Familial Cancer

, Volume 7, Issue 2, pp 163–172

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

  • Johanne Geary
  • Peter Sasieni
  • Richard Houlston
  • Louise Izatt
  • Ros Eeles
  • Stewart J. Payne
  • Samantha Fisher
  • Shirley V. Hodgson
Article

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.

Keywords

Lynch syndrome HNPCC Gene analysis Familial relative risk Clustering 

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. 1.
    Lynch HT, Ens J, Lynch JF, Watson P (1998) Tumor variation in three extended Lynch syndrome II kindreds. Am J Gastroenterol 83(7):741–747Google Scholar
  2. 2.
    Lynch HT, Lynch JF (1993) The Lynch syndromes. Curr Opin Oncol 5(4):687–696PubMedCrossRefGoogle Scholar
  3. 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):428–433PubMedCrossRefGoogle Scholar
  4. 4.
    Watson P, Riley B (2005) The tumor spectrum in the Lynch syndrome. Fam Cancer 4(3):245–248PubMedCrossRefGoogle Scholar
  5. 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):1836–1843PubMedCrossRefGoogle Scholar
  6. 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):1014–1019PubMedGoogle Scholar
  7. 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 63:63–70PubMedCrossRefGoogle Scholar
  8. 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):567–572PubMedCrossRefGoogle Scholar
  9. 9.
    Peltomaki P, Vasen H (2004) Mutations associated with HNPCC predisposition – Update of ICG-HNPCC/INSiGHT mutation database. Dis Markers 20(4–5):269–276PubMedGoogle Scholar
  10. 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):1535–1549PubMedGoogle Scholar
  11. 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):4074–4080PubMedGoogle Scholar
  12. 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):129–138PubMedCrossRefGoogle Scholar
  13. 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):17–25PubMedCrossRefGoogle Scholar
  14. 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, IARCGoogle Scholar
  15. 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):936–937PubMedCrossRefGoogle Scholar
  16. 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):4449–4451Google Scholar
  17. 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):590–599PubMedCrossRefGoogle Scholar
  18. 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):891–895PubMedCrossRefGoogle Scholar
  19. 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):3389–3393Google Scholar
  20. 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):807–808PubMedCrossRefGoogle Scholar
  21. 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):1591–1596PubMedCrossRefGoogle Scholar
  22. 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):281–285Google Scholar
  23. 23.
    Watson P, Lynch HT (1994) The tumor spectrum in HNPCC. Anticancer Res 14(4B):1635–9 (Review)PubMedGoogle Scholar
  24. 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):31–34Google Scholar
  25. 25.
    Greenland JE, Weston PM, Wallace DM (1993) Familial transitional cell carcinoma and the Lynch syndrome II. Br J Urol 72(2):177–180PubMedGoogle Scholar
  26. 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):665–671PubMedCrossRefGoogle Scholar
  27. 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):636–640PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2007

Authors and Affiliations

  • Johanne Geary
    • 1
    • 6
  • Peter Sasieni
    • 2
  • Richard Houlston
    • 3
  • Louise Izatt
    • 4
  • Ros Eeles
    • 3
  • Stewart J. Payne
    • 5
  • Samantha Fisher
    • 5
  • Shirley V. Hodgson
    • 1
  1. 1.Department of Medical GeneticsSt George’s University of LondonLondonUK
  2. 2.Cancer Research UK Centre for Epidemiology, Mathematics & StatisticsWolfson Institute of Preventive Medicine, Queen Mary’s School of MedicineLondonUK
  3. 3.Institute of Cancer ResearchBelmont, Sutton, SurreyUK
  4. 4.Department of Clinical GeneticsGuy’s and St. Thomas’ NHS Foundation TrustLondonUK
  5. 5.North West Thames Regional Genetics ServiceNorthwick Park & St Mark’s HospitalHarrow, LondonUK
  6. 6.Institute of Human Genetics, University of Newcastle upon Tyne, International Centre for Life Newcastle upon TyneUK

Personalised recommendations