Several studies have shown that the frequency of BRCA1 mutations in high-risk families differs widely between populations. In a recently published study from the Stockholm region, we found BRCA1 mutations in about 35% of the breast/ovarian families, but only in 1% of the families with site-specific breast cancer. To determine the frequency of BRCA1 mutations in families with a less increased risk for breast or ovarian cancer, a second study was performed. A total of 94 families with two and six families with only one affected member were included. Six mutations were found, all localized in exon 11, and five of them were previously known Swedish founder mutations. The mutation frequency was 6%, similar to the finding in families fulfilling the criteria for hereditary breast cancer (7%) that was disclosed in our first study. All families with a mutation had at least one individual with ovarian cancer. Thus, our study further implies that for a woman with breast cancer, a family history of ovarian cancer is far more important than a family history of breast cancer for predicting a BRCA1 mutation. Our results can be used to increase the specificity in selection of families for genetic testing.

Summary To estimate the prevalence of TP53 mutations in familial breast cancer, constant denaturant gel electrophoresis (CDGE) was used to screen exons 5-8 of the TP53 gene for germline mutations. Genomic DNA from 128 breast cancer patients belonging to 109 families with familial cancer were screened. No germline mutations were found in any of the patients. We also studied TP53 mutations in tumour DNA from 51 of the same individuals and found mutations in 14%. This is similar to what has been reported in sporadic breast cancer.Keywords: TP53; p53; mutation analysis; constant denaturant gel electrophoresis; familial breast cancer The p53 protein is a transcription factor and is frequently altered by mutation in most types of cancer. The majority of the mutations are missense mutations (Hollstein et al, 1994).Germline mutations in the TP53 gene were found to segregate in families with the Li-Fraumeni syndrome resulting in a very high risk for early onset breast cancer, sarcoma, leukaemia, brain tumours and other tumours (Malkin, 1994; Wang et al, 1995). It has also been shown that not all families with the classical criteria for Li-Fraumeni segregate a mutation in p53, while some other families with non-classical Li-Fraumeni syndrome do (Birch et al, 1994). Germline mutations have also been found in families with breast and ovarian cancer (Prosser et al, 1992;Jolly et al, 1994). However, germline mutations have not been found to segregate frequently in breast cancer families or patients with early onset or bilateral disease (Prosser et al, 1991;Sidransky et al, 1992;B0rresen et al, 1992;Lidereau and Soussi, 1992).One study, which compared the frequency of somatic TP53 mutations in sporadic breast carcinomas with tumours from patients with a family history, showed that, while sporadic TP53 mutations occurred in 13% of the sporadic tumours, the frequency in the familial cases was 58% (Glebov et al, 1994).We have used constant denaturant gel electrophoresis (CDGE) to screen for germline mutations in exons 5-8 of the TP53 gene in members from 109 breast cancer families. This study also involved searching for mutations in 51 of the tumours from our patients with familial breast cancer. MATERIALS AND METHODS PatientsA total of 128 patients from 109 families with familial cancer, predominantly breast cancer, were identified. The families were selected as described (Lindblom et al, 1992a Correspondence to: A Lindblom number of breast cancer and other cancer diagnoses, the families were categorized as follows: 45 families were defined as breast cancer families and 25 families were defined as cancer families using the following criteria. Breast cancer family -at least three first-or second-degree relatives with breast cancer. Cancer family -the index patient with breast cancer plus at least three first-or second-degree relatives with cancer. The remaining 39 families had a family history of two first-degree relatives with breast cancer. Tumour tissue was available from 51 of these patients.

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