Molecular analysis of the BRCA1 and BRCA2 genes in 32 breast and/or ovarian cancer Spanish families

Osorio, Ana; Barroso, Alicia; Martínez, Beatriz Fernández; Cebrián, A; Román, J.M. San; Lobo, Francisco; Robledo, Mercedes; Benı́tez, Javier

doi:10.1054/bjoc.1999.1089

Cited by 79 publications

(84 citation statements)

References 16 publications

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“…Concerning the 3 cases in which we detected positive LOH in the tumors (2 of them members of the same family and both affeceted by ovarian and bilateral breast cancer), all were carriers of the same variant, G1706E in BRCA1, which was highly suspicious of being deleterious because of the type of amino acid change, its segregation with the disease in one of the families, its absence in a control population of 100 individuals 14 and its location in the BRCA1 trans-activating domain. 20 Loss of the wild-type allele detected for this variant, showing the same behavior as a deleterious mutation, confirmed our suspicions and was easily interpreted.…”

Section: Discussionmentioning

confidence: 90%

“…Mutational screening has been described previously. 14,15 Tumor selection and DNA extraction In 2 cases, frozen tumor samples were available, but in the remaining 45 cases material was obtained from paraffin-embedded tissues selected from the files of the Department of Pathology of Fundación Jiménez Díaz and San Carlos University Hospital. Selection of an appropriate block was made after a complete optical and immunophenotypic study.…”

Section: Brca1/2 Screeningmentioning

confidence: 99%

“…1b). This variant was highly suspicious of representing a deleterious mutation for several reasons: (i) it resulted in the substitution of a small hydrophobic amino acid by a hydrophilic one and it was localized in the COOH terminal region of the gene, which is highly conserved and supposed to be functionally important; 21 (ii) we had performed a study in a control population of 100 individuals in whom the variant was not detected; 14 and (iii) in 1 of the 2 families in which the variant was detected, we could confirm its segregation with the disease (Fig. 2).…”

Section: Unclassified Variantsmentioning

confidence: 99%

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Loss of heterozygosity analysis at the BRCA loci in tumor samples from patients with familial breast cancer

Osorio

Hoya

Rodríguez‐López

et al. 2002

Intl Journal of Cancer

108

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The BRCA1 and BRCA2 genes are responsible for a high proportion of familial breast cancer; germline mutations in these genes confer a lifetime risk of about 70% for developing breast cancer. Most of the described deleterious mutations are small deletions or insertions that originate a truncated protein; however, in many cases, they are amino acid changes whose significance is unknown. In these cases, there are some tests that can analyze the meaning of these variants, but most remain unclassified. The BRCA genes are tumor supressors and it is beleived that complete loss of the wild-type allele is a common mechanism of inactivation in tumors from patients carrying a germline deleterious mutation in these genes; if this is true, loss of heterozygosity (LOH) analysis in the tumor sample could help to distinguish if a rare variant is either a deleterious mutation or a common polymorphism. In the present study, we performed LOH analysis at the BRCA loci in 47 tumors from patients who belonged to highrisk breast cancer families and were carriers of any type of alteration in these genes. Our results suggest that (i) loss of the wild-type allele is the most common mechanism of inactivation in tumors from patients who carry a deleterious mutation in any of the genes, (ii) this loss is not common when we analyze familial tumors not associated with mutations in BRCA and (iii) LOH can be used to clarify variants of unknown significance in the BRCA genes.

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Section: Discussionmentioning

confidence: 90%

Section: Brca1/2 Screeningmentioning

confidence: 99%

Section: Unclassified Variantsmentioning

confidence: 99%

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Loss of heterozygosity analysis at the BRCA loci in tumor samples from patients with familial breast cancer

Osorio

Hoya

Rodríguez‐López

et al. 2002

Intl Journal of Cancer

108

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“…These breast cancer samples were selected from families with at least three women affected with breast and/or ovarian cancer and at least one of them diagnosed before 50 years of age, or from families with female breast and/or ovarian cancer and at least one case of male breast cancer. All cases were studied for mutations and large rearrangements in the BRCA genes using standard procedures (Osorio et al, 2000;Diez et al, 2003). A total of 18 cases had mutations in the BRCA1 gene, 16 patients presented mutations in the BRCA2 gene and 28 cases were negative for germ-line mutations in the BRCA genes (non-BRCA1/2 or BRCAX).…”

Section: Tumor Samples and Patientsmentioning

confidence: 99%

Distinct genomic aberration patterns are found in familial breast cancer associated with different immunohistochemical subtypes

et al. 2007

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Five breast cancer subtypes have been described in sporadic breast cancer (SBC) using expression arrays: basal-like, ERBB2, normal breast-like, luminal A and B. These molecular subtypes show different genomic aberration patterns (GAPs). Recently, our group described these breast cancer subtypes in 50 non-BRCA1/2 familial tumors using immunohistochemistry assays. We extended this study to the other classes of familial breast cancer (FBC), including 62 tumors (18 BRCA1, 16 BRCA2 and 28 non-BRCA1/2), with the same panel of 25 immunohistochemical (IHC) markers and histological grade obtaining a similar classification. We combined these data with results generated by a 1 Mb BAC array-based CGH study to evaluate the genomic aberrations of each group. We found that BRCA1-related tumors are preferentially basal-like, whereas non-BRCA1/2 familial tumors are mainly luminal A subtype. We described distinct GAPs related to each IHC subtype. Basal tumors had a greater number of gains/losses, while luminal B tumors had more high-level DNA amplifications. Our data are similar to those obtained in SBC studies, highlighting the existence of distinct genetic pathways of tumor evolution, common to both SBC and FBC.

