Abstract
Current screening advice for high-risk mutations in BRCA1/2 is based family history of breast cancer or breast cancer development before age 35 years. A significant part of BRCA1/2 carriers may not be detected by these criteria. Additionally, within the Clinical Genetic Centers and in most studies, BRCA1/2 mutations were analyzed in DNA from blood from selected living probands and their (affected) family members. One study so far showed that BRCA1/2 mutations may also play a role in families where breast cancer is not common (King et al, 2003). Data on the proportion of BRCA1 and especially BRCA2 carriers in unselected hospital based series, not biased by survivorship (being alive to provide a blood sample) and selected irrespective of family history, are relatively scarce. We analyzed operable breast cancer patients diagnosed with invasive mamma carcinoma before the age of 50 years, in 10 Dutch hospitals in the period 1973-2002. DNA was isolated from formalin-fixed paraffin-embedded tissue. Based on a nationwide database of BRCA1/2 mutations in counseled Dutch breast cancer families, we chose to analyze the most frequent pathogenic BRCA1 and BRCA2 mutations, i.e., 39 BRCA1 and 41 BRCA2 mutations, capturing 70% of all known Dutch pathogenic BRCA1/2 families. Frame shift mutations were analyzed by fragment length detection: genomic BRCA1/2 fragments (n=22) were amplified with fluorescent-labeled primers in nine multiplex PCR reactions and then pooled and run in one lane on an ABI PRISM 3730 DNA analyzer. Substitutions were detected by the Allelic Discrimination: genomic BRCA1/2 fragments (n=8) were amplified with primers and fluorescent-labeled (\#8216;Taqman\#8217;) probes and run on the ABI PRISM 7500 Real-Time PCR. Suspect mutations were confirmed by direct sequencing. Among 3148 patients analyzed so far 3.3% BRCA1 and 1.1% BRCA2 carriers were detected. The proportion of BRCA1 carriers significantly declined with increasing age (p <0.001), in the youngest age group <30 years of age, 11% of the patients carried a BRCA1 mutation, compared to 1.6% in the oldest age group (45-50 years). In BRCA2 carriers this trend was less clear and not significant, possibly due to small numbers. On the other hand, a similar lack of trend for BRCA2 was observed in familial breast cancer patients counseled at the Clinical Genetic Center at our institute. Accounting for the incomplete screening (70%), the proportion of BRCA1/2 carriers in the cohort of unselected breast cancer patients would even in the age group of 35-40 years still be high (8%). In comparison, with current screening advice, in 25% of the families counseled at clinical genetic centers a BRCA1/2 mutation is found. In future analyses, tumor characteristics will be included for the prediction of BRCA1/2 carriership.
Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3033.
Footnotes
100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO
- American Association for Cancer Research