ras gene family and human carcinogenesis. Mutat Res 195: 255–271, 1988
Smith AJ, Stern HS, Penner M et al.: Somatic APC and K-ras codon 12 mutations in aberrant crypt foci from human colons. Cancer Res 54: 5527–5530, 1994
Durmer GC, Levine DS, Kulander BG et al.: c-Ki-ras mutations in chronic ulcerative colitis and sporadic colon carcinoma. Gastroenterol 99: 416–420, 1990
Minamoto T, Yamashita N, Ochiai A et al.: Mutant K-ras in apparently normal mucosa of colorectal cancer patients. Its potential as a biomarker of colorectal tumorigenesis. Cancer 75(6 Suppl): 1520–1526, 1995
Pretlow TP: Aberrant crypt foci and K-ras mutations: earliest recognised players or innocent bystanders in colon carcinogenesis? Gastroenterol 108: 600–603, 1995
Bird RP: Role of aberrant crypt foci in understanding the pathogenesis of colon cancer. Cancer Lett 93: 55–71, 1995
Jen J, Kim H, Piantadosi S et al.: Allelic loss of chromosome 18q and prognosis in colorectal cancer. N Engl J Med 331: 213–221, 1994
Vogelstein BV, Fearon ER, Hamilton SR et al.: Genetic alterations during colorectal tumour development. N Engl J Med 319: 525–532, 1988
Knudson AG: Hereditary cancer: two hits revisited. J Cancer Res Clin Oncol 122: 135–140, 1996
Kinzler KW, Nilbert MC, Vogelstein B et al.: Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers. Science 251: 1366–1370, 1991
Curtis LJ, Bubb VJ, Gledhill S, Morris RG, Bird CC, Wyllie AH: Loss of heterozygosity of MCC is not associated with mutation of the retained allele in sporadic colorectal cancer. Hum Mol Genet 3: 443–446, 1994
Hedrick L, Cho KR, Fearon ER, Wu TC, Kinzler KW, Vogelstein B: The DCC gene product in cellular differentiation and colorectal tumorigenesis. Genes Dev 8: 1174–1183, 1994
Thiagalingam S, Lengaver C, Leach ES et al.: Evaluation of candidate tumor suppressor genes on chromosome 18 in colorectal cancers. Nat Genet 13: 343–346, 1996
Baker SJ, Preisinger AC, Jessup JM et al.: p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis. Cancer Res 50: 7712–7722, 1990
Cunningham J, Lust JA, Schaid DJ et al.: Expression of p53 and allelic loss in colorectal carcinoma. Cancer Res 52: 1974–1980, 1992
Kawasaki Y, Monden T, Morimoto H et al.: Immunohistochemical study of p53 expression in microwave-fixed, paraffin-embedded sections of colorectal carcinoma and adenoma. Am J Pathol 97: 244–249, 1992
Lane DP: Cancer. p53, guardian of the genome. Nature 358: 15–16, 1992
Donehower LA, Bradley A: The tumor suppressor p53. Biochim Biophys Acta 1155: 181–205, 1993
Carder P, Wyllic AH, Purdie CA et al.: Stabilised p53 facilitates aneuploid clonal divergence in colorectal cancer. Oncogene 8: 1397–1401, 1993
Krawczak M, Smith SB, Schmidtke J et al.: Somatic spectrum of cancer-associated single basepair substitutions in the TP53 gene is determined mainly by endogenous mechanisms of mutations and by selection. Hum Mutat 5: 48–57, 1995
Ohta M, Inoue H, Cotticelli MG et al.: The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers. Cell 84: 587–597, 1996
Okamoto A, Demetrick DJ, Spillare EA et al.: Mutations and altered expression of p16INK4 in human cancer. Proc Natl Acad Sci USA 91: 11045–11049, 1994
Herman JG, Merlo A, Mao L et al.: Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res 55: 4525–4530, 1995
