Familial Cancer

, Volume 11, Issue 4, pp 579–585

Cancer risks and immunohistochemical profiles linked to the Danish MLH1 Lynch syndrome founder mutation

  • Christina Therkildsen
  • Anna Isinger-Ekstrand
  • Steen Ladelund
  • Anja Nissen
  • Eva Rambech
  • Inge Bernstein
  • Mef Nilbert
Original Article

Abstract

Founder mutations with a large impact in distinct populations have been described in Lynch syndrome. In Denmark, the MLH1 c.1667+2_1667_+8TAAATCAdelinsATTT mutation accounts for 25 % of the MLH1 mutant families. We used the national Danish hereditary nonpolyposis colorectal cancer register to estimate the cumulative lifetime risks for Lynch syndrome-associated cancer in 16 founder mutation families with comparison to 47 other MLH1 mutant families. The founder mutation conferred comparable risks for colorectal cancer (relative risks, RR, of 0.99 for males and 0.79 for females) and lower risks for extracolonic cancer (RR of 0.69 for endometrial cancer and 0.39 for all other extracolonic cancers). We also characterized expression of key Wnt-signaling proteins in colorectal cancers with the founder mutation. Aberrant staining affected β-catenin in 59 %, E-cadherin in 68 %, TCF-4 in 94 % and Cyclin D1 in 68 % with extensive inter-tumor variability despite the same underlying germline mutation. In conclusion, the Danish MLH1 founder mutation that accounts for a significant proportion of Lynch syndrome and is associated with a lower risk for extracolonic cancers.

Keywords

HNPCC Mismatch repair Colorectal cancer Endometrial cancer Cumulative risk Wnt-signaling 

Supplementary material

10689_2012_9552_MOESM1_ESM.xls (19 kb)
Supplementary material 1 (XLS 19 kb)

