Mutations of the BRCA1 and BRCA2 genes in patients with bilateral breast cancer

Steinmann, Diana; Bremer, Michael; Rades, Dirk; Skawran, Britta; Siebrands, Cornelia C.; Karstens, Johann H.; Dörk, Thilo

doi:10.1054/bjoc.2001.2016

Cited by 43 publications

(38 citation statements)

References 42 publications

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“…The literature is not unanimous about the predictive value of multiple primary (ipsilateral or contralateral) breast cancers for finding a mutation. Our results are in agreement with the studies of Bergthorsson et al (2001), de la Hoya et al (2002 and Ford et al (1998); however, others failed to demonstrate such a predictive value (Couch et al, 1997;Steinmann et al, 2001). Male breast cancer in combination with a family history of breast/ovarian cancer was indicative of finding a BRCA2 mutation (P ¼ 0.002), which is consistent with a recent population-based British study (Basham et al, 2002).…”

Section: Discussionsupporting

confidence: 93%

BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families

et al. 2004

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Worldwide variation in the distribution of BRCA1 and BRCA2 mutations is well recognised, and for the Belgian population no comprehensive studies about BRCA1/2 mutation spectra or frequencies have been published. We screened the complete coding region of both genes in 451 individuals from 349 Belgian families referred to a family cancer clinic and identified 49 families with a BRCA1 and 26 families with a BRCA2 mutation. Six major recurrent mutations (BRCA1 IVS5 þ 3A4G, 2478 -2479insG, E1221X and BRCA2 IVS6 þ 1G4A, 6503-6504delTT, 9132delC) accounted for nearly 60% of all mutations identified. Besides 75 true pathogenic mutations, we identified several variants of unknown clinical significance. In combination with a family history, an early average age of female breast cancer diagnosis (Po0.001), and the presence of a relative with ovarian cancer (Po0.0001) or multiple primary breast cancers (P ¼ 0.002), increased the chance for finding a mutation. Male breast cancer was indicative of a BRCA2 mutation segregating in the family (P ¼ 0.002). Mutations in the 5 0 -end of BRCA1 and BRCA2 were associated with a significantly increased risk for ovarian cancer relative to the central portion of the gene. Our study suggests a role for additional breast cancer susceptibility genes in the Belgian population, since mutation detection ratios were low in high-risk breast cancer-only families as compared to breast -ovarian cancer families. Given the large proportion of recurring mutations, molecular testing can now be organised in a more cost-effective way. Our data allow optimisation of genetic counselling and disease prevention in Belgian breast/ovarian cancer families. Since the mapping and the cloning of two genes that confer susceptibility to both breast and ovarian cancer, BRCA1 and BRCA2 (Miki et al, 1994;Wooster et al, 1995;Tavtigian et al, 1996), it became possible to offer genetic testing to families with a predisposition for breast and/or ovarian cancer. Consequently, individuals at risk can now be identified as candidates for surveillance programmes. A large number of distinct mutations in the BRCA1 and BRCA2 genes have been reported worldwide, but population-specific variation in the distribution of BRCA1/2 mutations is well recognised. In some populations or ethnic groups, founder mutations form a sufficient proportion of the total to justify the adoption of specific molecular screening strategies.To date, no comprehensive studies in the Belgian population have been published. Only data from small series are available (Claes et al, 1999a, b) or from studies in which the analysis was restricted to a few BRCA1/2 exons or to BRCA1 only Sibille-Hoang et al, 1998;Goelen et al, 1999). We performed mutation screening of the complete coding region of BRCA1 and BRCA2 in 349 unrelated Belgian families referred to our family cancer clinic and report here the nature and distribution of the mutations identified. We found phenotypic differences between families in whom a disease-causing mutation was identified vs BRCA1/2 muta...

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Section: Discussionsupporting

confidence: 93%

BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families

et al. 2004

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“…More surprisingly, the bilateral breast cancer sub-group showed a lower frequency of detected BRCA1 mutations (10%). It has been demonstrated that patients with hereditary breast cancer have a higher risk of contralateral breast cancer (Steinmann et al 2001). However, the number of bilateral cases (n=10) screened in our work was probably insufficient compared with those observed in other studies.…”

Section: Discussionmentioning

confidence: 61%

“…In addition, it has been demonstrated that patients with hereditary breast cancer have a higher risk of developing contralateral breast cancer (Steinmann et al 2001). Fortunately, different strategies for reducing this risk are available, including oophorectomy, mastectomy and chemoprevention (Narod et al 2000).…”

Section: Introductionmentioning

confidence: 99%

A mutation analysis of the BRCA1 gene in 140 families from southeast France with a history of breast and/or ovarian cancer

et al. 2003

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A mutation analysis of the BRCA1 gene in 140 French families with a history of breast cancer or breastovarian cancer revealed several deleterious germline mutations, as well as rare sequence variants. The 19 genetics variants were of 15 different types, two of which had not been reported in the Breast cancer Information Core (BIC) database. Five distinct truncating mutations, leading to putative nonfunctional proteins, were identified out of 140 index cases (3.5%). One novel nonsense mutation, C4491T, was reported, whereas the four other BRCA1 deleterious mutations identified consisted of frequent frameshifts in the nucleotide sequence. One splice variant (331+3A>G) and thirteen missense variations leading to amino acid substitutions of unknown structural and functional importance were identified. Among these, two BRCA1 missense mutations, A120G and T243C could be considered as suspected deleterious. The first missense mutation modified the initiation codon (M1V) and the second (C39R) may have consequences on the structure and functioning of the BRCA1 protein by modifying cysteine ligands from the RING finger domain. As expected BRCA1 gene alteration, including missense mutations of unknown biological significance, were more frequent in families with a history of breast-ovariancancer (32%) than in breast-cancer-only families (12%).

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“…The clinical history of our patients provided no evidence to suggest that our series might include cases of familial breast cancer, and the high mean age of our patients supports this assumption. Bilaterality does not necessarily reflect a genetic predisposition, 44 unless it is associated with an early age of onset 45 Tumor allelotyping is considered a powerful method for examining the clonal origin of multiple malignancies. [46][47][48] Allelotyping provides a single tumor-specific 'cytogenetic fingerprint' with a high, but limited, number of molecular markers investigated.…”

Section: Discussionmentioning

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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Mutations of the BRCA1 and BRCA2 genes in patients with bilateral breast cancer

Cited by 43 publications

References 42 publications

BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families

BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families

A mutation analysis of the BRCA1 gene in 140 families from southeast France with a history of breast and/or ovarian cancer

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

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