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  • Review Article
  • Published:

Clinical management of hereditary colorectal cancer syndromes

Key Points

  • Timely identification of hereditary colorectal cancer syndromes might prevent early death due to cancer

  • Systematic analysis of all newly diagnosed colorectal cancer for molecular features of Lynch syndrome will improve the identification of the syndrome

  • Comprehensive analysis of the genes known to be associated with polyposis syndromes facilitates making an appropriate diagnosis

  • Classification of hereditary colorectal cancer syndromes according to the underlying gene defect enables targeted surveillance and treatment

  • Inclusion of the underlying gene defect in disease terminology and diagnosis ensures appropriate management

Abstract

Hereditary factors are involved in the development of a substantial proportion of all cases of colorectal cancer. Inherited forms of colorectal cancer are usually subdivided into polyposis syndromes characterized by the development of multiple colorectal polyps and nonpolyposis syndromes characterized by the development of few or no polyps. Timely identification of hereditary colorectal cancer syndromes is vital because patient participation in early detection programmes prevents premature death due to cancer. Polyposis syndromes are fairly easy to recognize, but some patients might have characteristics that overlap with other clinically defined syndromes. Comprehensive analysis of the genes known to be associated with polyposis syndromes helps to establish the final diagnosis in these patients. Recognizing Lynch syndrome is more difficult than other polyposis syndromes owing to the absence of pathognomonic features. Most investigators therefore recommend performing systematic molecular analysis of all newly diagnosed colorectal cancer using immunohistochemical methods. The implementation in clinical practice of new high-throughput methods for molecular analysis might further increase the identification of individuals at risk of hereditary colorectal cancer. This Review describes the clinical management of the various hereditary colorectal cancer syndromes and demonstrates the advantage of using a classification based on the underlying gene defects.

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Figure 1: APC polyposis syndrome.
Figure 2: Peutz–Jeghers polyp with arborizing smooth muscle separating the glands into lobes.
Figure 3: Juvenile polyp in a patient with a mutation in BMPRA1.
Figure 4: Adenomatous polyp in a patient with MSH2-Lynch syndrome.

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References

  1. Lynch, H. T. & de la Chapelle, A. Hereditary colorectal cancer. N. Engl. J. Med. 348, 919–932 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Vasen, H. F. et al. Guidelines for the clinical management of familial adenomatous polyposis (FAP). Gut 57, 704–713 (2008).

    Article  CAS  PubMed  Google Scholar 

  3. Nieuwenhuis, M. H. et al. Genotype predicting phenotype in familial adenomatous polyposis: a practical application to the choice of surgery. Dis. Colon Rectum 52, 1259–1263 (2009).

    Article  PubMed  Google Scholar 

  4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal. version 2.2014 [online], (2014).

  5. Giardiello, F. M. et al. Primary chemoprevention of familial adenomatous polyposis with sulindac. N. Engl. J. Med. 346, 1054–1059 (2002).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Phillips, R. K. et al. A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis. Gut 50, 857–860 (2002).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Barrow, P., Khan, M., Lalloo, F., Evans, D. G. & Hill, J. Systematic review of the impact of registration and screening on colorectal cancer incidence and mortality in familial adenomatous polyposis and Lynch syndrome. Br. J. Surg. 100, 1719–1731 (2013).

    Article  CAS  PubMed  Google Scholar 

  8. Belchetz, L. A., Berk, T., Bapat, B. V., Cohen, Z. & Gallinger, S. Changing causes of mortality in patients with familial adenomatous polyposis. Dis. Colon Rectum 39, 384–387 (1996).

    Article  CAS  PubMed  Google Scholar 

  9. Nieuwenhuis, M. H. et al. Evaluation of management of desmoid tumours associated with familial adenomatous polyposis in Dutch patients. Br. J. Cancer 104, 37–42 (2011).

    Article  CAS  PubMed  Google Scholar 

  10. Fallen, T., Wilson, M., Morlan, B. & Lindor, N. M. Desmoid tumors—a characterization of patients seen at Mayo Clinic 1976–1999. Fam. Cancer 5, 191–194 (2006).

    Article  PubMed  Google Scholar 

  11. Hansmann, A., Adolph, C., Vogel, T., Unger, A. & Moeslein, G. High-dose tamoxifen and sulindac as first-line treatment for desmoid tumors. Cancer 100, 612–620 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Nielsen, M., Morreau, H., Vasen, H. F. & Hes, F. J. MUTYH-associated polyposis (MAP). Crit. Rev. Oncol. Hematol. 79, 1–16 (2011).