References

  1. 1.
    Mukherjee B, Rennert G, Ahn J et al (2011) High risk of colorectal and endometrial cancer in Ashkenazi families with the MSH2 A636P founder mutation. Gastroenterology 140(7):1919–1926PubMedCrossRefGoogle Scholar
  2. 2.
    Raskin L, Schwenter F, Freytsis M et al (2011) Characterization of two Ashkenazi Jewish founder mutations in MSH6 gene causing Lynch syndrome. Clin Genet 79(6):512–522PubMedCrossRefGoogle Scholar
  3. 3.
    Clendenning M, Baze ME, Sun S et al (2008) Origins and prevalence of the American founder mutation of MSH2. Cancer Res 68(7):2145–2153PubMedCrossRefGoogle Scholar
  4. 4.
    Tomsic J, Liyanarachchi S, Hampel H et al (2012) An American founder mutation in MLH1. Int J Cancer 130(9):2088–2095PubMedCrossRefGoogle Scholar
  5. 5.
    Chan TL, Chan YW, Ho JW et al (2004) MSH2 c.1452-1455delAATG is a founder mutation and an important cause of hereditary nonpolyposis colorectal cancer in the southern Chinese population. Am J Hum Genet 74(5):1035–1042PubMedCrossRefGoogle Scholar
  6. 6.
    Alonso-Espinaco V, Giraldez MD, Trujillo C et al (2011) Novel MLH1 duplication identified in Colombian families with Lynch syndrome. Genet Med 13(2):155–160PubMedCrossRefGoogle Scholar
  7. 7.
    Tang R, Hsiung C, Wang JY et al (2009) Germ line MLH1 and MSH2 mutations in Taiwanese Lynch syndrome families: characterization of a founder genomic mutation in the MLH1 gene. Clin Genet 75(4):334–345PubMedCrossRefGoogle Scholar
  8. 8.
    van Riel E, Ausems MG, Hogervorst FB et al (2010) A novel pathogenic MLH1 missense mutation, c.112A>C, p.Asn38His, in six families with Lynch syndrome. Hered Cancer Clin Pract 8(1):7–16PubMedCrossRefGoogle Scholar
  9. 9.
    Lastella P, Patruno M, Forte G et al (2011) Identification and surveillance of 19 Lynch syndrome families in southern Italy: report of six novel germline mutations and a common founder mutation. Fam Cancer 10(2):285–295PubMedCrossRefGoogle Scholar
  10. 10.
    de Leon MP, Benatti P, Di Gregorio C et al (2007) Genotype-phenotype correlations in individuals with a founder mutation in the MLH1 gene and hereditary non-polyposis colorectal cancer. Scand J Gastroenterol 42(6):746–753PubMedCrossRefGoogle Scholar
  11. 11.
    Borràs E, Pineda M, Blanco I et al (2011) MLH1 founder mutations with moderate penetrance in Spanish Lynch syndrome families. Cancer Res 70(19):7379–7391CrossRefGoogle Scholar
  12. 12.
    Moisio AL, Sistonen P, Weissenbach J, de la Chapelle A, Peltomaki P (1996) Age and origin of two common MLH1 mutations predisposing to hereditary colon cancer. Am J Hum Genet 59(6):1243–1251PubMedGoogle Scholar
  13. 13.
    Cederquist K, Emanuelsson M, Wiklund F, Golovleva I, Palmqvist R, Gronberg H (2005) Two Swedish founder MSH6 mutations, one nonsense and one missense, conferring high cumulative risk of Lynch syndrome. Clin Genet 68(6):533–541PubMedCrossRefGoogle Scholar
  14. 14.
    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
  15. 15.
    Vasen HF, Moslein G, Alonso A et al (2007) Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet 44(6):353–362PubMedCrossRefGoogle Scholar
  16. 16.
    Ekstrand AI, Jonsson M, Lindblom A, Borg A, Nilbert M (2010) Frequent alterations of the PI3 K/AKT/mTOR pathways in hereditary nonpolyposis colorectal cancer. Fam Cancer 9(2):125–129PubMedCrossRefGoogle Scholar
  17. 17.
    Barrow E, Robinson L, Alduaij W et al (2009) Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations. Clin Genet 75(2):141–149PubMedCrossRefGoogle Scholar
  18. 18.
    Bonadona V, Bonaiti B, Olschwang S et al (2011) Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 305(22):2304–2310PubMedCrossRefGoogle Scholar
  19. 19.
    Quehenberger F, Vasen HF, van Houwelingen HC (2005) Risk of colorectal and endometrial cancer for carriers of mutations of the hMLH1 and hMSH2 gene: correction for ascertainment. J Med Genet 42(6):491–496PubMedCrossRefGoogle Scholar
  20. 20.
    Watson P, Vasen HF, Mecklin JP et al (2008) The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome. Int J Cancer 123(2):444–449PubMedCrossRefGoogle Scholar
  21. 21.
    Kopciuk KA, Choi YH, Parkhomenko E et al (2009) Penetrance of HNPCC-related cancers in a retrolective cohort of 12 large Newfoundland families carrying a MSH2 founder mutation: an evaluation using modified segregation models. Hered Cancer Clin Pract 7(1):16–24PubMedCrossRefGoogle Scholar
  22. 22.
    Schneikert J, Behrens J (2007) The canonical Wnt signalling pathway and its APC partner in colon cancer development. Gut 56(3):417–425PubMedCrossRefGoogle Scholar
  23. 23.
    Mirabelli-Primdahl L, Gryfe R, Kim H et al (1999) Beta-catenin mutations are specific for colorectal carcinomas with microsatellite instability but occur in endometrial carcinomas irrespective of mutator pathway. Cancer Res 59(14):3346–3351PubMedGoogle Scholar
  24. 24.
    Balaz P, Plaschke J, Kruger S, Gorgens H, Schackert HK (2010) TCF-3, 4 protein expression correlates with beta-catenin expression in MSS and MSI-H colorectal cancer from HNPCC patients but not in sporadic colorectal cancers. Int J Colorectal Dis 25(8):931–939PubMedCrossRefGoogle Scholar
  25. 25.
    Kariola R, Abdel-Rahman WM, Ollikainen M, Butzow R, Peltomaki P, Nystrom M (2005) APC and beta-catenin protein expression patterns in HNPCC-related endometrial and colorectal cancers. Fam Cancer 4(2):187–190PubMedCrossRefGoogle Scholar
  26. 26.
    Isinger-Ekstrand A, Therkildsen C, Bernstein I, Nilbert M (2011) Deranged Wnt signaling is frequent in hereditary nonpolyposis colorectal cancer. Fam Cancer 10(2):239–243PubMedCrossRefGoogle Scholar
  27. 27.
    Dilek FH, Topak N, Tokyol C, Akbulut G, Dilek ON (2010) Beta-catenin and its relation to VEGF and cyclin D1 expression in pT3 rectosigmoid cancers. Turk J Gastroenterol 21(4):365–371PubMedGoogle Scholar
  28. 28.
    Corin I, Larsson L, Bergstrom J, Gustavsson B, Derwinger K (2010) A study of the expression of Cyclin E and its isoforms in tumor and adjacent mucosa, correlated to patient outcome in early colon cancer. Acta Oncol 49(1):63–69PubMedCrossRefGoogle Scholar
  29. 29.
    Shin KH, Park YJ, Park JG (2001) PTEN gene mutations in colorectal cancers displaying microsatellite instability. Cancer Lett 174(2):189–194PubMedCrossRefGoogle Scholar
  30. 30.
    Kim NH, Kim HS, Kim NG et al (2011) p53 and MicroRNA-34 Are Suppressors of Canonical Wnt Signaling. Sci Signal 4(197):ra71PubMedCrossRefGoogle Scholar
  31. 31.
    Sinicrope FA, Roddey G, Lemoine M et al (1998) Loss of p21WAF1/Cip1 protein expression accompanies progression of sporadic colorectal neoplasms but not hereditary nonpolyposis colorectal cancers. Clin Cancer Res 4(5):1251–1261PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Christina Therkildsen
    • 1
  • Anna Isinger-Ekstrand
    • 1
  • Steen Ladelund
    • 1
  • Anja Nissen
    • 1
  • Eva Rambech
    • 2
  • Inge Bernstein
    • 1
  • Mef Nilbert
    • 1
    • 2
  1. 1.HNPCC Register, Clinical Research CentreCopenhagen University HospitalHvidovreDenmark
  2. 2.Department of Oncology, Institute of Clinical SciencesLund UniversityLundSweden

Personalised recommendations