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Genetic predisposition to colorectal cancer


High-penetrance mutations in several genes have been identified that contribute to hereditary colorectal cancer. The role of these mutations in cancer pathogenesis is well understood and their detection is successfully used in clinical diagnosis. In stark contrast, our understanding of the influence of low-penetrance mutations that account for most of the remaining familial cases of colorectal cancer, as well as an unknown proportion of sporadic cases, is far less advanced. Extensive ongoing research into low-penetrance, multifactorial predisposition to colorectal cancer is now beginning to bear fruit, with important implications for understanding disease aetiology and developing new diagnostic, preventive and therapeutic strategies.

Key Points

  • Cancer is a genetic disease. Most cancer-causing mutations are somatic, occurring in the affected tissue during the course of carcinogenesis; however, most cancers also have a hereditary component that is caused by predisposing mutations that affect the germline, are heritable and contribute to the initiation of carcinogenesis.

  • Colorectal cancer is probably the type of cancer for which the most is known about the genes affected by cancer-causing mutations, their normal functions and their carcinogenic effects when mutated.

  • High-penetrance mutations confer predisposition to colorectal cancer mainly in Lynch syndrome (which involves mutations in mismatch-repair genes) and in familial adenomatous polyposis (which involves mutations in the APC tumour suppressor). Together, these conditions account for 5% or less of all cases of colorectal cancer.

  • Determining carriership for the mutations that underlie these conditions is important in the management and prevention of cancer in these patients and their families.

  • Low-penetrance mutations account for a high proportion of all the attributable risk of colorectal cancer, in both familial and sporadic cases. These mutations are more difficult to identify, but — mainly due to the implementation of association studies — are increasingly being detected and characterized.

  • The identification of both high- and low-penetrance mutations contributes significantly to our understanding of the molecular genetic processes occurring in cancer. This understanding facilitates the development of therapeutic drugs and preventive strategies.

  • Gene–gene and gene–environment interactions have a significant influence on susceptibility to colorectal cancer. Our current understanding of these interactions is limited, and concerted research efforts in this area will be important for a full understanding of predisposition to this cancer.

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  1. 1

    Potter, J. D. Colorectal cancer: molecules and populations. J. Natl Cancer Inst. 91, 916–932 (1999). A comprehensive review of the molecular population-genetics aspects of colorectal cancer.

  2. 2

    Mayer, R. J. Harrison's Principles of Internal Medicine 15th Edition (eds Braunwals, E. et al.) 581–588 (McGraw-Hill, New York, 2001).

  3. 3

    Fearon, E. R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990). A comprehensive early review of the molecular basis of colorectal cancer.

  4. 4

    Kinzler, K. W. & Vogelstein, B. Lessons from hereditary colorectal cancer. Cell 87, 159–170 (1996).

  5. 5

    Salovaara, R. et al. Population-based molecular detection of hereditary nonpolyposis colorectal cancer. J. Clin. Oncol. 18, 2193–2200 (2000).

  6. 6

    Olsson, L. & Lindblom, A. Family history of colorectal cancer in a Swedish county. Familial Cancer 2, 87–93 (2003).

  7. 7

    St. John, D. J. B. et al. Cancer risk in relatives of patients with common colorectal cancer. Ann. Int. Med. 118, 785–790 (1993).

  8. 8

    Johns, L. E. & Houlston, R. S. A systematic review and meta-analysis of familial colorectal cancer risk. Am. J. Gastroenterol. 96, 2992–3003 (2001).

  9. 9

    Goss, K. H., Trzepacz, C., Tuohy, T. M. F. & Groden, J. Attenuated APC alleles produce functional protein from internal translation initiation. Proc. Natl Acad. Sci. 99, 8161–8166 (2002). The explanation of the paradox that truncating mutations in the most proximal part of the APC gene cause a milder 'attenuated' form of familial adenomatous polyposis.

