Familial Breast Cancer Patients Research Articles

Absence of mutations in the ATM gene in forty-seven cases of sporadic breast cancer.

Epidemiological evidence points to an increased risk of breast cancer in ataxia telangiectasia (AT) heterozygote women. Previous attempts to screen early onset or familial breast cancer patients failed to confirm an association. The issue of AT and late onset sporadic breast cancer remained unresolved. We screened 47 women who developed later onset, sporadic breast cancer for ataxia telangiectasia mutated (ATM) mutations. No mutations were found. © 1999 Cancer Research Campaign

Frequency of BRCA1 Mutation 5382insC in German Breast Cancer Patients

Objective.The aim of the study was to determine the frequency of the BRCA1 mutation 5382insC in German breast cancer patients with and without prior knowledge of a family history of breast cancer.Methods.Two groups of breast cancer patients were tested for the presence or absence of the 5382insC mutation using a PCR primer mismatch assay. A sample of 248 patients unrelated by genealogy was selected based on a history of breast and/or ovarian cancer in the families. In addition, a population-based sample of 800 unselected breast cancer patients was included in the analysis. Three intragenic DNA markers D17S1323, D17S1322, and D17S855, located at BRCA1 introns 12, 19, and 20, respectively, were utilized for allelic association studies as well as for haplotype analysis in 4 breast/ovarian cancer families.Results.The 5382insC mutation was identified in 10/248 (4.0%) familial breast cancer patients and in 8/800 (1.0%) unselected cases. Allelic association studies and haplotype analysis revealed an association of allele Nos. “6” at D17S1323 (χ2value = 9.34,P= 0.007), “5” at D17S1322 (χ2value = 3.62,P= 0.171), and “4” at D17S855 (χ2value = 11.34,P= 0.002) with the mutation 5382insC.Conclusion.5382insC constitutes a frequent BRCA1 mutation in German breast cancer patients. The significant allelic association between this mutation and two intragenic DNA markers (D17S1323, D17S855) and the elevated allele frequency at marker D17S1322 suggest an ancient founder in the German breast cancer population. The PCR primer mismatch assay described herein provides a rapid and reliable detection method for the recurrent 5382insC mutation and will be useful for the analysis of large breast cancer populations.

93 The germline p53 13964 gc mutation confers resistance to radiation in familial breast cancer patients

93 The germline p53 13964 gc mutation confers resistance to radiation in familial breast cancer patients

Truncated TSG101 transcripts are present in peripheral blood from both familial breast cancer patients and controls.

TSG101 is a recently identified putative tumour suppressor gene which has been implicated in human breast cancer. To address whether germline disruption of TSG101 predisposes individuals to this disease, we analysed genomic DNA and mRNA isolated from peripheral blood from 20 familial breast cancer cases. No evidence of large intragenic insertions/deletions or point mutations in TSG101 was found by Southern blot analysis and sequence analysis of the entire coding region. However, in 11 of 20 samples, 'aberrant' transcripts were detected. Sequence analysis suggested that these variants were generated by the use of different cryptic splicing sites. Such alternative/aberrant splicing events were not restricted to cancer patients, but were also detected in peripheral blood of non-cancer patients and in normal tissues.

DNA repair proficiency: a potential marker for identification of high risk members in breast cancer families

Breast cancer is the single largest cancer and causes the high rate of cancer mortality among women. A positive family history of breast cancer is recognized as one of the major risk factors for this disease. The present study evaluates bleomycin (BLM)-induced chromosome sensitivity analysis in breast cancer families which provides indirectly a measure of the DNA repair defect of each person. BLM sensitivity assay on cultured lymphocytes of 36 familial breast cancer patients, their 85 first or second degree female relatives, 36 sporadic breast cancer patients and 40 age- and sex-matched controls (without any family history of cancer) were carried out to measure interindividual variation in their DNA repair capacity through mutagen-induced chromosome sensitivity analysis. Fifty percent of familial breast cancer patients and seven unaffected relatives showed hypersensitivity. Compared to hyposensitive relatives these seven subjects may be considered as high risk individuals.

A rare CYP19 (aromatase) variant may increase the risk of breast cancer.

The aromatase P450 (coded by the CYP19 gene) is responsible for the rate limiting step in the metabolism of C19 steroids to estrogens and is expressed in most breast carcinomas. A polymorphic tetranucleotide repeat (TTTA)n in intron 5, about 80 nucleotides downstream of exon 4 has previously been described. The allele frequencies of the polymorphic repeat were studied in series of 182 sporadic and 185 familial breast cancer patients as well as in 252 healthy control individuals. Five different alleles containing 7, 8, 9, 11 and 12-TTTA-repeats were detected. A relatively rare allele (A1) containing the longest repeat (TTTA)12 was found significantly more frequently in breast cancer patients than in control individuals. This indicates that individuals carrying the A1 allele of CYP19 may have an increased risk of developing breast cancer, OR 2.42 (95% confidence interval [CI] 1.03-5.80). The higher frequency was observed in both sporadic and familial patients, although when each of the groups was compared to the control group only a borderline significance was seen. A higher frequency of A1 allele carriers was also found in the group of patients with positive estrogen receptor and progesterone receptor positive tumors. These data suggest that the CYP19 gene may be involved as a low penetrance gene in breast cancer susceptibility.

