Clinical impact of detection of loss of heterozygosity of BRCA1 and BRCA2 markers in sporadic breast cancer

Beckmann, Matthias W.; Picard, Frauke; An, Heeyoung; Roeyen, Claudia R.C. van; Dominik, S.; Mosny, D. S.; Schnürch, H.-G.; Bender, Hans; Niederacher, Dieter

doi:10.1038/bjc.1996.234

Cited by 104 publications

(67 citation statements)

References 22 publications

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“…Although no link was found between the percentage of LOH at BRCA2 and Scarff-Bloom-Richardson (SBR) histopathological grade (P = 0.42), there was a correlation with the mitotic index, which is one of the three components of the SBR classification (P = 0.017). This was in partial agreement with previous reports of a link between LOH at BRCA2 and SBR histopathological grade III (Beckmann et al, 1996;Kelsell et al, 1996). Univariate analysis of MFS and S (log-rank test) showed no link with BRCA2 status (P = 0.34, P = 0.29 respectively).…”

supporting

confidence: 91%

“…However, aberrant subcellular location (Chen et al, 1995) and reduced expression of BRCAJ (Thompson et al, 1995), together with high frequencies of loss of heterozygosity (LOH) on 17ql2-q21 and 13ql2-ql3 (sites of BRCAI and BRCA2) (Bieche and Lidereau, 1995), point to a significant role of these two genes in the tumorigenesis of sporadic breast cancer, but through a mechanism other than structural mutation. LOH on 13ql2-ql3 occurs in 30-60% of somatic breast tumours (Cleton-Jansen et al, 1995;Kerangueven et al, 1995;Beckmann et al, 1996;Hamann et al, 1996;Kelsell et al, 1996). These (Bignon et al, 1995;Beckmann et al, 1996;Kelsell et al, 1996).…”

mentioning

confidence: 99%

“…LOH on 13ql2-ql3 occurs in 30-60% of somatic breast tumours (Cleton-Jansen et al, 1995;Kerangueven et al, 1995;Beckmann et al, 1996;Hamann et al, 1996;Kelsell et al, 1996). These (Bignon et al, 1995;Beckmann et al, 1996;Kelsell et al, 1996). Recently, in a pilot study, LOH at BRCA2 was found to be an independent prognostic factor (van den Berg et al, 1996).…”

mentioning

confidence: 99%

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Prognostic value of loss of heterozygosity at BRCA2 in human breast carcinoma

Bièche

Noguès²,

Rivoilan³

et al. 1997

Br J Cancer

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Summary To confirm several recent studies pointing to loss of heterozygosity (LOH) at BRCA2 as a prognostic factor in sporadic breast cancer, we examined this genetic alteration in a large series of human primary breast tumours for which long-term patient outcomes were known. LOH at BRCA2 correlated only with low oestrogen and progesterone receptor content. Univariate analysis of metastasis-free survival and overall survival (log-rank test) showed no link with BRCA2 status (P = 0.34, P = 0.29 respectively). LOH at BRCA2 does not therefore appear to be a major prognostic marker in sporadic breast cancer.Keywords: BRCA2; loss of heterozygosity; prognostic value; breast cancer Breast cancer, one of the most common life-threatening diseases in women, occurs in hereditary and sporadic forms. The two major breast cancer susceptibility genes, BRCAI and BRCA2, were recently isolated (Miki et al, 1994;Wooster et al, 1995;Couch et al, 1996). Both are considered to be tumour-suppressor genes and are thought to be inactivated by a 'two-hit' mechanism originally proposed by Knudson to explain the tumorigenesis of retinoblastoma. In hereditary cancer, the first hit would be a germline mutation in a specific cancer gene, whereas in sporadic cancer the first hit would be a somatic mutation or another inactivating molecular event. The second hit would be a loss of the second gene copy in the somatic cell, in both hereditary and sporadic forms. A number of germline mutations in the BRCAJ and BRCA2 genes have been identified in families prone to breast cancer (Shattuck-Eidens et al, 1995;Couch et al, 1996. In sporadic forms, somatic BRCA2 mutations, like somatic mutations in the BRCAJ gene, are rare Miki et al, 1996;Teng et al, 1996). However, aberrant subcellular location (Chen et al, 1995) and reduced expression of BRCAJ (Thompson et al, 1995), together with high frequencies of loss of heterozygosity (LOH) on 17ql2-q21 and 13ql2-ql3 (sites of BRCAI and BRCA2) (Bieche and Lidereau, 1995), point to a significant role of these two genes in the tumorigenesis of sporadic breast cancer, but through a mechanism other than structural mutation. LOH on 13ql2-ql3 occurs in 30-60% of somatic breast tumours (Cleton-Jansen et al, 1995;Kerangueven et al, 1995;Beckmann et al, 1996;Hamann et al, 1996;Kelsell et al, 1996). These LOH studies identified a consensus region of deletion involving BRCA2 and excluding the RB 1 locus. Several studies have pointed to a link between BRCA2 inactivation (mutation and/or LOH) and Scarff, Bloom and Richardson (SBR) histopathological grade 3, in both hereditary and sporadic forms of breast cancer, suggesting the involvement of

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supporting

confidence: 91%

mentioning

confidence: 99%

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Prognostic value of loss of heterozygosity at BRCA2 in human breast carcinoma

Bièche

Noguès²,

Rivoilan³

et al. 1997

Br J Cancer

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“…Only 1 of them (5.5%) showed LOH at the BRCA1 locus, which could be explained either by the presence of an undetected mutation in the gene or by the occurrence of spontaneous LOH for the BRCA1 gene in a case not associated with this gene. Our results suggest that, unlike the sporadic cases, in which the rate of LOH for the BRCA1 locus is at least 30%, 8,12,13,24,25 in the familial cases not associated with the BRCA genes, the occurrence of LOH was very uncommon, confirming the idea of different mechanisms of tumorigenesis.…”

Section: Discussionsupporting

confidence: 71%

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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“…It is well established that the frequency of loss of heterozygosity at the BRCA2 locus increases in histologic grade III tumors compared to grade I and II tumors. 30 Thus, if loss of heterozygosity plays an important role in the downregulation of BRCA2 mRNA levels, BRCA2 mRNA levels in histologic grade III tumors should be lower than those in grade I and II tumors. However, we found that BRCA2 mRNA levels in histologic grade III tumors were significantly higher than those in grade I and II tumors.…”

Section: Discussionmentioning

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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Clinical impact of detection of loss of heterozygosity of BRCA1 and BRCA2 markers in sporadic breast cancer

Abstract: Summary The development of familial and sporadic breast cancer is based on genetic alterations of tumoursuppressor genes, for which loss of heterozygosity (LOH) is one mechanism of gene inactivation.

Cited by 104 publications

References 22 publications

Prognostic value of loss of heterozygosity at BRCA2 in human breast carcinoma

Prognostic value of loss of heterozygosity at BRCA2 in human breast carcinoma

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

High BRCA2 mRNA expression predicts poor prognosis in breast cancer patients

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