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“…[1][2][3][4] BRCA1 and BRCA2 are typical tumor-suppressor genes and loss of a wild-type allele has been reported in almost all breast tumors arising in BRCA1 or BRCA2 germline mutation carriers. 5,6 Although the function of these genes remains to be established, both have been implicated in the repair of double-stranded DNA breaks in cooperation with Rad51 as well as in regulation of the G 2 -M checkpoint.…”

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confidence: 99%

High BRCA2 mRNA expression predicts poor prognosis in breast cancer patients

Egawa

Miyoshi

Taguchi

et al. 2002

Intl Journal of Cancer

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The prognostic significance of BRCA 2 mRNA levels in tumor tissues was studied in sporadic breast cancer patients. BRCA 2 mRNA levels were determined by real-time PCR. Histologic grade III tumors showed significantly (p ‫؍‬ 0.001) higher BRCA 2 mRNA levels (0.828 ؎ 0.102 BRCA 2/␤-glucuronidase mRNA ratio, mean ؎ SE) than histologic grade I and II tumors (0.438 ؎ 0.055) and estrogen receptor (ER)-negative tumors (0.773 ؎ 0.102) showed a nonsignificant (p ‫؍‬ 0.072) trend toward an increase in BRCA 2 mRNA levels compared to ER-positive tumors (0.541 ؎ 0.079). Other clinicopathologic parameters, such as menopausal status, lymph node status and tumor size, were not significantly associated with BRCA 2 mRNA levels. Patients with high BRCA 2 mRNA levels showed a significantly (p ‫؍‬ 0.006) lower 5-year disease free survival rate (63%) than those with low levels (94%). Lymph node metastases, ER negativity and high histologic grade were also significantly (p < 0.05) associated with poor prognosis. Multivariate analysis revealed that BRCA 2 mRNA levels were a significant prognostic factor, being independent of the other conventional prognostic factors. Our results suggest that BRCA 2 mRNA levels might serve as a clinically useful prognostic factor in breast cancer patients. © 2002 Wiley-Liss, Inc. Key words: breast cancer; BRCA2; prognosis; ER; histologic grade BRCA1 and BRCA2 are the well-established breast cancer susceptibility genes and germline mutations of these genes are found in 20 -30% of breast cancer families. 1-4 BRCA1 and BRCA2 are typical tumor-suppressor genes and loss of a wild-type allele has been reported in almost all breast tumors arising in BRCA1 or BRCA2 germline mutation carriers. 5,6 Although the function of these genes remains to be established, both have been implicated in the repair of double-stranded DNA breaks in cooperation with Rad51 as well as in regulation of the G 2 -M checkpoint. 7 In addition, the ubiquitin ligase activity of the BRCA1-BARD1 complex has been described. 8 Somatic mutations of BRCA1 and BRCA2 appear to be very rare, 9 -12 but loss of heterozygosity of BRCA1 and BRCA2 is frequently observed, suggesting involvement of these genes in the pathogenesis of sporadic breast cancers. BRCA1 mRNA levels are downregulated in sporadic breast cancers compared to normal breast tissues and hypermethylation of the promoter region of BRCA1 explains this downregulation in some cases. 13,14 However, BRCA2 mRNA levels do not show a consistent tendency and are both upregulated and downregulated among sporadic breast cancers. 15 Unlike BRCA1, the promoter region of BRCA2 is not hypermethylated. 16 Thus, the contributions of BRCA1 and BRCA2 to the pathogenesis of sporadic breast cancers might be different.Downregulation of BRCA1 mRNA and protein levels is associated with an aggressive phenotype of sporadic breast cancers 17,18 and poor prognosis. 19 In contrast, Bieche et al. 15 reported that high BRCA2 mRNA levels are associated with an aggressive phenotype of sporadic breast cancer. We have...

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Molecular analysis of the BRCA1 and BRCA2 genes in 32 breast and/or ovarian cancer Spanish families

Cited by 79 publications

References 16 publications

Loss of heterozygosity analysis at the BRCA loci in tumor samples from patients with familial breast cancer

Loss of heterozygosity analysis at the BRCA loci in tumor samples from patients with familial breast cancer

Distinct genomic aberration patterns are found in familial breast cancer associated with different immunohistochemical subtypes

High BRCA2 mRNA expression predicts poor prognosis in breast cancer patients

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