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Gene-related cancer spectrum in families with hereditary non-polyposis colorectal cancer (HNPCC)

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Abstract

The family histories of 130 individuals with documented hereditary non-polyposis colorectal cancer (HNPCC) (caused by mutations in mismatch-repair (MMR) genes MSH2 (n = 64), MLH1 (n = 62) or MSH6 (n = 4)) were obtained, and incidence of cancers in those families was compared to that in the general population. There were a total of 982 cancers in 723 individuals. Colorectal cancer (CRC) was the commonest type (64% and 55% in individuals from families with germline MLH1 and MSH2 mutations respectively). Median age at diagnosis of first CRC in MSH6 mutation families was 59 years compared to 45 years in both MLH1 and MSH2 mutation families. The relative risk (RR) of endometrial cancer was 55 in MSH2 mutation families, compared with 27 in MLH1 mutation families, and 37 in MSH6 mutation families; median age at diagnosis 49 years. Even within MSH2 families, endometrial cancer tended to cluster, with 28 of the 58 cases coming from families with three or more cases (P < 0.001). Absolute risk of endometrial cancer in MLH1 families was still greater than any other cancer (other than CRC). 5% of cancers in both MLH1 and MSH2 mutation families were gastric (RR = 12); 53% of these were diagnosed before 50 years. Seven cases of small intestinal cancer occurred in MSH2 and MLH1 mutation families (RR = 26). There were 13 cases of cancer of the ureter; all were in MSH2 families. These cancers tended to cluster within families (P < 0.001); three of seven families with urothelial cancer had such cases in two or more individuals; two others had kidney cancer. Nineteen of 27 ovarian cancers (70%) were in MSH2 mutation families and 70% of these were diagnosed before age 50 years. There were 9 cases of sebaceous skin cancer, 3 in two MLH1 and 6 in four MSH2 mutation families. Of 22 pancreatic cancers, 14 were known to be diagnosed before 60 years. Breast cancer RR was 1.7 overall. The type of mutation (truncating or other type, and site of mutation) showed no obvious correlation with the presence or absence of extra-colonic cancers in families.

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Abbreviations

AER:

absolute excess risk

CNS:

central nervous system

CRC:

colorectal cancer

HNPCC:

hereditary non-polyposis colorectal cancer

MMR:

mismatch-repair

RR:

relative risk

References

  1. Lynch HT, Ens J, Lynch JF, Watson P (1998) Tumor variation in three extended Lynch syndrome II kindreds. Am J Gastroenterol 83(7):741–747

    Google Scholar 

  2. Lynch HT, Lynch JF (1993) The Lynch syndromes. Curr Opin Oncol 5(4):687–696

    Article  PubMed  CAS  Google Scholar 

  3. Lin KM, Shashidharan M, Ternent CA, Thorson AG, Blatchford GJ, Christensen MA, Lanspa SJ, Lemon SJ, Watson P, Lynch HT (1998) Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary nonpolyposis colorectal cancer kindreds and the general population. Dis Colon Rectum 41(4):428–433

    Article  PubMed  CAS  Google Scholar 

  4. Watson P, Riley B (2005) The tumor spectrum in the Lynch syndrome. Fam Cancer 4(3):245–248

    Article  PubMed  Google Scholar 

  5. Risinger JI, Barrett JC, Watson P, Lynch HT, Boyd J (1996) Molecular genetic evidence of the occurrence of breast cancer as an integral tumor in patients with the hereditary nonpolyposis colorectal carcinoma syndrome. Cancer 77(9):1836–1843

    Article  PubMed  CAS  Google Scholar 

  6. Muller A, Edmonston TB, Corao DA, Rose DG, Palazzo JP, Becker H, Fry RD, Rueschoff J, Fishel R (2002) Exclusion of breast cancer as an integral tumor of hereditary nonpolyposis colorectal cancer. Cancer Res 62(4):1014–1019

    PubMed  CAS  Google Scholar 

  7. Kruse R, Rütten A, Lamberti C, Hosseiny-Malayeri HR, Wang Y, Ruelfs C, Jungck M, Mathiak M, Ruzicka T, Hartschuh W, Bisceglia M, Friedl W, Propping P (1998) Muir-Torre phenotype has a frequency of DNA mismatch-repair-gene mutations similar to that in Hereditary Nonpolyposis Colorectal Cancer families defined by the Amsterdam criteria. Am J Hum Genet 63:63–70