    Article  PubMed  Google Scholar 

  13. Sampson, J. R. & Jones, N. MUTYH-associated polyposis. Best Pract. Res. Clin. Gastroenterol. 23, 209–218 (2009).

    Article  CAS  PubMed  Google Scholar 

  14. Boparai, K. S. et al. Hyperplastic polyps and sessile serrated adenomas as a phenotypic expression of MYH-associated polyposis. Gastroenterology 135, 2014–2018 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Vogt, S. et al. Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. Gastroenterology 137, 1976–1985 (2009).

    Article  CAS  PubMed  Google Scholar 

  16. Theodoratou, E. et al. A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants. Br. J. Cancer 103, 1875–1884 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Palles, C. et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat. Genet. 45, 136–144 (2013).

    Article  CAS  PubMed  Google Scholar 

  18. Valle, L. et al. New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis. Hum. Mol. Genet. 23, 3506–3512 (2014).

    Article  CAS  PubMed  Google Scholar 

  19. Elsayed, F. A. et al. Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer. Eur. J. Hum. Genet. http://dx.doi.org/10.1038/ejhg.2014.242.

  20. Wimmer, K. & Etzler, J. Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg? Hum. Genet. 124, 105–122 (2008).

    Article  PubMed  Google Scholar 

  21. Wimmer, K. et al. Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium 'care for CMMRD' (C4CMMRD). J. Med. Genet. 51, 355–365 (2014).

    Article  CAS  PubMed  Google Scholar 

  22. Vasen, H. F. et al. Guidelines for surveillance of individuals with constitutional mismatch repair-deficiency proposed by the European Consortium “Care for CMMR-D” (C4CMMR-D). J. Med. Genet. 51, 283–293 (2014).

    Article  CAS  PubMed  Google Scholar 

  23. Hes, F. J. et al. Colorectal cancer risk variants on 11q23 and 15q13 are associated with unexplained adenomatous polyposis. J. Med. Genet. 51, 55–60 (2014).

    Article  CAS  PubMed  Google Scholar 

  24. Beggs, A. D. et al. Peutz–Jeghers syndrome: a systematic review and recommendations for management. Gut 59, 975–986 (2010).

    Article  CAS  PubMed  Google Scholar 

  25. van Lier, M. G., Mathus-Vliegen, E. M., Wagner, A., van Leerdam, M. E. & Kuipers, E. J. High cumulative risk of intussusception in patients with Peutz-Jeghers syndrome: time to update surveillance guidelines? Am. J. Gastroenterol. 106, 940–945 (2011).

    Article  CAS  PubMed  Google Scholar 

  26. van Lier, M. G. et al. High cancer risk in Peutz–Jeghers syndrome: a systematic review and surveillance recommendations. Am. J. Gastroenterol. 105, 1258–1264 (2010).

    CAS  PubMed  Google Scholar 

  27. Kara, C., Kutlu, A. O., Tosun, M. S., Apaydin, S. & Senel, F. Sertoli cell tumor causing prepubertal gynecomastia in a boy with Peutz–Jeghers syndrome: the outcome of 1-year treatment with the aromatase inhibitor testolactone. Horm. Res. 63, 252–256 (2005).

    CAS  PubMed  Google Scholar 

  28. Gammon, A., Jasperson, K., Kohlmann, W. & Burt, R. W. Hamartomatous polyposis syndromes. Best Pract. Res. Clin. Gastroenterol. 23, 219–231 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Brosens, L. A. et al. Gastrointestinal polyposis syndromes. Curr. Mol. Med. 7, 29–46 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Howe, J. R. et al. The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations. J. Med. Genet. 41, 484–491 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Brosens, L. A. et al. Risk of colorectal cancer in juvenile polyposis. Gut 56, 965–967 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Friedl, W. et al. Juvenile polyposis: massive gastric polyposis is more common in MADH4 mutation carriers than in BMPR1A mutation carriers. Hum. Genet. 111, 108–111 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Schwenter, F. et al. Juvenile polyposis, hereditary hemorrhagic telangiectasia, and early onset colorectal cancer in patients with SMAD4 mutation. J. Gastroenterol. 47, 795–804 (2012).

    Article  CAS  PubMed  Google Scholar 

  34. Howe, J. R., Ringold, J. C., Hughes, J. H. & Summers, R. W. Direct genetic testing for Smad4 mutations in patients at risk for juvenile polyposis. Surgery 126, 162–170 (1999).

    Article  CAS  PubMed  Google Scholar 

  35. Nieuwenhuis, M. H. et al. Cancer risk and genotype-phenotype correlations in PTEN hamartoma tumor syndrome. Fam. Cancer 13, 57–63 (2014).

    Article  CAS  PubMed  Google Scholar 

  36. Tan, M. H. et al. Lifetime cancer risks in individuals with germline PTEN mutations. Clin. Cancer Res. 18, 400–407 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Bubien, V. et al. High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome. J. Med. Genet. 50, 255–263 (2013).

