Homozygosity for a CHEK2*1100delC mutation identified in familial colorectal cancer does not lead to a severe clinical phenotype.

It has recently been suggested that the frequency of the germline CHEK2*1100delC mutation is higher among breast cancer families with colorectal cancer, although the mutation does not seem to be significantly associated with familial colorectal cancer. Five hundred and sixty-four familial colorectal tumours were studied for expression of CHEK2 using tissue microarrays and an antibody against the NH2-terminal SQ regulatory domain of the CHEK2 protein. Normal colonic tissue from patients whose tumours showed loss of CHEK2 expression was investigated further using fragment and sequence analysis for the presence of a CHEK2*1100delC mutation and five other (R117G, R137Q, R145W, I157T, and R180H) known germline variants in CHEK2. Twenty-nine tumours demonstrated loss of expression for CHEK2. Analysis of matched normal colonic tissue from these patients revealed germline CHEK2*1100delC mutation in three cases. In two of these, the mutation was heterozygous but, interestingly, the third patient proved to be homozygous for the deletion, using six different primer pair combinations. None of the other tested germline variants were identified. No CHEK2*1100delC mutations were found in patients whose tumours stained positive. Homozygosity for the CHEK2*1100delC mutation appears not to be lethal in humans. No severe clinical phenotype was apparent, although the patient died from colonic carcinoma at age 52 years. This observation is in line with recent knockout mouse models, although in the latter, cellular defects in apoptosis and increased resistance to irradiation seem to exist. It is also concluded that CHEK2 protein abrogation is not caused by the CHEK2 germline variants R117G, R137Q, R145W, I157T, and R180H in familial colorectal cancer. Copyright 2005 Pathological Society of Great Britain and Ireland