Risk of multiple colorectal cancer development depends on age and subgroup in individuals with hereditary predisposition

  • Lars J. LindbergEmail author
  • Wia Wegen-Haitsma
  • Steen Ladelund
  • Lars Smith-Hansen
  • Christina Therkildsen
  • Inge Bernstein
  • Mef Nilbert
Original Article


Development of multiple colorectal cancers (CRCs), synchronously or metachronously, is associated with hereditary predisposition for cancer and accurate risk estimates of multiple tumour development are relevant to recommend rational surveillance programs. A cross-sectional study design was used to estimate the risks of synchronous CRC (SCRC) and metachronous CRC (MCRC) based on data from the National Danish Hereditary Nonpolyposis Register. In total, 7100 individuals from families within the subgroups Lynch syndrome, familial CRC (FCC) and moderate risk were used with estimates relative to a non-hereditary population control cohort. SCRC was diagnosed in 7.4% of the Lynch syndrome cases, in 4.2% of FCC cases and 2.5% of the moderate risk cases, which translated to relative risks of 1.9–5.6. The risk of MCRC was distinctively linked to Lynch syndrome with a life-time risk up to 70% and an incidence rate ratio of 5.0. The risk of SCRC was significantly increased in all subgroups of FCC and hereditary CRC, whereas the risk of MCRC was specifically linked to Lynch syndrome. These observations suggest that individuals with FCC or hereditary CRC should be carefully screened for second primary CRC at the time of diagnosis, whereas intensified surveillance for second primary CRC is motivated in Lynch syndrome with lower-intensity programs in families with yet unidentified genetic causes.


HNPCC Lynch syndrome Colonoscopy Cross-sectional study Metachronous neoplasms Synchronous neoplasms Multiple primary neoplasms 



Financial support was granted from the Danish Cancer Society (Grant No. R90-A6150) and from the Swedish Cancer Society (Grant No. 2014/442). We would also like to thank all clinicians who have contributed with data to the Danish HNPCC Register.

Supplementary material

10689_2018_109_MOESM1_ESM.pdf (317 kb)
Supplementary material 1 (PDF 317 KB)


