Familial Cancer

, Volume 6, Issue 1, pp 53–62 | Cite as

Very high incidence of familial colorectal cancer in Newfoundland: a comparison with Ontario and 13 other population-based studies

  • R. C. GreenEmail author
  • J. S. Green
  • S. K. Buehler
  • J. D. Robb
  • D. Daftary
  • S. Gallinger
  • J. R. McLaughlin
  • P. S. Parfrey
  • H. B. Younghusband
Original Paper


Newfoundland has the highest rate of colorectal cancer (CRC) of any Canadian province. In order to investigate the factors, especially genetic components, responsible for CRC we established the Newfoundland Colorectal Cancer Registry. In a 5-year period we examined every case of CRC diagnosed under the age of 75 years and obtained consent from 730 cases. Careful analysis of family history was used to assign a familial cancer risk, based on established criteria. We observed that 3.7% of CRC cases came from families meeting the Amsterdam II criteria and a further 0.9% of cases involved familial adenomatous polyposis (FAP). An additional 43% of cases met one or more of the revised Bethesda criteria and 31% of all cases had a first-degree relative affected with CRC. We compared the Newfoundland data with data from the province of Ontario, where the same recruitment and risk-assessment criteria were used. In all categories, the indicators of familial risk were significantly higher in Newfoundland. These data were also compared to results published from 13 other population-based studies worldwide. In every category the proportion of Newfoundland cases meeting the criteria was higher than in any other population. The mean differences were: 3.5-fold greater for FAP, 2.8-fold higher for Amsterdam criteria, 2.0-fold higher for Bethesda criteria and 1.9-fold higher for the number of affected first-degree relatives. We conclude that the high incidence of CRC in Newfoundland may be attributable to genetic, or at least familial, factors. In the high-risk families we provide evidence for the involvement of founder mutations in the APC and MSH2 genes.


Colorectal cancer Family history Founder effect HNPCC Incidence Lynch syndrome Meta-analysis MYH Newfoundland Ontario 



This work was supported by an Interdisciplinary Health Research Team award from the Canadian Institutes of Health Research (CRT-43821) and by the National Cancer Institute, National Institutes of Health, USA, under RFA No.CA-95-011 (Grant no. U01-CA74783). We extend our thanks and appreciation to the many patients and their relatives who gave of their time to make this research possible. We gratefully acknowledge the work done by Angie Batstone, Elizabeth Dicks, Katrina Hurley, Montgomery Keough, Carol Negrijn, and Jackie Stokes (Newfoundland) and Rose Sarvaria, Neerav Monga, Kristyn Langeraap, Wing Chan, Seanny Yu and Teresa Bianco (Ontario) in contacting study participants and collecting data.