  10. 10

    Yan, H. et al. Small changes in expression affect predisposition to tumorigenesis. Nature Genet. 30, 25–26 (2002). First evidence that allele-specific reduction in APC expression is heritable and causes predisposition to familial adenomatous polyposis.

  11. 11

    Lynch, H. T., Guirgis, H. A., Lynch, P. M., Lynch, J. F. & Harris, R. E. Familial cancer syndromes: a survey. Cancer (Suppl) 39, 1867–1881 (1977).

  12. 12

    Lynch, H. T. & Krush, A. J. Cancer family 'G' revisited: 1895–1970. Cancer 27, 1505–1511 (1971). An early reminder from Henry Lynch that predisposition to non-polyposis colorectal and other cancers can be inherited as a dominant trait.

  13. 13

    Umar, A., Risinger, J. I., Hawk, E. T. & Barrett, J. C. Testing guidelines for hereditary non-polyposis colorectal cancer. Nature Rev. Cancer 4, 153–158 (2004).

  14. 14

    Lynch, H. T. & de la Chapelle, A. Genomic medicine: hereditary colon cancer. N. Engl. J. Med. 348, 919–932 (2003).

  15. 15

    Aaltonen, L. A. et al. Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. N. Engl. J. Med. 338, 1481–1487 (1998).

  16. 16

    Cunningham, J. M. et al. The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas. Am. J. Hum. Genet. 69, 780–790 (2001).

  17. 17

    Percesepe, A. et al. Molecular screening for hereditary nonpolyposis colorectal cancer: a prospective, population-based study. J. Clin. Oncol. 19, 3944–3950 (2001).

  18. 18

    Samowitz, W. S. et al. The colon cancer burden of genetically defined hereditary nonpolyposis colon cancer. Gastroenterology 121, 830–838 (2001).

  19. 19

    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. 37, 533–536 (2000).

  20. 20

    Parsons, R. et al. Hypermutability and mismatch repair deficiency in RER+ tumor cells. Cell 75, 1227–1236 (1993).

  21. 21

    Hemminki, A. et al. Loss of the wild type MLH1 gene is a feature of hereditary nonpolyposis colorectal cancer. Nature Genet. 8, 405–410 (1994).

  22. 22

    Liu, B. et al. hMSH2 mutations in hereditary non–polyposis colorectal cancer kindreds. Cancer Res. 54, 4590–4594 (1994).

  23. 23

    Liu, B. et al. Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. Nature Genet. 9, 48–55 (1995).

  24. 24

    Kane, M. F. et al. Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res. 57, 808–811 (1997).

  25. 25

    Aaltonen, L. A. et al. Clues to the pathogenesis of familial colorectal cancer. Science 260, 812–816 (1993). The first demonstration that microsatellite instability is a hallmark of Lynch syndrome.

  26. 26

    Aaltonen, L. A. et al. Replication errors in benign and malignant tumors from hereditary nonpolyposis colorectal cancer patients. Cancer Res. 54, 1645–1648 (1994).

  27. 27

    Boland, C. R. 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. 58, 5248–5257 (1998).

  28. 28

    Konishi, M. et al. Molecular nature of colon tumors in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer. Gastroenterology 111, 307–317 (1996).

  29. 29

    Markowitz, S. et al. Inactivation of the type II TGF-β receptor in colon cancer cells with microsatellite instability. Science 268, 1336–1338 (1995).

  30. 30

    Peltomäki, P. & Vasen, H. F. Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer. Gastroenterology 113, 1146–1158 (1997). An early, comprehensive summary of the mutational spectrum in Lynch syndrome.

  31. 31

    Renkonen, E. et al. Altered expression of MLH1, MSH2, and MSH6 in predisposition to hereditary nonpolyposis colorectal cancer. J. Clin. Oncol. 21, 3629–3637 (2003).

  32. 32

    Miyaki, M. et al. Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nature Genet. 17, 271–272 (1997).