Constant denaturant gel electrophoresis (CDGE) in BRCA1 mutation screening

Screening for mutations in the breast and ovarian cancer susceptibility gene, BRCA1, is complicated by the wide spectrum of mutations found in this large gene. In the present study a constant denaturant gel electrophoresis (CDGE) mutation screening strategy was established for ˜80% of the genomic coding sequence (exons 2, 11, 13–16, 20, 24). This strategy was applied to screen genomic DNA from 50 familial breast and/or ovarian cancer patients who had previously been examined for BRCA1 mutations by SSCP. A total of 14 carriers of 12 distinct disease-associated mutations and 7 carriers of 6 distinct rare substitutions leading to amino acid substitutions were identified. The SSCP failed to detect 40% of the different deletions/insertions (4/10) and 75% (6/8) of the different base substitutions leading to terminating codons or rare amino acid changes. SSCP did, however, identify one rare base substitution that could not be detected in the CDGE screening. To evaluate the CDGE mutation screening strategy further, 25 unrelated patients from Norwegian breast and/or ovarian cancer families were examined for BRCA1 mutations using a combined genomic DNA/cDNA approach covering the entire coding sequence of the gene. A total of six mutation carriers were detected, all of whom had cases of ovarian cancer in their families. Three patients from independent families carried an 1135insA mutation in exon 11, two others had a Gly484ter and an 1675delA mutation, respectively, and the sixth carried a splice mutation (5194-2 a→c) causing deletion of exon 18. CDGE may become an efficient tool in diagnostic and population based screening for BRCA1 mutations. Hum Mutat 11:166–174, 1998. © 1998 Wiley-Liss, Inc.

Constant denaturant gel electrophoresis (CDGE) in BRCA1 mutation screening.

Screening for mutations in the breast and ovarian cancer susceptibility gene, BRCA1, is complicated by the wide spectrum of mutations found in this large gene. In the present study a constant denaturant gel electrophoresis (CDGE) mutation screening strategy was established for approximately 80% of the genomic coding sequence (exons 2, 11, 13-16, 20, 24). This strategy was applied to screen genomic DNA from 50 familial breast and/or ovarian cancer patients who had previously been examined for BRCA1 mutations by SSCP. A total of 14 carriers of 12 distinct disease-associated mutations and 7 carriers of 6 distinct rare substitutions leading to amino acid substitutions were identified. The SSCP failed to detect 40% of the different deletions/insertions (4/10) and 75% (6/8) of the different base substitutions leading to terminating codons or rare amino acid changes. SSCP did, however, identify one rare base substitution that could not be detected in the CDGE screening. To evaluate the CDGE mutation screening strategy further, 25 unrelated patients from Norwegian breast and/or ovarian cancer families were examined for BRCA1 mutations using a combined genomic DNA/cDNA approach covering the entire coding sequence of the gene. A total of six mutation carriers were detected, all of whom had cases of ovarian cancer in their families. Three patients from independent families carried an 1135insA mutation in exon 11, two others had a Gly484ter and an 1675delA mutation, respectively, and the sixth carried a splice mutation (5194-2 a-->c) causing deletion of exon 18. CDGE may become an efficient tool in diagnostic and population based screening for BRCA1 mutations.

