Loss of Heterozygosity in Bilateral Breast Cancer

Kollias, James; Man, S.; Marafie, Makia J.; Carpenter, K.; Pinder, Sarah; Ellis, Ian O.; Blamey, R. W.; Cross, Gareth; Brook, David

doi:10.1023/a:1026575619155

Cited by 36 publications

(28 citation statements)

References 31 publications

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“…Thus, in germline mutation carriers, tumor progression depends on loss of the wild-type allele, often molecularly detectable as loss of heterozygosity (LOH) 17,18 . However, LOH at the BRCA1 and BRCA2 loci has been detected in 20% and 70% of sporadic breast and ovarian cancers respectively, leaving open the possibility that these two susceptibility genes could be involved in a proportion of breast cancer in non-mutation carriers [17][18][19][20][21] . In this study we evaluated the distribution of molecular subtypes of breast tumors in a group of very young Brazilian women using an immunohistochemical panel of biomarkers on tissue microarray (TMA) to address the frequency of basallike carcinomas among this special group of women with breast cancer.…”

Section: Artigo Original Introductionmentioning

confidence: 99%

Molecular characterization of breast cancer in young Brazilian women

Carvalho¹,

Pereira²,

Frappart³

et al. 2010

Rev. Assoc. Med. Bras.

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SummaryObjective. To evaluate the distribution of molecular subtypes of breast tumors diagnosed in young Brazilian women and to analyze the frequency of loss of heterozygocity (LOH) in BRCA1 among different molecular subtypes of early-onset breast cancer. MethOds. Samples from 72 cases of invasive breast carcinoma diagnosed in women aged between 19 and 40 years were evaluated using an immunohistochemical panel of biomarkers. Three intragenic BRCA1 locus microsatellites, D17S1322, D17S1323, and D17S855, were PCR amplified from matched normal (lymphocyte) and tumor DNAs for (LOH) analysis. Results. We found 13 cases (18%) that had an immunohistochemical profile consistent with being basal-like. Forty cases (55%) were luminal A type; 11% (8 cases) were luminal B type, 13% (9 cases) were HER2-overexpressing tumors and two cases were ER-/HER2-carcinomas lacking basal marker expression. Four of the 16 informative cases at D17S1322, one of the four informative cases at D17S855, and none of the five informative cases at D17S1323 displayed LOH (four basal-like and one Luminal A). Microsatellite instability (MSI) at D17S855 and D17S1322 was found in two cases (one a basal-like and one Luminal A). cOnclusiOn. In our study, basal-like tumor was the second most frequent molecular type among young Brazilian women and was only observed in women diagnosed under the age of 35 years. There was no significant difference of LOH at BRCA1 locus rates between basal-like breast tumors and not-basal-like breast tumors (p=0.62). LOH in BRCA1 and MSI in these breast cancers were not frequent but may indicate a small group of breast cancers with a specific molecular makeup.

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Section: Artigo Original Introductionmentioning

confidence: 99%

Molecular characterization of breast cancer in young Brazilian women

Carvalho¹,

Pereira²,

Frappart³

et al. 2010

Rev. Assoc. Med. Bras.

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“…15 Accumulating literature presents contradicting results. 11,[17][18][19][20][21][22][23][24][25] Some authors have demonstrated similarity in histologic subtype, 12,23 tumor grade, 17 and hormone receptor status 16,18 between the two tumors, suggesting a single-cell origin, whereas others had different results. 25 In addition, similar mammographic appearance may be seen in bilateral breast carcinomas with a mirror image location.…”

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confidence: 99%

“…26,27 Neither clinical nor histopathologic features can definitively determine the relationship between multiple deposits of breast cancer at the individual patient level with certainty. Using molecular techniques, few studies showed the presence of similarities in bilateral breast cancer, indicating that these carcinomas may result from a metastatic event, 11,24 while other investigators present evidence for the independent pathogenesis in majority of these tumors. 16,[19][20][21][22]25 This controversy reflects the lack of a definitive methodology to distinguish de novo primary from metastatic tumor deposition.…”