  33. 33

    Nicolaides, N. C. et al. Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 371, 75–80 (1994).

  34. 34

    Nicolaides, N. C. et al. Genomic organization of the human PMS2 gene family. Genomics 30, 195–206 (1995)

  35. 35

    Nicolaides, N. C., Littman, S., Modrich, P., Kinzler, K. W. & Vogelstein, B. A naturally occurring hPMS2 mutation can confer a dominant negative phenotype. Mol. Cell. Biol. 18, 1635–1641 (1998).

  36. 36

    Nakagawa, H. et al. Mismatch repair gene PMS2: disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein but paralogous genes obscure mutation detection and interpretation. Cancer Res. 64, 4721–4727 (2004).

  37. 37

    De Vos, M. et al. Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome. Am. J. Hum. Genet. 74, 954–964 (2004).

  38. 38

    Wu, Y. et al. A role for MLH3 in hereditary nonpolyposis colorectal cancer. Nature Genet. 29, 137–138 (2001).

  39. 39

    Lammi, L. et al. Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. Am. J. Hum. Genet. 74, 1043–1050 (2004).

  40. 40

    Lu, S. -L. et al. HNPCC associated with germline mutation in the TGF-β type II receptor gene. Nature Genet. 19, 17–18 (1998).

  41. 41

    da Costa, L. T. et al. Polymerase δ variants in RER colorectal tumours. Nature Genet. 9, 10–11 (1995).

  42. 42

    Froggatt, N. J. et al. A common MSH2 mutation in English and North American HNPCC families: origin, phenotypic expression, and sex specific differences in colorectal cancer. J. Med. Genet. 36, 97–102 (1999).

  43. 43

    Desai, D. C. et al. Recurrent germline mutation in MSH2 arises frequently de novo. J. Med. Genet. 37, 646–652 (2000).

  44. 44

    Chan, T. L. et al. A novel germline 1.8-kb deletion of hMLH1 mimicking alternative splicing: a founder mutation in the Chinese population. Oncogene 20, 2976–2981 (2001).

  45. 45

    Jaeger, A. C. et al. Reduced frequency of extracolonic cancers in hereditary nonpolylposis colorectal cancer families with monoallelic hMLH1 expression. Am. J. Hum. Genet. 61, 129–138 (1997).

  46. 46

    Stella, A. et al. A nonsense mutation in MLH1 causes exon skipping in three unrelated HNPCC families. Cancer Res. 61, 7020–7024 (2001).

  47. 47

    Caluseriu, O. et al. A founder MLH1 mutation in families from the districts of Modena and Reggio-Emilia in northern Italy with hereditary non-polyposis colorectal cancer associated with protein elongation and instability. J. Med. Genet. 41, e34 (2004).

  48. 48

    Chan, T. L. et al. MSH2 c. 1452-1455delAATG is a founder mutation and an important cause of hereditary nonpolyposis colorectal cancer in the southern Chinese populations. Am. J. Hum. Genet. 74, 1035–1042 (2004).

  49. 49

    Hemminki, A. et al. A serine/threonine kinase gene defective in Peutz–Jeghers syndrome. Nature 39, 184–187 (1998).

  50. 50

    Lim, W. et al. Further observations of LKB1/STK11 status and cancer risk in Peutz–Jeghers syndrome. Br. J. Cancer 89, 308–313 (2003).

  51. 51

    Howe, J. R. et al. Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science 280, 1086–1088 (1998).

  52. 52

    Howe, J. R. et al. Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nature Genet. 28, 184–187 (2001).

  53. 53

    Houlston, R. et al. Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only account for a minority of cases. Hum. Mol. Genet. 7, 1907–1912 (1998).

  54. 54

    Sayed, M. G. et al. Germline SMAD4 or BMPR1A mutations and phenotype of juvenile polyposis. Ann. Surg. Oncol. 9, 901–906 (2002).