  1. 1.
    National Cancer Institute of Canada (2003) Canadian cancer statistics 2003. Toronto, CanadaGoogle Scholar
  2. 2.
    Lynch HT, De La CA (2003) Hereditary colorectal cancer. N Engl J Med 348:919–932PubMedCrossRefGoogle Scholar
  3. 3.
    Spirio L, Olschwang S, Groden J, Robertson M, Samowitz W, Joslyn G et al (1993) Alleles of the APC gene: an attenuated form of familial polyposis. Cell 75:951–957PubMedCrossRefGoogle Scholar
  4. 4.
    Lamlum H, Al Tassan N, Jaeger E, Frayling I, Sieber O, Reza FB et al (2000) Germline APC variants in patients with multiple colorectal adenomas, with evidence for the particular importance of E1317Q. Hum Mol Genet 9:2215–2221PubMedGoogle Scholar
  5. 5.
    Peltomaki P (2003) Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol 21:1174–1179PubMedCrossRefGoogle Scholar
  6. 6.
    Narayan S, Roy D (2003) Role of APC and DNA mismatch repair genes in the development of colorectal cancers. Mol Cancer 2:41–55PubMedCrossRefGoogle Scholar
  7. 7.
    Aaltonen LA, Peltomäki P, Mecklin J-P, Järvinen H, Jass JR, Green JS et al (1994) Replication errors in benign and malignant tumors from hereditary nonpolyposis colorectal cancer patients. Cancer Res 54:1645–1648PubMedGoogle Scholar
  8. 8.
    Vasen HF, Mecklin JP, Khan PM, Lynch HT (1991) The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum 34:424–425PubMedCrossRefGoogle Scholar
  9. 9.
    Vasen HF, Watson P, Mecklin JP, Lynch HT (1999) New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 116:1453–1456PubMedCrossRefGoogle Scholar
  10. 10.
    Rodriguez-Bigas MA, Boland CR, Hamilton SR, Henson DE, Jass JR, Khan PM et al (1997) A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst 89:1758–1762PubMedCrossRefGoogle Scholar
  11. 11.
    Umar A, Boland CR, Terdiman JP, Syngal S, De La CA, Ruschoff J et al (2004) Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96:261–268PubMedCrossRefGoogle Scholar
  12. 12.
    Slattery ML, Levin TR, Ma K, Goldgar D, Holubkov R, Edwards S (2003) Family history and colorectal cancer: predictors of risk. Cancer Causes Control 14:879–887PubMedCrossRefGoogle Scholar
  13. 13.
    Murff HJ, Spigel DR, Syngal S (2004) Does this patient have a family history of cancer? An evidence-based analysis of the accuracy of family cancer history. JAMA 292:1480–1489PubMedCrossRefGoogle Scholar
  14. 14.
    Ainsworth PJ, Koscinski D, Fraser BP, Stuart JA (2004) Family cancer histories predictive of a high risk of hereditary non-polyposis colorectal cancer associate significantly with a genomic rearrangement in hMSH2 or hMLH1. Clin Genet 66:183–188PubMedCrossRefGoogle Scholar
  15. 15.
    Evans DG, Eccles DM, Rahman N, Young K, Bulman M, Amir E et al (2004) A new scoring system for the chances of identifying a BRCA1/2 mutation outperforms existing models including BRCAPRO. J Med Genet 41:474–480PubMedCrossRefGoogle Scholar
  16. 16.
    Lindor NM, Rabe K, Petersen GM, Haile R, Casey G, Baron J et al (2005) Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA 293:1979–1985PubMedCrossRefGoogle Scholar
  17. 17.
    Boland CR (2005) Evolution of the nomenclature for the hereditary colorectal cancer syndromes. Fam Cancer 4:211–218PubMedCrossRefGoogle Scholar
  18. 18.
    Veigl ML, Kasturi L, Olechnowicz J, Ma AH, Lutterbaugh JD, Periyasamy S et al (1998) Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc Natl Acad Sci USA 95:8698–8702PubMedCrossRefGoogle Scholar
  19. 19.
    Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa JP et al (1998) Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA 95:6870–6875PubMedCrossRefGoogle Scholar
  20. 20.