    Article  PubMed  CAS  Google Scholar 

  8. Mangold E, Pagenstecher C, Leister M, Mathiak M, Rutten A, Friedl W, Propping P, Ruzicka T, Kruse R (2004) A genotype-phenotype correlation in HNPCC: strong predominance of MSH2 mutations in 41 patients with Muir-Torre syndrome. J Med Genet 41(7):567–572

    Article  PubMed  CAS  Google Scholar 

  9. Peltomaki P, Vasen H (2004) Mutations associated with HNPCC predisposition – Update of ICG-HNPCC/INSiGHT mutation database. Dis Markers 20(4–5):269–276

    PubMed  Google Scholar 

  10. Lynch HT, Smyrk TC, Watson P, Lanspa SJ, Lynch JF, Lynch PM, Cavalieri RJ, Boland CR (1993) Genetics, natural history, tumor spectrum, and pathology of Hereditary Nonpolyposis Colorectal Cancer: an updated review. Gastroenterology 104(5):1535–1549

    PubMed  CAS  Google Scholar 

  11. Vasen HF, Stormorken A, Menko FH, Nagengast FM, Kleibeuker JH, Griffioen G, Taal BG, Moller P, Wijnen JT (2001) MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of Hereditary Nonpolyposis Colorectal Cancer families. J Clin Oncol 19(20):4074–4080

    PubMed  CAS  Google Scholar 

  12. Jager AC, Bisgaard ML, Myrhoj T, Bernstein I, Rehfeld JF, Nielsen FC (1997) Reduced frequency of extracolonic cancers in hereditary nonpolyposis colorectal cancer families with monoallelic hMLH1 expression. Am J Hum Genet 61(1):129–138

    Article  PubMed  CAS  Google Scholar 

  13. Hendriks YM, Wagner A, Morreau H, Menko F, Stormorken A, Quehenberger F, Sandkuijl L, Moller P, Genuardi M, Van Houwelingen H, Tops C, Van Puijenbroek M, Verkuijlen P, Kenter G, Van Mil A, Meijers-Heijboer H, Tan GB, Breuning MH, Fodde R, Wijnen JT, Brocker-Vriends AH, Vasen H (2004) Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counselling and surveillance. Gastroenterology 127(1):17–25

    Article  PubMed  CAS  Google Scholar 

  14. Parkin DM, Whelan SL, Ferlay J, Teppo L, Thomas DB (eds) (2002) Cancer Incidence in Five Continents, Vol. VIII. IARC Scientific Publications No. 155, Lyon, IARC

    Google Scholar 

  15. Bandipalliam P, Garber J, Kolodner RD, Syngal S (2004) Clinical presentation correlates with the type of mismatch repair gene involved in Hereditary Nonpolyposis Colon Cancer. Gastroenterology 126(3):936–937

    Article  PubMed  Google Scholar 

  16. Plaschke J, Engel C, Kruger S, Holinski-Feder E, Pagenstecher C, Mangold E, Moeslein G, Schulmann K, Gebert J, von Knebel Doeberitz M, Ruschoff J, Loeffler M, Schackert HK (2004) Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium. J Clin Oncol 15;22(22):4449–4451

    Google Scholar 

  17. Schulmann K, Brasch FE, Kunstmann E, Engel C, Pagenstecher C, Vogelsang H, Kruger S, Vogel T, Knaebel HP, Ruschoff J, Hahn SA, Knebel-Doeberitz MV, Moeslein G, Meltzer SJ, Schackert HK, Tympner C, Mangold E, Schmiegel W (2005) The German HNPCC Consortium. HNPCC-associated small bowel cancer: clinical and molecular characteristics. Gastroenterology 128(3):590–599

    Article  PubMed  CAS  Google Scholar 

  18. Lynch HT, Richardson JD, Amin M, Lynch JF, Cavalieri RJ, Bronson E, Fusaro RM (1991) Variable gastrointestinal and urologic cancers in a Lynch syndrome II kindred. Dis Colon Rectum 34(10):891–895