  55. 55

    Al-Tassan, N. et al. Inherited variants of MYH associated with somatic G:C→T:A mutations in colorectal tumors. Nature Genet. 30, 227–232 (2002). The first demonstration of a gene that causes a high level of predisposition to colorectal cancer when both alleles are mutated, and therefore shows typical recessive inheritance.

  56. 56

    Jones, S. et al. Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C→T:A mutations. Hum. Mol. Genet. 11, 2961–2967 (2002).

  57. 57

    Sieber, O. M. et al. Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N. Engl. J. Med. 348, 791–799 (2003).

  58. 58

    Gismondi, V. et al. Prevalence of the Y165C, G382D and 1395delGGA germline mutations of the MYH gene in Italian patients with adenomatous polyposis coli and colorectal adenomas. Int. J. Cancer 109, 680 (2004).

  59. 59

    Enholm, S. et al. Proportion and phenotype of MYH-associated colorectal neoplasia in a population-based series of Finnish colorectal cancer patients. Am. J. Pathol. 163, 827–832 (2003).

  60. 60

    Fleischmann, C. et al. Comprehensive analysis of the contribution of germline MYH variation to early-onset colorectal cancer. Int. J. Cancer 109, 554–558 (2004).

  61. 61

    Wiesner, G. L. et al. A subset of familial colorectal neoplasia kindreds linked to chromosome 9q22. 2-31. 2. Proc. Natl Acad. Sci. USA 100, 12961–12965 (2003).

  62. 62

    Tomlinson, I. et al. Inherited susceptibility to colorectal adenomas and carcinomas: evidence for a new predisposition gene on 15q14-q22. Gastroenterology 116, 789–795 (1999).

  63. 63

    Jaeger, A. C. et al. An ancestral Ashkenazi haplotype at the HPS/CRAC1 locus on 15q13-q14 is associated with hereditary mixed polyposis syndrome. Am. J. Hum. Genet. 72, 1261–1267 (2003).

  64. 64

    Park, W. S. et al. A distinct tumor suppressor gene locus on chromosome 15q21. 1 in sporadic form of colorectal cancer. Cancer Res. 60, 70–73 (2000).

  65. 65

    Laiho, P. et al. Genome-wide allelotyping of 104 Finnish colorectal cancers reveals an excel of allelic imbalance in chromosome 10q in familial cases. Oncogene 22, 2206–2214 (2003).

  66. 66

    Gustafson, C. E. et al. Functional evidence for a colorectal cancer tumor suppressor gene at chromosome 8p22-23 by monochromosome transfer. Cancer Res. 56, 5238–5245 (1996).

  67. 67

    Laken, S. J. et al. Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC. Nature Genet. 17, 79–83 (1997). The first convincing description of a common low-penetrance allele predisposing to colorectal cancer.

  68. 68

    Rozen, P. et al. Prevalence of the I1307K APC gene variant in Israeli Jews of differing ethnic origin and risk for colorectal cancer. Gastroenterology 116, 54–57 (1999).

  69. 69

    Woodage, T. et al. The APC I1307K allele and cancer risk in a community-based study of Ashkenazi Jews. Nature Genet. 20, 62–65 (1998).

  70. 70

    Gryfe, R., DiNicola, N., Gallinger, S. & Redston, M. Somatic instability of the APC I1307K allele in colorectal neoplasia. Cancer Res. 58, 4040 –4043 (1998).

  71. 71

    Drucker, L. et al. Adenomatous polyposis coli I1307K mutation in Jewish patients with different ethnicity. Cancer 88, 755–760 (2000).

  72. 72

    Zauber, N. P., Sabbath-Solitare, M., Marotta, S. P. & Bishop, D. T. The characterization of somatic APC mutations in colonic adenomas and carcinomas in Ashkenazi Jews with the APC I1307K variant using linkage disequilibrium. J. Pathol. 199, 146–151 (2003).