    Cotterchio M, Keown-Eyssen G, Sutherland H, Buchan G, Aronson M, Easson AM et al (2000) Ontario familial colon cancer registry: methods and first-year response rates. Chronic Dis Can 21:81–86PubMedGoogle Scholar
  21. 21.
    Cotterchio M, Manno M, Klar N, McLaughlin J, Gallinger S (2005) Colorectal screening is associated with reduced colorectal cancer risk: a case–control study within the population-based Ontario Familial Colorectal Cancer Registry. Cancer Causes Control 16:865–875PubMedCrossRefGoogle Scholar
  22. 22.
    Green RC, McLaughlin JR, Younghusband HB (2005) SISE matters: the Sum of Information on Seventy-yr-old Equivalents measures pedigree information content when assessing the risk of HNPCC in a family. Fam Cancer 4:169–175PubMedCrossRefGoogle Scholar
  23. 23.
    St John DJ, McDermott FT, Hopper JL, Debney EA, Johnson WR, Hughes ES (1993) Cancer risk in relatives of patients with common colorectal cancer. Ann Intern Med 118:785–790PubMedGoogle Scholar
  24. 24.
    Mecklin JP, Jarvinen HJ, Hakkiluoto A, Hallikas H, Hiltunen KM, Harkonen N et al (1995) Frequency of hereditary nonpolyposis colorectal cancer. A prospective multicenter study in Finland. Dis Colon Rectum 38:588–593PubMedCrossRefGoogle Scholar
  25. 25.
    Olsson L, Lindblom A (2003) Family history of colorectal cancer in a Sweden county. Fam Cancer 2:87–93PubMedCrossRefGoogle Scholar
  26. 26.
    Evans DG, Walsh S, Jeacock J, Robinson C, Hadfield L, Davies DR et al (1997) Incidence of hereditary non-polyposis colorectal cancer in a population-based study of 1137 consecutive cases of colorectal cancer. Br J Surg 84:1281–1285PubMedCrossRefGoogle Scholar
  27. 27.
    Cravo ML, Fidalgo PO, Lage PA, Albuquerque CM, Chaves PP, Claro I et al (1999) Validation and simplification of Bethesda guidelines for identifying apparently sporadic forms of colorectal carcinoma with microsatellite instability. Cancer 85:779–785PubMedCrossRefGoogle Scholar
  28. 28.
    De Leon MP, Pedroni M, Benatti P, Percesepe A, Di Gregorio C, Foroni M et al (1999) Hereditary colorectal cancer in the general population: from cancer registration to molecular diagnosis. Gut 45:32–38PubMedCrossRefGoogle Scholar
  29. 29.
    Cunningham JM, Kim CY, Christensen ER, Tester DJ, Parc Y, Burgart LJ et al (2001) The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas. Am J Hum Genet 69:780–790PubMedCrossRefGoogle Scholar
  30. 30.
    Katballe N, Christensen M, Wikman FP, Orntoft TF, Laurberg S (2002) Frequency of hereditary non-polyposis colorectal cancer in Danish colorectal cancer patients. Gut 50:43–51PubMedCrossRefGoogle Scholar
  31. 31.
    Furukawa T, Konishi F, Shitoh K, Kojima M, Nagai H, Tsukamoto T (2002) Evaluation of screening strategy for detecting hereditary nonpolyposis colorectal carcinoma. Cancer 94:911–920PubMedCrossRefGoogle Scholar
  32. 32.
    Grover S, Stoffel EM, Bussone L, Tschoegl E, Syngal S (2004) Physician assessment of family cancer history and referral for genetic evaluation in colorectal cancer patients. Clin Gastroenterol Hepatol 2:813–819PubMedCrossRefGoogle Scholar
  33. 33.
    Pinol V, Andreu M, Castells A, Paya A, Bessa X, Rodrigo J (2004) Frequency of hereditary non-polyposis colorectal cancer and other colorectal cancer familial forms in Spain: a multicentre, prospective, nationwide study. Eur J Gastroenterol Hepatol 16:39–45PubMedCrossRefGoogle Scholar
  34. 34.
    Pinol V, Castells A, Andreu M, Castellvi-Bel S, Alenda C, Llor X et al (2005) Accuracy of revised Bethesda guidelines, microsatellite instability, and immunohistochemistry for the identification of patients with hereditary nonpolyposis colorectal cancer1. JAMA 293:1986–1994PubMedCrossRefGoogle Scholar
  35. 35.
