Familial Cancer

, Volume 11, Issue 4, pp 579–585 | Cite as

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


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.


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



The study was financially supported by the Hvidovre University Hospital, the Danish Cancer Fund and the Lundbeck Foundation. Statistical support was obtained from Linda Werner-Hartman.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

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


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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

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