  73. 73

    Strul, H. et al. The I1307K adenomatous polyposis coli gene variant does not contribute in the assessment of the risk for colorectal cancer in Ashkenazi Jews. Cancer Epidemiol. Biomarkers Prev. 12, 1012–1015 (2003).

  74. 74

    Sieber, O., Lipton, L., Heinimann, K. & Tomlinson, I. Colorectal tumorigenesis in carriers of the APC I1307K variant: lone gunman or conspiracy? J. Pathol. 199, 137–139 (2003)

  75. 75

    Prior, T. W. et al. I1307K polymorphism of the APC gene in colorectal cancer. Gastroenterology 116, 58–63 (1999).

  76. 76

    Patael, Y. et al. Common origin of the I1307K APC polymorphism in Ashkenazi and non-Ashkenazi Jews. Eur. J. Hum. Genet. 7, 555–559 (1999).

  77. 77

    Shtoyerman-Chen, R. et al. The I1307K APC polymorphism: prevalence in Non-Ashkenazi Jews and evidence for a founder effect. Genet. Testing 5, 141–146 (2001).

  78. 78

    Niell, B. L., Long, J. C., Rennert, G. & Gruber, S. B. Genetic anthropology of the colorectal cancer-susceptibility allele APC I1307K: evidence of genetic drift within the Ashkenazim. Am. J. Hum. Genet. 73, 1250–1260 (2003).

  79. 79

    Rozen, P. et al. Clinical and screening implications of the I1307K adenomatous polyposis coli gene variant in Israeli Ashkenazi Jews with familial colorectal neoplasia. Evidence for a founder effect. Cancer 94, 2561–2568 (2002).

  80. 80

    Benichou, J. A review of adjusted estimators of attributable risk. Stat. Methods Med. Res. 10, 195–216 (2001).

  81. 81

    Kaklamani, V. G. et al. TGFBR1*6A and cancer risk: a meta-analysis of seven case-control studies. J. Clin. Oncol. 21, 3236–3243 (2003).

  82. 82

    Pasche, B. et al. TBFBR1*6A and cancer: a meta-analysis of 12 case-control studies. J. Clin. Oncol. 22, 756–758 (2004).

  83. 83

    Stefanovska, A. -M. et al. TβR-I(6A) Polymorphism is not a tumor susceptibility allele in Macedonian colorectal cancer patients. Cancer Res. 61, 8351–8352 (2001).

  84. 84

    Chen, T. et al. Structural alterations of transforming growth factor-β receptor genes in human cervical carcinoma. Int. J. Cancer 82, 43–51 (1999).

  85. 85

    Pasche, B. et al. TβR-I(6A) is a candidate tumor susceptibility allele. Cancer Res. 59, 5678–5682 (1999).

  86. 86

    Lipkin, S. M. et al. The MLH1 D132H variant is associated with susceptibility to sporadic colorectal cancer. Nature Genet. 36, 694–699 (2004).

  87. 87

    Houlston, R. S. & Tomlinson, I. P. M. Polymorphisms and colorectal tumor risk. Gastroenterology 121, 282–301 (2001). An extensive critical review of published papers on polymorphisms thought to affect colorectal cancer risk.

  88. 88

    Peltomäki, P., Gao, X. & Mecklin, J. P. Genotype and phenotype in hereditary nonpolyposis colon cancer: a study of families with different vs. shared predisposing mutations. Fam. Cancer. 1, 9–15 (2001).

  89. 89

    Moser, A. R., Pitot, H. C. & Dove, W. F. A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 247, 322–324 (1990).

  90. 90

    Dietrich, W. et al. Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal neoplasia in the mouse. Cell 75, 631–639 (1993).

  91. 91

    Cormier, R. T. et al. Secretory phospholipase Pla2g2a confers resistance to intestinal tumorigenesis. Nature Genet. 17, 88–91 (1997).