    Article  CAS  PubMed  Google Scholar 

  38. Nieuwenhuis, M. H. et al. Is colorectal surveillance indicated in patients with PTEN mutations? Colorectal Dis. 14, 562–566 (2012).

    Article  Google Scholar 

  39. Squarize, C. H., Castilho, R. M. & Gutkind, J. S. Chemoprevention and treatment of experimental Cowden's disease by mTOR inhibition with rapamycin. Cancer Res. 68, 7066–7072 (2008).

    Article  CAS  PubMed  Google Scholar 

  40. Jaeger, E. et al. Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1. Nat. Genet. 44, 699–703 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Cao, X. et al. Mapping of hereditary mixed polyposis syndrome (HMPS) to chromosome 10q23 by genomewide high-density single nucleotide polymorphism (SNP) scan and identification of BMPR1A loss of function. J. Med. Genet. 43, e13 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Rosty, C. et al. Phenotype and polyp landscape in serrated polyposis syndrome: a series of 100 patients from genetics clinics. Am. J. Surg. Pathol. 36, 876–882 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Snover, D. C., Ahnen, D. J., Burt, R. W. & Odze, R. D. in WHO Classification of Tumours of the Digestive System Ch. 8 (ed Bosman F. T. et al.) 160–165 (IARC, 2010).

    Google Scholar 

  44. Jasperson, K. W. et al. Serrated polyposis: colonic phenotype, extracolonic features, and familial risk in a large cohort. Dis. Colon Rectum 56, 1211–1216 (2013).

    Article  PubMed  Google Scholar 

  45. Boparai, K. S. et al. Increased colorectal cancer risk in first-degree relatives of patients with hyperplastic polyposis syndrome. Gut 59, 1222–1225 (2010).

    Article  CAS  PubMed  Google Scholar 

  46. Win, A. K. et al. Cancer risks for relatives of patients with serrated polyposis. Am. J. Gastroenterol. 107, 770–778 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Hazewinkel, Y. et al. Incidence of colonic neoplasia in patients with serrated polyposis syndrome who undergo annual endoscopic surveillance. Gastroenterology 147, 88–95 (2014).

    Article  PubMed  Google Scholar 

  48. Lynch, H. T. et al. Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin. Genet. 76, 1–18 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Martin-Lopez, J. V. & Fishel, R. The mechanism of mismatch repair and the functional analysis of mismatch repair defects in Lynch syndrome. Fam. Cancer 12, 159–168 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Vasen, H. F., Nagengast, F. M. & Khan, P. M. Interval cancers in hereditary non-polyposis colorectal cancer (Lynch syndrome). Lancet 345, 1183–1184 (1995).

    Article  CAS  PubMed  Google Scholar 

  51. Vasen, H. F. et al. Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts. Gut 62, 812–823 (2013).

    Article  PubMed  CAS  Google Scholar 

  52. Vasen, H. F. & de Vos tot Nederveen Cappel, W. H. Cancer: Lynch syndrome—how should colorectal cancer be managed? Nat. Rev. Gastroenterol. Hepatol. 8, 184–186 (2011).

    Article  PubMed  Google Scholar 

  53. Burn, J. et al. Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome. N. Engl. J. Med. 359, 2567–2578 (2008).

    Article  CAS  PubMed  Google Scholar 

  54. Burn, J. et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet 378, 2081–2087 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Barrow, E., Hill, J. & Evans, D. G. Cancer risk in Lynch Syndrome. Fam. Cancer 12, 229–240 (2013).

    Article  CAS  PubMed  Google Scholar 

  56. ten Broeke, S. W. et al. Lynch syndrome caused by germline PMS2 mutations; delineating the cancer risk. J. Clin. Oncol. http://dx.doi.org/10.1200/JCO.2014.57.8088.

  57. Senter, L. et al. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology 135, 419–428 (2008).

    Article  PubMed  CAS  Google Scholar 

  58. Baglietto, L. et al. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J. Natl Cancer. Inst. 102, 193–201 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Engel, C. et al. Risks of less common cancers in proven mutation carriers with lynch syndrome. J. Clin. Oncol. 30, 4409–4415 (2012).

    Article  PubMed  Google Scholar 

  60. Vasen, H. F. et al. Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J. Med. Genet. 44, 353–362 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Barrow, E. et al. Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations. Clin. Genet. 75, 141–149 (2009).

    Article  CAS  PubMed  Google Scholar 

  62. Grindedal, E. M. et al. Germ-line mutations in mismatch repair genes associated with prostate cancer. Cancer Epidemiol. Biomarkers Prev. 18, 2460–2467 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. Ligtenberg, M. J. 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. 41, 112–117 (2009).