449 BRCA1 gene mutation carrier analysis in familial breast cancer patients

BRCA1, the predisposing gene for familial breast and ovarian cancer localized on chromosome 17q21.3 has been recently cloned. The gene comprises 22 coding exons which span 100 kB of genomic sequence. The protein predicted is 1863 aminoacids long. 31 mutations have been identified in constitutional DNA of affected member from various family of which 22 were distinct. Not one of 22 transcribed exons seems to be a preferential target site for mutations. Overall germline BRCA1 mutations account for 1–2% of all breast cancers and about 3% of ovarian cancers. The lifetime risk of breast and ovarian cancer in BRCA1 mutation carriers is high: the risk of breast cancer is about 50% by age 50 and 70% by age 70. The average risk of ovarian cancer is 40% by age 70. BRCA1 has never been found mutated in sporadic carcinomas, however, loss of heterozigosity in the region of BRCA1 has been observed in 40% of breast and about 60% of ovarian cancers. The lifetime risk to develop the familial form of the disease may be calculated by identifying mutations in BRCA1 or BRCA2 genes. From the screening of 1100 medical records of patients subjected to mastectomy in S. Chiara Hospital in Pisa during the period 1990–1994, the patients with a referred familial recurrence of breast or ovarian cancer were selected for interview. 81 patients belonging to 75 families fitted the BRCA1 eligibility criteria. 37 patients belonging to different families were analyzed for BRCA1 germline mutation. All 37 families are Caucasian and principally reside in Tuscany. Mutation screening was done by ASO (allelic specific oligo hybridization) for three common mutations and by direct sequencing of each of the coding exons. The analysis is under way and approximately 50% ofthe coding region has been screened up to now. We have so far identified 7 mutations of which 5 are different. Three are frameshift and 2 missense. Only one of the mutations found has been reported previously (5382insC). The insertion of an A has been reported in three different families, the aplotype analysis has been performed to ascertain if a common ancestor exist for those three families. No evident correlation between phenotype and genotype has been detected. CG and GC are fellows of the Italian Association for Cancer Research. This work was supported by AIRC and CNR PF ACRO grants.

Screening for germline mutations of the p53 gene in familial breast cancer patients

The constitutive DNA from members of four families showing predisposition to breast cancer was amplified by PCR in the region of exons 5, 6, 7 and 8 of the p53 proto-oncogene. Single-strand conformation polymorphism (SSCP) gels were used to compare patient DNA with mutant and wild-type control samples. No cases of anomalous mobility were observed in samples from the susceptible families. The lack of inherited mutations was confirmed for exons 5 and 7 by solid-phase DNA sequencing. The results lend further support to the view that inherited mutations in p53 alleles are not a significant contributor to breast cancer predisposition and it is not, therefore, clinically worthwhile to screen predisposed or potentially predisposed families for germline mutations in the p53 gene.

The expression of aphidicolin-induced fragile sites in familial breast cancer patients

The expression frequency of aphidicolin-induced fragile sites was examined in familial breast cancer patients to determine whether this parameter could be used as a marker of genetic susceptibility in at-risk individuals. No difference was found in expression frequency between the breast cancer patients and a group of normal individuals ( p = 0.61). This indicates that the expression frequency of aphidicolin-induced fragile sites is not a suitable marker for assessing genetic susceptibility in familial breast cancer.

Serum bioactive lactogenic hormone levels in women with familial breast cancer and their relatives

Serum levels of bioactive lactogenic hormone (BLH), immunoreactive prolactin and growth hormone (ir-PRL and ir-GH) were measured in a group of familial breast cancer patients and their first degree female relatives and compared to those found in normal healthy women. The ratio of BLH to the sum of ir-PRL and ir-GH was slightly but significantly decreased in the familial breast cancer group (P = 0.018 by the Mann-Whitney U test) although there were no significant differences in the levels of BLH, ir-PRL and ir-GH between the two groups. No differences in the levels of the lactogenic hormones could be detected when the pre-menopausal women were considered separately or when 20 women from the familial group were compared to normal controls matched for age, parity, weight and menopausal status. The levels of BLH were highly correlated with the sum of ir-PRL and ir-GH in both the familial breast cancer group and the controls (P < 0.001 for both groups by Spearman's rank correlation test). These findings are not indicative of the presence of an additional species of bioactive, but not immunoreactive, lactogen in the sera of women with or at high risk of breast cancer. However, the presence of different, but equipotent, forms of lactogen cannot be excluded in these women.

Familial breast cancer.

Familial breast cancer is important because of all the known risk factors associated with developing the disease. The one with the most predictability is a positive family history. It is also important because a family history causes anxiety in the families concerned, and young women will often ask their chance of developing the disease. This form of breast cancer accounts for 10% of causes and has factors that distinguish it from the sporadic variety. Relatives of familial breast cancer patients are not only at an increased risk of developing the disease (if female) but also of developing other tumours especially colonic.

Bilaterality in familial breast cancer patients

Bilaterality in familial breast cancer patients

Bilaterality in familial breast cancer patients.

The authors conducted this study to determine the probability of a second primary developing in the contralateral breast of a patient, based on her present age, age at her first breast primary, and family history of breast cancer in her mother, sister, or second-degree relative. The study involved 556 patients. With premenopausal diagnosis of the first primary, the probabilities to the 19th year for the three types of family histories ranged from 35% to 38%; with postmenopausal diagnosis, they ranged from 11% to 26%. The probability for all familial patients was 28%. This contrasts with a probability of 13% reported for a general series of patients. An early age at diagnosis and family history of the disease thus have important enhancing effects on the development of second primaries. This information could be useful to physicians in deciding how best to manage the treatment of their patients.