Gonzalez ZM, Bender CM, Yang AS et al.: Methylation of the 5′ CpG island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissues correlates with gene silencing. Cancer Res 55: 4531–4535, 1995
Leister I, Weith A, Bruderlein S et al.: Human colorectal cancer: high frequency of deletions at chromosome 1p35. Cancer Res 50: 7232–7225, 1990
Praml C, Finke LH, Herfarth C et al.: Deletion mapping defines different regions in 1p34.2-pter that may harbor genetic information related to human colorectal cancer. Oncogene 11(7): 1357–1362, 1995
Wildrick D, Alfaro S, Gope R, Boman B: A study of chromosome-6 allele loss in human colorectal carcinomas. Anticancer Res 12: 1717–1719, 1992
Fujiwara Y, Emi M, Ohata H et al.: Evidence for the presence of two tumor suppressor genes on chromosome 8p for colorectal carcinoma. Cancer Res 53: 1172–1174, 1993
Cunningham C, Dunlop MG, Wyllie AH, Bird CC: Deletion mapping in colorectal cancer of a putative tumour suppressor gene in 8p22–p21.3. Oncogene 8: 1391–1396, 1993
Young J, Leggett B, Ward M et al.: Frequent loss of heterozygosity on chromosome-14 occurs in advanced colorectal carcinomas. Oncogene 8: 671–675, 1993
Yana I, Kurahashi H, Nakamori S et al.: Frequent loss of heterozygosity at telomeric loci on 22q in sporadic colorectal cancers. Int J Cancer 60: 174–177, 1995
Houldsworth J, Chaganti RS: Comparative genomic hybridisation: an overview. Am J Pathol 145: 1253–1260, 1994
Liu B, Parsons R, Papadopoulos N et al.: Analysis of mismatch repair genes in hereditary non-polyposis colorectal cancer patients. Nat Med 2: 169–174, 1996
Kim H, Jen J, Vogelstem B, Hamilton SR: Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol 145: 148–156, 1994
Young J, Leggett B, Gustafson C et al.: Genomic instability occurs in colorectal carcinomas but not in adenomas. Hum Mutat 2: 351–354, 1993
Ilyas M, Tomlinson IPM, Novelli MR et al.: Clinico-pathological features and p53 expression in left-sided sporadic colorectal cancers with and without microsatellite instability. J Pathol 179: 370–375, 1996
Tomlinson IPM, Bodmer WF: Failure of programmed cell death and differentiation as causes of tumors: some simple mathematical models Proc Natl Acad Sci USA 92: 11130–11134, 1995
Tomlinson IPM, Bodmer WF: Models of non-autonomous interactions of tumour cells. Brit J Cancer 1997, in press
Leek RD, Harris AL, Lewis CE: Cytokine networks in solid human tumors: regulation of angiogenesis. J Leukoc Biol 56: 423–435, 1994
Browning MJ, Krausa P, Rowan A et al.: Loss of human leukocyte antigen expression on colorectal tumor cell lines: implications for anti-tumor immunity and immunotherapy. J Immunother 14: 163–168, 1993
Linn SC, Giaccone G: MDR1/P-glycoprotein expression in colorectal cancer. Eur J Cancer 31A: 1291–1294, 1995
Nuovo GJ: In situ PCR: protocols and applications. PCR Methods Appl 4:S151–167, 1995
Pignatelli M, Liu D, Nasim MM et al.: Morphoregulatory activities of E-cadherin and beta-1 integrins in colorectal tumour cells. Br J Cancer 66: 629–634, 1992
Kinsella AR, Lepts GC, Hill CL, Jones M: Reduced E-cadherin expression correlates with increased invasiveness in colorectal carcinoma cell lines. Clin Exp Metastasis 12: 335–342, 1994
Dorudi S, Sheffield JP, Poulsom R et al.: E-cadherin expression in colorectal cancer. An immunocytochemical and in situ hybridization study. Am J Pathol 142: 981–986, 1993
Ilyas M, Tomlinson IPM, Hanby A et al.: Allele loss, replication errors and loss of expression of E-cadherin in colorectal cancers. Gut 1977, in press