  1. 1.
    Lichtenstein P, Holm NV, Verkasalo PK et al (2000) Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 343:78–85. CrossRefGoogle Scholar
  2. 2.
    Valle L (2017) Recent discoveries in the genetics of familial colorectal cancer and polyposis. Clin Gastroenterol Hepatol 15:809–819. CrossRefPubMedGoogle Scholar
  3. 3.
    Kanth P, Grimmett J, Champine M et al (2017) Hereditary colorectal polyposis and cancer syndromes: a primer on diagnosis and management. Am J Gastroenterol 112:1509–1525. CrossRefPubMedGoogle Scholar
  4. 4.
    Win AK, Jenkins MA, Dowty JG et al (2017) Prevalence and penetrance of major genes and polygenes for colorectal cancer. Cancer Epidemiol Biomark Prev 26:404–412. CrossRefGoogle Scholar
  5. 5.
    Pajares JA, Perea J (2015) Multiple primary colorectal cancer: individual or familial predisposition? World J Gastrointest Oncol 7:434–444. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Samadder NJ, Curtin K, Wong J et al (2014) Epidemiology and familial risk of synchronous and metachronous colorectal cancer: a population-based study in Utah. Clin Gastroenterol Hepatol 12:2078–2084.e2. CrossRefPubMedGoogle Scholar
  7. 7.
    Lautrup CK, Mikkelsen EM, Lash TL et al (2015) Familial colorectal cancer risk may be lower than previously thought: a Danish cohort study. Cancer Epidemiol 39:714–719. CrossRefPubMedGoogle Scholar
  8. 8.
    Mesher D, Dove-Edwin I, Sasieni P et al (2014) A pooled analysis of the outcome of prospective colonoscopic surveillance for familial colorectal cancer. Int J Cancer 134:939–947. CrossRefPubMedGoogle Scholar
  9. 9.
    Lam AK-Y, Carmichael R, Gertraud Buettner P et al (2011) Clinicopathological significance of synchronous carcinoma in colorectal cancer. Am J Surg 202:39–44. CrossRefPubMedGoogle Scholar
  10. 10.
    Jayasekara H, Reece JC, Buchanan DD et al (2016) Risk factors for metachronous colorectal cancer following a primary colorectal cancer: a prospective cohort study. Int J Cancer 139:1081–1090. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Latournerie M, Jooste V, Cottet V et al (2008) Epidemiology and prognosis of synchronous colorectal cancers. Br J Surg 95:1528–1533. CrossRefPubMedGoogle Scholar
  12. 12.
    Hu H, Chang DT, Nikiforova MN et al (2013) Clinicopathologic features of synchronous colorectal carcinoma: a distinct subset arising from multiple sessile serrated adenomas and associated with high levels of microsatellite instability and favorable prognosis. Am J Surg Pathol 37:1660–1670. CrossRefPubMedGoogle Scholar
  13. 13.
    Bos ACRK, Matthijsen RA, Erning FN van et al (2018) Treatment and outcome of synchronous colorectal carcinomas: a nationwide study. Ann Surg Oncol 25:414–421. CrossRefPubMedGoogle Scholar
  14. 14.
    Greenstein AJ, Slater G, Heimann TM et al (1986) A comparison of multiple synchronous colorectal cancer in ulcerative colitis, familial polyposis coli, and de novo cancer. Ann Surg 203:123–128CrossRefGoogle Scholar
  15. 15.
    Fante R, Roncucci L, Di Gregorio C et al (1996) Frequency and clinical features of multiple tumors of the large bowel in the general population and in patients with hereditary colorectal carcinoma. Cancer 77:2013–2021.;2-R CrossRefPubMedGoogle Scholar
  16. 16.
    Mulder SA, Kranse R, Damhuis RA et al (2012) The incidence and risk factors of metachronous colorectal cancer: an indication for follow-up. Dis Colon Rectum 55:522–531. CrossRefPubMedGoogle Scholar
  17. 17.
    Win AK, Parry S, Parry B et al (2013) Risk of metachronous colon cancer following surgery for rectal cancer in mismatch repair gene mutation carriers. Ann Surg Oncol 20:1829–1836. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Anele CC, Adegbola SO, Askari A et al (2017) Risk of metachronous colorectal cancer following colectomy in Lynch syndrome: a systematic review and meta-analysis. Colorectal Dis 19:528–536. CrossRefPubMedGoogle Scholar
  19. 19.
    Møller P, Seppälä T, Bernstein I et al (2017) Incidence of and survival after subsequent cancers in carriers of pathogenic MMR variants with previous cancer: a report from the prospective Lynch syndrome database. Gut 66:1657–1664. CrossRefPubMedGoogle Scholar
  20. 20.
    Renkonen-sinisalo L, Seppälä TT, Järvinen HJ, Mecklin J (2017) Subtotal colectomy for colon cancer reduces the need for subsequent surgery in Lynch syndrome. Dis Colon Rectum 60:792–799. CrossRefPubMedGoogle Scholar