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confidence: 99%

Diagnostic and Prognostic Utility of Molecular Markers in Synchronous Bilateral Breast Carcinoma

et al. 2008

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Histologic criteria have a limited role in determining whether the synchronous bilateral breast carcinomas represent two primaries or a metastasis to the contralateral breast. We studied the molecular analysis of synchronous bilateral breast carcinoma and whether they are originating from a single or different clone. We examined 17 patients with breast carcinoma, including 12 patients with synchronous bilateral carcinomas and control group of 5 infiltrating ductal carcinomas with regional lymph node metastases. Mutations were quantitatively determined to detect loss of heterozygosity (LOH) and microsatellite size alterations for a broad panel of 15 markers, involving 10 chromosomes using polymerase chain reaction. The carcinomas were classified as de novo or metastasis based on three levels of concordance: (1) marker-affected tumors were considered concordant if 50% or more of the same markers were mutated, (2) same gene copy affected, and (3) temporal sequence of mutation acquisition. In synchronous bilateral breast carcinoma patients, molecular analysis showed discordant mutations in all cases, supporting the diagnosis of de novo bilateral primary breast carcinomas. In patients with lymph node metastases, the primary breast carcinoma and metastases shared the same mutations, revealing a metastatic lesion. In conclusion, the application of molecular technology may play an important role for the differential diagnosis of dual primary carcinomas vs a metastatic breast cancer to contralateral breast. In this study, synchronous bilateral breast cancers represent two independent primaries rather than metastatic events. Keywords: synchronous bilateral breast carcinoma; molecular pathology; LOH Contralateral breast carcinoma is the most common second malignancy for breast carcinoma patients, with an incidence as high as 12%.1-3 Bilateral breast carcinomas exist in two forms, synchronous, in which both tumors occur at the same time, or metachronous, in which the carcinomas occur at different times. Synchronous bilateral breast carcinoma is uncommon, reported to range from 0.3 to 8% in the literature. [4][5][6][7] This wide range of reported incidence rates for synchronous bilateral breast carcinoma is a result of different time cutoff. Although some authors require both breast carcinomas to be diagnosed simultaneously or within less than 1 month, 7-10 others used up to 12 months as a cutoff time to differentiate synchronous from metachronous bilateral breast carcinomas.11-13 Using criteria of less than 1 month, the incidence of synchronous bilateral breast is less than 2%. 7,14 When cancer is detected in the opposite breast, the question arises whether this tumor is a second cancer (polyclonal origin) or a metastatic spread from the first breast cancer (monoclonal origin). The answer to this question is critical as both tumor staging and management will be different depending upon the results.11 Currently, this distinction is attempted using histopathologic features. Different histologic types, a better histologic diff...

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“…Six years ago, the human breast cancer susceptibility gene Brca2 was identified [22,23]. After sequencing the full-length cDNA, many reports described mutational analyses of the gene in families and in primary tumors [7,9,19]. The Brca2 gene consists of 27 exons, which encode an 11-to 12-kb transcript.…”

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confidence: 99%

Cloning and Sequencing Full Length of Canine Brca2 and Rad51 cDNA.

et al. 2001

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ABSTRACT. Mammary tumors are the most common neoplasm in female dogs, Canis canis, and in women. Mutations in human Brca2 confer an increased risk of female breast cancer. Previous studies have shown that the Brca2 tumor suppressor protein interacts with the recombinational repair protein Rad51. We cloned the full-length cDNA of the canine homologues of Brca2 and Rad51 to obtain a basis for studying their relationship with susceptibility to mammary tumors. The canine Brca2 and Rad51 cDNAs are 11 and 1.5 kb long, encoding 3,471 and 339 amino acids, respectively. The amino acid sequence of canine Brca2 showed 68% homology with the human protein, and 58% homology with a murine protein. There were highly conserved regions in the C-terminus of all three proteins, where the Rad51 interacting domain and putative nuclear localization signals are located. Comparing with the partial genomic sequence previously reported, we found possible nuclear polymorphisms in exon 11, some of which result in amino acid substitutions. On the other hand, canine Rad51 protein had extremely high homology (99%) to the human and murine proteins. Expression of both Brca2 and Rad51 was detected in the mammary gland, suggesting that these two genes interact in the canine mammary gland. KEY WORDS: Brca2, genetic instability, mammary tumor, Rad51, tumor suppressor gene.

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Loss of Heterozygosity in Bilateral Breast Cancer

Cited by 36 publications

References 31 publications

Molecular characterization of breast cancer in young Brazilian women

Molecular characterization of breast cancer in young Brazilian women

Diagnostic and Prognostic Utility of Molecular Markers in Synchronous Bilateral Breast Carcinoma

Cloning and Sequencing Full Length of Canine Brca2 and Rad51 cDNA.

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