De Bruin PAF, Griffioen G, Verspaget HW et al.: Plasminogen activator profiles in neoplastic tissues of the human colon. Cancer Res 48: 4520–4524, 1988
Sier CFM, Vloedgraven HJM, Griffioen G et al.: Plasminogen activators and inhibitor type 1 in neoplastic colonic tissue from patients with familial adenomatous polyposis. Br J Cancer 71: 393–396, 1995
MacDonald NJ, de la Rosa A, Steeg PS: The potential roles of nm23 in cancer metastasis and cellular differentiation. Eur J Cancer 31A: 1096–1100, 1995
Martinez JA, Prevot S, Nordlinger B et al.: Overexpression of nm23-H1 and nm23-H2 genes in colorectal carcinomas and loss of nm23-H1 expression in advanced tumour stages. Gut 37: 712–720, 1995
Iacopetta B, DiGrandi S, Dix B, Haig C, Soong R, House A: Loss of heterozygosity of tumour suppressor gene loci in human colorectal carcinoma. Eur J Cancer 30A: 664–670, 1994
Cawkwell L, Lewis FA, Quirke P: Frequency of allele loss of DCC, p53, RBI, WT1, FF1, NM23 and APC/MCC in colorectal cancer assayed by fluorescent multiplex polymerase chain reaction. Br J Cancer 70: 813–818, 1994
Campo E, Miquel R, Jares P et al.: Prognostic-significance of the loss of heterozygosity of nm23-h1 and p53 genes in human colorectal carcinomas. Cancer 73: 2913–2921, 1994
Ichikawa W: Positive relationship between expression of CD44 and hepatic metastases in colorectal cancer. Pathobiology 62: 172–179, 1994
Plummer SJ, Casey G: Are we any closer to genetic testing for common malignancies? Nat Med 2: 156–158, 1996
Lynch HT, Smyrk T, Jass JR: Hereditary non-polyposis colorectal cancer and colonic adenomas: aggressive adenomas? Semin Surg Oncol 11: 406–410, 1995
Rhodes M, Bradburn DM: Overview of screening and management of familial adenomatous polyposis. Gut 33: 125–131, 1992
Lynch HT, Smyrk T, Lynch JF: Overview of natural history, pathology, molecular genetics and management of HNPCC (Lynch syndrome). Int J Cancer 69: 38–43, 1996
Lynch HT, Smyrk TC, Watson P et al.: Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. Gastroenterol 104: 1535–1549, 1993
Jass JR: Colorectal adenomas in surgical specimens from subjects with hereditary non-polyposis colorectal cancer. Histopathol 27: 263–267, 1995
Jass JR, Stewart SM, Stewart J, Lane MR: Hereditary nonpolyposis colon cancer — morphologies, genes and mutations. Mutat Res 310: 125–133, 1994
Percesepe A, Anti M, Roncucci L et al.: The effect of family size on estimates of the frequency of hereditary nonpolyposis colorectal cancer. Br J Cancer 72: 1320–1323, 1995
Duffy MJ: Can molecular markers now be used for early diagnosis of malignancy? Clin Chem 41: 1419–1413, 1995
Leather AJ, Gallegos NC, Kocjan G et al.: Detection and enumeration of circulating tumour cells in colorectal cancer. Br J Surg 80: 777–780, 1993
Lowe SW, Bodis S, McClatchey A et al.: p53 status and the efficacy of cancer therapy in vivo. Science 266: 807–810, 1994
Hargest R, Williamson R: Expression of the APC gene after transfection into a colonic cancer cell line. Gut 37: 826–829, 1995
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Tomlinson, I., Ilyas, M. & Novelli, M. Molecular genetics of colon cancer. Cancer Metastasis Rev 16, 67–79 (1997). https://doi.org/10.1023/A:1005744323215
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DOI: https://doi.org/10.1023/A:1005744323215