  21. 21.
    Malik SS, Lythgoe MP, McPhail M, Monahan KJ (2017) Metachronous colorectal cancer following segmental or extended colectomy in Lynch syndrome: a systematic review and meta-analysis. Fam Cancer. CrossRefPubMedCentralGoogle Scholar
  22. 22.
    Vasen HFA, Watson P, Mecklin J, Lynch HT (1999) New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC. Gastroenterology 116:1453–1456. CrossRefPubMedGoogle Scholar
  23. 23.
    Lindberg LJ, Ladelund S, Frederiksen BL et al (2017) Outcome of 24 years national surveillance in different hereditary colorectal cancer subgroups leading to more individualised surveillance. J Med Genet 54:297–304. CrossRefPubMedGoogle Scholar
  24. 24.
    R Core Team (2017) R: a language and environment for statistical computing. R Foundation for Statistical Computing, ViennaGoogle Scholar
  25. 25.
    Wilschut JA, Steyerberg EW, van Leerdam ME et al (2011) How much colonoscopy screening should be recommended to individuals with various degrees of family history of colorectal cancer? Cancer 117:4166–4174. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Shiovitz S, Copeland WK, Passarelli MN et al (2014) Characterisation of familial colorectal cancer type X, Lynch syndrome, and non-familial colorectal cancer. Br J Cancer 111:598–602. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Silva FC da, Oliveira Ferreira JR, de, Torrezan GT et al (2015) Clinical and molecular characterization of Brazilian patients suspected to have Lynch syndrome. PLoS ONE 10:e0139753. CrossRefGoogle Scholar
  28. 28.
    Parry S, Win AK, Parry B et al (2011) Metachronous colorectal cancer risk for mismatch repair gene mutation carriers—the advantage of more extensive colon surgery. Gut. CrossRefPubMedGoogle Scholar
  29. 29.
    Box JC, Rodriguez-Bigas MA, Weber TK, Petrelli NJ (1999) Clinical implications of multiple colorectal carcinomas in hereditary nonpolyposis colorectal carcinoma. Dis Colon Rectum 42:717–721CrossRefGoogle Scholar
  30. 30.
    Kalady MF, Lipman J, McGannon E, Church JM (2012) Risk of colonic neoplasia after proctectomy for rectal cancer in hereditary nonpolyposis colorectal cancer. Ann Surg 255:1121–1125. CrossRefPubMedGoogle Scholar
  31. 31.
    Stupart DA, Goldberg PA, Baigrie RJ et al (2011) Surgery for colonic cancer in HNPCC: total vs segmental colectomy. Colorectal Dis 13:1395–1399. CrossRefPubMedGoogle Scholar
  32. 32.
    Vasen HFA, Abdirahman M, Brohet R et al (2010) One to 2-year surveillance intervals reduce risk of colorectal cancer in families with Lynch syndrome. Gastroenterology 138:2300–2306. CrossRefPubMedGoogle Scholar
  33. 33.
    Mulder SA, Kranse R, Damhuis RA et al (2011) Prevalence and prognosis of synchronous colorectal cancer: a Dutch population-based study. Cancer Epidemiol 35:442–447. CrossRefPubMedGoogle Scholar
  34. 34.
    Zauber P, Huang J, Sabbath-Solitare M, Marotta S (2013) Similarities of molecular genetic changes in synchronous and metachronous colorectal cancers are limited and related to the cancers’ proximities to each other. J Mol Diagn 15:652–660. CrossRefPubMedGoogle Scholar
  35. 35.
    Arriba M, Sánchez R, Rueda D et al (2017) Toward a molecular classification of synchronous colorectal cancer: clinical and molecular characterization. Clin Colorectal Cancer 16:31–37. CrossRefPubMedGoogle Scholar
  36. 36.
    Dykes SL, Qui H, Rothenberger DA, García-Aguilar J (2003) Evidence of a preferred molecular pathway in patients with synchronous colorectal cancer. Cancer 98:48–54. CrossRefPubMedGoogle Scholar
  37. 37.
    Lindor NM, Rabe K, Petersen GM et al (2005) Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency. JAMA 293:1979–1985. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  • Lars J. Lindberg
    • 1
    Email author
  • Wia Wegen-Haitsma
    • 1
  • Steen Ladelund
    • 1
  • Lars Smith-Hansen
    • 1
  • Christina Therkildsen
    • 1
  • Inge Bernstein
    • 2
  • Mef Nilbert
    • 1
    • 3
    • 4
  1. 1.The Danish HNPCC Register, Clinical Research CentreCopenhagen University Hospital, HvidovreHvidovreDenmark
  2. 2.Department of Surgical GastroenterologyAalborg University HospitalÅlborgDenmark
  3. 3.Institute of Clinical Sciences, Division of Oncology and PathologyLund UniversityLundSweden
  4. 4.The Danish Cancer Society Research CenterCopenhagenDenmark

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