    Article  CAS  PubMed  Google Scholar 

  64. Kovacs, M. E., Papp, J., Szentirmay, Z., Otto, S. & Olah, E. Deletions removing the last exon of TACSTD1 constitute a distinct class of mutations predisposing to Lynch syndrome. Hum. Mutat. 30, 197–203 (2009).

    Article  CAS  PubMed  Google Scholar 

  65. Ligtenberg, M. J., Kuiper, R. P., Geurts van, K. A. & Hoogerbrugge, N. EPCAM deletion carriers constitute a unique subgroup of Lynch syndrome patients. Fam. Cancer 12, 169–174 (2013).

    Article  CAS  PubMed  Google Scholar 

  66. Kempers, M. J. et al. Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study. Lancet Oncol. 12, 49–55 (2011).

    Article  PubMed  Google Scholar 

  67. Ramsoekh, D. et al. A high incidence of MSH6 mutations in Amsterdam criteria II-negative families tested in a diagnostic setting. Gut 57, 1539–1544 (2008).

    Article  CAS  PubMed  Google Scholar 

  68. Hendriks, Y. M. et al. Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counseling and surveillance. Gastroenterology 127, 17–25 (2004).

    Article  CAS  PubMed  Google Scholar 

  69. Mensenkamp, A. R. et al. Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in Lynch syndrome-like tumors. Gastroenterology 146, 643–646 (2014).

    Article  CAS  PubMed  Google Scholar 

  70. Lindor, N. M. et al. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA 293, 1979–1985 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Mesher, D. et al. A pooled analysis of the outcome of prospective colonoscopic surveillance for familial colorectal cancer. Int. J. Cancer 134, 939–947 (2014).

    Article  CAS  PubMed  Google Scholar 

  72. Dove-Edwin, I. et al. Prospective results of surveillance colonoscopy in dominant familial colorectal cancer with and without Lynch syndrome. Gastroenterology 130, 1995–2000 (2006).

    Article  PubMed  Google Scholar 

  73. Hampel, H. et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N. Engl. J. Med. 352, 1851–1860 (2005).

    Article  CAS  PubMed  Google Scholar 

  74. Vasen, H. F., Mecklin, J. P., Khan, P. M. & Lynch, H. T. The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis. Colon Rectum 34, 424–425 (1991).

    Article  CAS  PubMed  Google Scholar 

  75. Vasen, H. F., Watson, P., Mecklin, J. P. & Lynch, H. T. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 116, 1453–1456 (1999).

    Article  CAS  PubMed  Google Scholar 

  76. Park, J. G. et al. Suspected hereditary nonpolyposis colorectal cancer: International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC) criteria and results of genetic diagnosis. Dis. Colon Rectum 42, 710–715 (1999).

    Article  CAS  PubMed  Google Scholar 

  77. Rodriguez-Bigas, M. A. et al. A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: meeting highlights and Bethesda guidelines. J. Natl Cancer Inst. 89, 1758–1762 (1997).

    Article  CAS  PubMed  Google Scholar 

  78. 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).

    CAS  PubMed  Google Scholar 

  79. Pinol, V. et al. Accuracy of revised Bethesda guidelines, microsatellite instability, and immunohistochemistry for the identification of patients with hereditary nonpolyposis colorectal cancer. JAMA 293, 1986–1994 (2005).

    Article  CAS  PubMed  Google Scholar 

  80. Kastrinos, F., Balmana, J. & Syngal, S. Prediction models in Lynch syndrome. Fam. Cancer 12, 217–228 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Balaguer, F. et al. Validation and extension of the PREMM1,2 model in a population-based cohort of colorectal cancer patients. Gastroenterology 134, 39–46 (2008).

    Article  PubMed  Google Scholar 

  82. van Dijk, D. A., Oostindier, M. J., Kloosterman-Boele, W. M., Krijnen, P. & Vasen, H. F. Family history is neglected in the work-up of patients with colorectal cancer: a quality assessment using cancer registry data. Fam. Cancer 6, 131–134 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Vasen, H. F. et al. Recommendations to improve identification of hereditary and familial colorectal cancer in Europe. Fam. Cancer 9, 109–115 (2010).

    Article  CAS  PubMed  Google Scholar 

  84. Hampel, H. & de la Chapelle, A. How do we approach the goal of identifying everybody with Lynch syndrome? Fam. Cancer 12, 313–317 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

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H.F.A.V. researched data and wrote the manuscript. I.T. and A.C. substantially contributed to discussion of content, and reviewed and edited the manuscript before submission.

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Correspondence to Hans F. A. Vasen.

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Vasen, H., Tomlinson, I. & Castells, A. Clinical management of hereditary colorectal cancer syndromes. Nat Rev Gastroenterol Hepatol 12, 88–97 (2015). https://doi.org/10.1038/nrgastro.2014.229

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