To establish the importance of CHEK2 mutations for familial breast cancer incidence in the German population, we have screened all 14 of the coding exons in 516 families negative for mutations in both the BRCA1 and BRCA2 genes. We found 12 distinct variants in 30 unrelated patients (5.81%), including 5 that are novel and an additional 4 found for the first time in breast cancer. These aberrations were evaluated in 500 healthy women aged over 50 years and in the case of the 2 exon 10 mutations, 1100delC and 1214del4bp, in 1315 randomized healthy controls. According to our results, a statistically significant association for the exon 10 mutations was observed (p ‫؍‬ 0.006). The prevalence of the 1100delC mutation in the German population, however, is significantly lower than those reported for other Caucasian populations both in familial breast cancer patients (1.6%) and controls (0.5%), and shows independent segregation with breast cancer in 2 of 4 families analyzed. The remaining 10 variants were more abundant in patients (21) compared to the controls (12) although the difference was not statistically significant. Interestingly, we found no increased breast cancer risk associated with the splice site mutation IVS2؉1G3 A or the most common missense mutation I157T, which account for more than half (12/21) of the variants observed in patients. The low prevalence and penetrance of the exon 10 deletion mutations together with no, or an uncertain elevation in risk for other CHEK2 mutations suggests a limited relevance for CHEK2 mutations in familial breast cancer. Further evaluation of the unique variants observed in breast cancer is required to determine if they may play a role in a polygenic model of familial breast cancer. Nevertheless, it seems premature to include CHEK2 screening in genetic testing.

NCT 00567554, www.clinicaltrials.gov.

No abstract

A prospective follow-up study was carried out to evaluate the influence of risk and genetic counselling on use of early cancer detection. Five hundred and fifty-six subjects who fulfilled inclusion criteria for a genetic analysis of the BRCA1/2 genes (the high-risk group A) and 205 who did not fulfil the inclusion criteria (the lower risk group B) attended primary consultation in the interdisciplinary cancer genetic clinic. Information about participation in the early cancer detection programme was documented. Information about changes in use after consultation could be evaluated from 349 women (94 group B and 255 group A). Methods such as monthly self-palpation, breast palpation by gynaecologist, ultrasound of the breast, transvaginal ultrasound and pelvic examination had all been commonly used. Consultees at higher risk used mammography less often than women at lower risk. Magnetic resonance imaging of the breast was used rarely. Most methods were used more often at the recommended interval by women at higher risk during the follow-up period. In conclusion, at present intensified early cancer detection programmes for women at risk provide a less invasive option than chemoprevention or prophylactic surgery. Although the methods are used at high frequency it seems feasible to motivate women at risk to participate. This can be done by providing information and counselling in the cancer genetic clinic.

Methods of improving and increasing participation in ECD facilities, and of encouraging women who are at risk to start on such programs at a younger age, need to be discussed. In this study, familial risk already resulted in a younger age of uptake of ECD facilities.