Screening for TP53 mutations in patients and tumours from 109 Swedish breast cancer families

Abstract

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.

Novel germline mutations in breast cancer susceptibility genes BRCA1, BRCA2 and p53 gene in breast cancer patients from India

“…The patient (21NF) showed a novel missense change G5403A (Val97Ile) in exon 4 but nothing in exon 5 replacing one hydrophobic amino acid by another in the transcription activation domain of p53 protein along with protein truncating 4956insG of BRCA1 gene. Our results are in good agreement with Schlichtholz et al [34] and Zelada-Hedman et al [35] who also observed low frequency of germline p53 mutation in familial breast cancer with or without BRCA1 mutation. Thus, apart from Li Fraumeni syndrome [36], p53 gene mutation appears to be of rare occurrence in familial breast cancer with or without BRCA1 mutation and is unlikely to play a major role in breast carcinogenesis.…”

The R72P P53 mutation is associated with familial breast cancer in Jewish women

“…In addition, based on its pivotal role in DNA damage repair and its physical and functional interactions with BRCA1 and BRCA2 proteins (Storey et al, 1998), p53 seems to be a strong candidate breast cancer predisposition gene. However, previous analyses of high-risk families of different ethnic background yielded a paucity of germline mutations in p53 gene in familial breast cancer (Zelada-Hedman et al, 1997;Balz et al, 2002).…”

Germline TP53 Testing in Breast Cancers: Why, When and How?

“…Breast cancer risk increases significantly after the second decade, is very high under the age 31 close to 20%-30% on the basis of the Breast cancer RIsk after Diagnostic GEne Sequencing (BRIDGES) study [37], reaches a peak between 25-35 years, and this does tally with estimates from kindreds [38]. This risk drops after 40 years of age based on the relative frequency of TP53 carriers identified [37,39,40], and cumulative risk reaches a plateau before 60 [35,36,38] [38], these likely suffer from ascertainment and survival bias with many carriers dying from other malignancies at young ages. There is clearly a very high rate of contralateral breast cancer approaching 4%-7% annually and significantly higher than BRCA1 or BRCA2 in those diagnosed aged <35 [41].…”

“…Breast cancer risk increases significantly after the second decade, is very high under the age 31 close to 20%–30% on the basis of the Breast cancer RIsk after Diagnostic GEne Sequencing (BRIDGES) study [ 37 ], reaches a peak between 25–35 years, and this does tally with estimates from kindreds [ 38 ]. This risk drops after 40 years of age based on the relative frequency of TP53 carriers identified [ 37 , 39 , 40 ], and cumulative risk reaches a plateau before 60 [ 35 , 36 , 38 ]. For instance, of 65 known TP53 carriers with breast cancer in the Genomic Medicine Centre in Manchester 32/65 occurred aged <31 (49%), 24 (37%) occurred aged 31–39, 5 (7.5%) aged 40–44 and only 3/65 (4.5%) over age 45.…”