    Article  PubMed  CAS  Google Scholar 

  19. Park JG, Kim DW, Hong CW, Nam BH, Shin YK, Hong SH, Kim IJ, Lim SB, Aronson M, Bisgaard ML, Brown GJ, Burn J, Chow E, Conrad P, Douglas F, Dunlop M, Ford J, Greenblatt MS, Heikki J, Heinimann K, Lynch EL, Macrae F, McKinnon WC, Moeslein G, Rossi BM, Rozen P, Schofield L, Vaccaro C, Vasen H, Velthuizen M, Viel A, Wijnen J (2006) International Society for Gastrointestinal Hereditary Tumours. Germ line mutations of mismatch repair genes in Hereditary Nonpolyposis Colorectal Cancer patients with small bowel cancer: International Society for Gastrointestinal Hereditary Tumours Collaborative Study. Clin Cancer Res 1;12(11 Pt 1):3389–3393

    Google Scholar 

  20. Medina Arana V, Barrios del Pino Y, Garcia-Castro C, Gonzalez-Aguilera JJ, Fernandez-Peralta A, Gonzalez Hermoso F (2002) Highly aggressive leiomyosarcoma associated with Lynch II syndrome: increasing the range of extracolonic cancers related with hereditary non-polyposis colonic cancer. Ann Oncol 13(5):807–808

    Article  PubMed  CAS  Google Scholar 

  21. Maul JS, Warner NR, Kuwada SK, Burt RW, Cannon-Albright LA (2006) Extracolonic cancers associated with Hereditary Nonpolyposis Colorectal Cancer in the Utah Population Database. Am J Gastroenterol 101(7):1591–1596

    Article  PubMed  Google Scholar 

  22. Heinimann K, Muller H, Weber W, Scott RJ (1997) Disease expression in Swiss Hereditary Non-Polyposis Colorectal Cancer (HNPCC) kindreds. Int J Cancer 20;74(3):281–285

    Google Scholar 

  23. Watson P, Lynch HT (1994) The tumor spectrum in HNPCC. Anticancer Res 14(4B):1635–9 (Review)

    PubMed  CAS  Google Scholar 

  24. Vasen HF, Offerhaus GJ, den Hartog Jager FC, Menko FH, Nagengast FM, Griffioen G, van Hogezand RB, Heintz AP (1990) The tumour spectrum in Hereditary Non-Polyposis Colorectal Cancer: a study of 24 kindreds in the Netherlands. Int J Cancer 15;46(1):31–34

  25. Greenland JE, Weston PM, Wallace DM (1993) Familial transitional cell carcinoma and the Lynch syndrome II. Br J Urol 72(2):177–180

    PubMed  CAS  Google Scholar 

  26. de Jong AE, Hendriks YM, Kleibeuker JH, de Boer SY, Cats A, Griffioen G, Nagengast FM, Nelis FG, Rookus MA, Vasen HF (2006) Decrease in mortality in Lynch syndrome families because of surveillance. Gastroenterology 130(3):665–671

    Article  PubMed  Google Scholar 

  27. Hutter P, Couturier A, Scott RJ, Alday P, Delozier-Blanchet C, Cachat F, Antonarakis SE, Joris F, Gaudin M, D’Amato L, Buerstedde JM (1996) Complex genetic predisposition to cancer in an extended HNPCC family with an ancestral hMLH1 mutation. J Med Genet 33(8):636–640

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

Our thanks go to Mr Huw JW Thomas, Mr James Mackay, Dr Huw Dorkins, Dr Susan Shanley and Professor Naz Rahman; also to all staff at the CR-UK Family Cancer Clinic, the Cancer Genetics Clinic, Royal Marsden NHS Foundation Trust, the North East Thames Regional Genetics Centre, the North West Thames Regional Genetics Service, the South East Thames Regional Genetics Centre and the South West Thames Regional Genetics Service for providing access to data to make this work possible. We are also grateful to the NHS: Audit, Information & Analysis Unit for funding the work on which this paper is based.

NCBI Reference Sequences: MLH1 RefSeq accession number NM_000249, MSH2 RefSeq accession number NM_000251.1, Mutation nomenclature based on A of ATG start methionine codon designated nucleotide number 1

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Correspondence to Shirley V. Hodgson.

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Geary, J., Sasieni, P., Houlston, R. et al. Gene-related cancer spectrum in families with hereditary non-polyposis colorectal cancer (HNPCC). Familial Cancer 7, 163–172 (2008). https://doi.org/10.1007/s10689-007-9164-6

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  • DOI: https://doi.org/10.1007/s10689-007-9164-6

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