Late Onset Colorectal Cancer; fenotypic and genotypic features

Mef Nilbert1,2, Lukas Adrian Berchtold3, Thomas van Overeem Hansen 3, Eva Rambech2, Christina Therkildsen1

1HNPCC-register, Clinical Research Center, Hvidovre Hospital and Copenhagen University, Copenhagen, Denmark. 2Institute of Clinical Medicine, Division of Oncology, Lund, Sweden. 3Genomic Medicine, Rigshospitalet, Copenhagen, Denmark



The genetic background in families with seemingly dominant inheritance of colorectal cancer and an age at onset above age 50 is largely unknown. Surveillance colonoscopies have proven to effectively reduce morbidity and mortality from colorectal cancer also in individuals with families non-genetically defined risk, but to increase the efficiency of these programs, better selection of individuals at-risk would be valuable.


We used the Danish HNPCC-register to assess risk of colorectal cancer in such families and further invited a subset of the cohort to panel-based diagnostic sequencing.


In Denmark (population 5.6 M), 406 families have based on heredity been classified as “late onset” colorectal cancer families. Disease-predisposing MMR gene mutations were identified in 3% of these families with MSH6 mutations accounting for half. In the remaining families, the mean age at onset was 61 years (50-98). Tumour location was predominantly in the left colon (31%) and the rectum (36%). From these families, 60 individuals, all of whom had been diagnosed with colorectal cancer, were invited for a new genetic test based on a panel of 23 genes associated with hereditary colorectal cancer.

Possibly or presumably disease-predisposing mutations were identified in the genes APC, MSH6, PMS2, POLE, TP53, BLM, CDH1 and FAN1.


The variable mutation pattern observed in families with late onset colorectal cancer suggests that these families will benefit from broader molecular testing and indicates that this phenotypically defined cohort is genotypically heterogenous.