  92. 92

    Nadeau, J. H. Modifier genes in mice and humans. Nature Rev. Genet. 2, 165–174 (2001).

  93. 93

    Nimmrich, I. et al. Loss of the PLA2G2A gene in a sporadic colorectal tumor of a patient with a PLA2G2A germline mutation and absence of PLA2G2A germline alterations in patients with FAP. Hum. Genet. 100, 345–349 (1997).

  94. 94

    Terry, P. et al. Fruit, vegetables, dietary fiber, and risk of colorectal cancer. J. Natl Cancer Inst. 93, 525–533 (2001).

  95. 95

    Risch, N. A note on multiple testing procedures in linkage analysis. Am. J. Hum. Genet. 48, 1058–1064 (1991).

  96. 96

    Botstein, D. & Risch, N. Discovering genotypes underlying human phenotypes: past successes for Mendelian disease, future approaches for complex disease. Nature Genet. Suppl. 33, 228–237 (2003).

  97. 97

    Risch, N. The genetic epidemiology of cancer: interpreting family and twin studies and their implications for molecular genetic approaches. Cancer Epidemiol. Biomarkers Prev. 10, 733–741 (2001). An insightful interpretation and evaluation of studies into the heritability of cancer.

  98. 98

    Goldgar, D. E., Easton, D. F., Cannon-Albright, L. A. & Skolnick, M. H. Systematic population-based assessment of cancer risk in first-degree relatives of cancer probands. J. Natl Cancer Inst. 21, 1600–1608 (1994).

  99. 99

    Dong, C. & Hemminki, K. Modification of cancer risks in offspring by sibling and parental cancers from 2,122,616 nuclear families. Int. J. Cancer 92, 144–150 (2001).

  100. 100

    Lichtenstein, P. et al. Environmental and heritable factors in the causation of cancer. New Engl. J. Med. 343, 78–85 (2000).

  101. 101

    Nysträm-Lahti, M. et al. Founding mutations and Alu-mediated recombination in hereditary colon cancer. Nature Med. 1, 1203–1206 (1995). The first demonstration of widespread founder mutations in Lynch syndrome.

  102. 102

    Moisio, A. -L., Sistonen, P., Weissenbach, J., de la Chapelle, A. & Peltomäki, P. Age and origin of two common MLH1 mutations predisposing to hereditary colon cancer. Am. J. Hum. Genet. 59, 1243–1251 (1996).

  103. 103

    Hutter, P. et al. Complex genetic predisposition to cancer in an extended HNPCC family with an ancestral hMLH1 mutation. J. Med. Genet. 33, 636–640 (1996).

  104. 104

    Froggatt, N. J. et al. Genetic linkage analysis in hereditary nonpolyposis colon cancer syndrome. J. Med. Genet. 32, 352–357 (1995).

  105. 105

    Green, J. et al. Impact of gender and parent of origin on the phenotypic expression of hereditary nonpolyposis colorectal cancer in a large Newfoundland kindred with a common MSH2 mutation. Dis. Colon Rect. 45, 1223–1232 (2002).

  106. 106

    Foulkes, W. D. et al. The founder mutation MSH2*1906G→C is an important cause of hereditary non-polyposis colorectal cancer in the Ashkenazi Jewish population. Am. J. Hum. Genet. 71, 1395–1412 (2002).

  107. 107

    Wagner, A. et al. Molecular analysis of hereditary nonpolyposis colorectal cancer in the United States: high mutation detection rate among clinically selected families and characterization of an American founder genomic deletion of the MSH2 gene. Am. J. Hum. Genet. 72, 1088–1100 (2003).

  108. 108

    Nakagawa, H., Hampel, H. & de la Chapelle, A. Identification and characterization of genomic rearrangements of MSH2 and MLH1 in Lynch syndrome (HNPCC) by novel techniques. Hum. Mut. 22, 258 (2003).