    Kerber RA, Neklason DW, Samowitz WS, Burt RW (2005) Frequency of familial colon cancer and hereditary nonpolyposis colorectal cancer (Lynch syndrome) in a large population database. Fam Cancer 4:239–244PubMedCrossRefGoogle Scholar
  36. 36.
    Sarroca C, Valle AD, Fresco R, Renkonen E, Peltomaki P, Lynch H (2005) Frequency of hereditary non-polyposis colorectal cancer among Uruguayan patients with colorectal cancer. Clin Genet 68:80–87PubMedCrossRefGoogle Scholar
  37. 37.
    Spirio L, Green J, Robertson J, Robertson M, Otterud B, Sheldon J et al (1999) The identical 5′ splice-site acceptor mutation in five attenuated APC families from Newfoundland demonstrates a founder effect. Hum Genet 105:388–398PubMedCrossRefGoogle Scholar
  38. 38.
    Froggatt NJ, Green J, Brassett C, Evans DG, Bishop DT, Kolodner R et al (1999) A common MSH2 mutation in English and North American HNPCC families: origin, phenotypic expression, and sex specific differences in colorectal cancer [In Process Citation]. J Med Genet 36:97–102PubMedGoogle Scholar
  39. 39.
    Woods MO, Hyde AJ, Curtis FK, Stuckless S, Green JS, Pollett AF et al (2005) High frequency of hereditary colorectal cancer in Newfoundland likely involves Novel Susceptibility Genes. Clin Cancer Res 11:6853–6861PubMedCrossRefGoogle Scholar
  40. 40.
    Hampel H, Frankel WL, Martin E, Arnold M, Khanduja K, Kuebler P et al (2005) Screening for the Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer). N Engl J Med 352:1851–1860PubMedCrossRefGoogle Scholar
  41. 41.
    Percesepe A, Anti M, Roncucci L, Armelao F, Marra G, Pahor M et al (1995) The effect of family size on estimates of the frequency of hereditary non-polyposis colorectal cancer. Br J Cancer 72:1320–1323PubMedGoogle Scholar
  42. 42.
    Hampel H, Stephens JA, Pukkala E, Sankila R, Aaltonen LA, Mecklin JP et al (2005) Cancer risk in hereditary nonpolyposis colorectal cancer syndrome: later age of onset. Gastroenterology 129:415–421PubMedCrossRefGoogle Scholar
  43. 43.
    Grewal KK, Stefanelli MG, Meijer IA, Hand CK, Rouleau GA, Ives EJ (2004) A founder effect in three large Newfoundland families with a novel clinically variable spastic ataxia and supranuclear gaze palsy. Am J Med Genet A 131:249–254PubMedCrossRefGoogle Scholar
  44. 44.
    Young TL, Woods MO, Parfrey PS, Green JS, Hefferton D, Davidson WS (1999) A founder effect in the Newfoundland population reduces the Bardet–Biedl syndrome I (BBS1) interval to 1 cM. Am J Hum Genet 65:1680–1687PubMedCrossRefGoogle Scholar
  45. 45.
    Parfrey PS, Davidson WS, Green JS (2002) Clinical and genetic epidemiology of inherited renal disease in Newfoundland. Kidney Int 61:1925–1934PubMedCrossRefGoogle Scholar
  46. 46.
    Olufemi SE, Green JS, Manickam P, Guru SC, Agarwal SK, Kester MB et al (1998) Common ancestral mutation in the MEN1 gene is likely responsible for the prolactinoma variant of MEN1 (MEN1Burin) in four kindreds from Newfoundland. Hum Mutat 11:264–269PubMedCrossRefGoogle Scholar
  47. 47.
    Croitoru ME, Cleary SP, Di NN, Manno M, Selander T, Aronson M et al (2004) Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk. J Natl Cancer Inst 96:1631–1634PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media B.V. 2006

Authors and Affiliations

  • R. C. Green
    • 1
    Email author
  • J. S. Green
    • 1
  • S. K. Buehler
    • 1
  • J. D. Robb
    • 1
  • D. Daftary
    • 2
  • S. Gallinger
    • 3
  • J. R. McLaughlin
    • 2
  • P. S. Parfrey
    • 1
  • H. B. Younghusband
    • 1
  1. 1.Faculty of MedicineMemorial University of NewfoundlandSt. John’sCanada
  2. 2.Cancer Care OntarioTorontoCanada
  3. 3.Samuel Lunenfeld Research InstituteUniversity of TorontoTorontoCanada

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