Original Article

Familial Cancer

, Volume 11, Issue 4, pp 579-585

First online:

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

  • Christina TherkildsenAffiliated withHNPCC Register, Clinical Research Centre, Copenhagen University Hospital Email author 
  • , Anna Isinger-EkstrandAffiliated withHNPCC Register, Clinical Research Centre, Copenhagen University Hospital
  • , Steen LadelundAffiliated withHNPCC Register, Clinical Research Centre, Copenhagen University Hospital
  • , Anja NissenAffiliated withHNPCC Register, Clinical Research Centre, Copenhagen University Hospital
  • , Eva RambechAffiliated withDepartment of Oncology, Institute of Clinical Sciences, Lund University
  • , Inge BernsteinAffiliated withHNPCC Register, Clinical Research Centre, Copenhagen University Hospital
  • , Mef NilbertAffiliated withHNPCC Register, Clinical Research Centre, Copenhagen University HospitalDepartment of Oncology, Institute of Clinical Sciences, Lund University

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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