  109. 109

    Lynch, H. T. et al. A founder mutation of the MSH2 gene and hereditary nonpolyposis colorectal cancer in the United States. JAMA 291, 718–724 (2004).

  110. 110

    Gruber, S. B. et al. BLM heterozygosity and the risk of colorectal cancer. Science 297, 2013 (2002).

  111. 111

    Shaheen, N. J. et al. Association between hemochromatosis (HFE) gene mutation carrier status and the risk of colon cancer. J. Natl. Cancer Inst. 95, 154–159 (2003).

  112. 112

    Porter, T. R. et al. Contribution of cyclin d1 (CCND1) and E-cadherin (CDH1) polymorphisms to familial and sporadic colorectal cancer. Oncogene 21, 1928–1933 (2002).

  113. 113

    Cleary, S. P. et al. Heterozygosity for the BLMASH mutation and cancer risk. Cancer Res. 63, 1769–1771 (2003).

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The author wishes to thank R. Davuluri, C. Eng, J. Green, J. Groden, P. Peltomäki and B. Vogelstein for advice. The author's work is funded by grants from the United States National Institutes of Health and from the State of Ohio Biomedical Research and Technology Transfer Commission. The content reflects the views of the Grantee and does not necessarily reflect the views of the State of Ohio Biomedical Research and Technology Transfer Commission.

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At this stage, cancer has spread beyond the innermost lining of the colon to the second and third cell layers and involves the inside wall of the colon. The cancer has not spread to the outer wall of the colon or outside the colon.


At this stage, cancer has spread outside the colon to other parts of the body, such as the liver or the lungs. The tumour can be any size and might or might not include affected lymph nodes.


The family member who was initially ascertained (that is, who came to the attention of the researcher) in a study of familial aggregation of cancer (or other disease).


The frequency with which individuals who carry a given mutation show the phenotype associated with that mutation. If the penetrance of a disease allele is 100%, then all individuals carrying that allele will express the associated phenotype.


A benign overgrowth of tissue that is composed of cells that are normally present at that site. In the gastrointestinal tract, hamartomas typically have a marked expansion of the muscular and fibrous tissue layer.


A gene that alters the phenotype of another gene, or that of a mutation in another gene.


A mutation that does not completely inactivate the product of a gene.


DNA repair in response to incorrect pairing of bases.


Regions of DNA with a high density of cytosine– phosphoguanine nucleotides, which are usually located in the promoter region or the first exons of a gene. CpG islands are involved in the regulation of transcription, because their methylation can lead to permanent silencing of the associated gene.


Genetic or epigenetic abnormality that leads to an increased rate of mutation. Often caused by defects in the DNA mismatch-repair pathway.


Characterized by expansion or contraction of short repeated DNA sequences (that is, microsatellite repeats) caused by insertion or deletion of repeated units. This instability, also known as a 'mutator phenotype' or 'replication error', indicates probable defects in mismatch-repair genes.


The type of involvement or extent to which a particular organ or structure is affected by a specific genotype.


An experimentally determined profile of genetic markers that are present on a single chromosome of any given individual.


A Jewish population originating from eastern or central Europe. Because of isolation from other communities until the past few generations, this population has a less diverse gene pool than most other groups and represents a typical founder population.


A situation in which a loss-of-function phenotype is produced by mutation of one allele of a gene in a diploid cell, even though the other allele is wild-type.


Carrying two different mutations in each allele of a gene.


A pair of twins in which the same trait is observed in each twin.


A pair of twins in which the same trait is not observed in each twin.


Indicates how much greater or smaller the lifetime risk of disease is in a carrier of the allele than in a non-carrier. A typical value is a twofold greater risk.


The proportion of all cases of a disease in population that is caused by a specific allele.

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Figure 1: A global view of the genetic contribution to colorectal cancer.
Figure 2: Distribution of mismatch-repair mutations in Lynch syndrome.