Phenotypic expression of double heterozygosity for BRCA1 and BRCA2 germline mutations

Leegte, B; Hout, AH van der; Deffenbaugh, AM; Bakker, Marian K.; Mulder, IM; Berge, A ten; Leenders, EP; Wesseling, Jelle; Hullu, Joanne de; Hoogerbrugge, Nicoline; Ligtenberg, M. J. L.; Ardern‐Jones, Audrey; Bancroft, Elizabeth; Salmon, Asher; Barwell, Julian; Eeles, Rosalind; Oosterwijk, Jan C.

doi:10.1136/jmg.2004.027243

Cited by 58 publications

(74 citation statements)

References 31 publications

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“…These mutations are associated with a dramatically increased lifetime risk of breast and ovarian carcinoma with an early manifestation [2,3]. Approximately 10% of breast cancers and >30% of ovarian cancers in Ashkenazi Jewish women are the result of genetic predisposition due to germline mutations in the BRCA1 and BRCA2 genes [1,3] While sporadic case reports of women with double mutations in both BRCA1 and BRCA2 are available [4][5][6][7], none came from systematic carriers series or from population-based studies. This study describes the frequency and characteristics of people heterozygote to more than one founder mutation in BRCA1 and BRCA2.…”

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confidence: 99%

Double heterozygosity in the BRCA1 and BRCA2 genes in the Jewish population

et al. 2011

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Background: The frequency and characteristics of disease in individuals who concomitantly harbor pathogenic mutations in both BRCA1 and BRCA2 genes are not established.Materials and methods: Data were collected from the database of Clalit Health Services National Familial Cancer Consultation Service. Probands referred to this clinical service and their family members are routinely tested for the three Jewish founder mutations (BRCA1:185delAG, 5382insC, BRCA2:6174delT). In addition, carriers identified in a population-based cohort of all cases diagnosed with breast cancer in Israel in 1987-1988 allowed the estimation of the population frequency of this phenomenon.Results: In the clinic-based series of 1191 carriers of mutations in BRCA1 or BRCA2 belonging to 567 families, 22 males and females (1.85%) from 17 different families (3.0%) were found to harbor two different mutations. These included 18 individuals (1.51%) who concomitantly carried the 185delAG BRCA1 and the 6174delT BRCA2 mutations and four individuals (0.34%) who carried the 5382insC BRCA1 and the 6174delT mutations. All individuals were heterozygote carriers and none had a double mutation of both founder mutations in the BRCA1 gene itself. Seven of the 16 double carrier women (46.7%) had a personal history of breast carcinoma, diagnosed at a mean age of 44.6, compared with 372/926 (40.2%) carriers of a single mutation diagnosed with a mean age at diagnosis of 48.1 [odds ratio (OR) = 1.3, 95% confidence interval (CI) 0.4-4.0]. One case (6.7%) had a personal history of ovarian carcinoma diagnosed at the age of 53 compared with 55/926 (5.9%) of the women with single mutation (OR = 1.1, CI = 0.2-7.6). The frequency of double mutations in the population-based national breast cancer cohort was 2.2% of all carriers, and 0.3% of all breast cancer cases in the Ashkenazi population in the cohort. The mean age at diagnosis of breast cancer was younger in the carriers of two mutations.Conclusion: Double carriers of mutations in the BRCA genes are rare and seem to be carrying a similar probability of developing breast and ovarian cancers as carriers of single mutations.

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Double heterozygosity in the BRCA1 and BRCA2 genes in the Jewish population

et al. 2011

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“…Indeed, BRCA1 NT_5382insC has been reported in DH very few times [10,18] showing biallelic inactivation of either BRCA1 or BRCA2 thus suggesting that these genetic events are functionally equivalent in initiating tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

“…By reviewing published data about Ashkenazi Jewish descent, Leegte et al [10] analyzes 4 cases of double heterozygosity and reviews 30 cases reported in literature in order to assess phenotypic expression with respect to age of onset, cumulative lifetime risk and multiple primary tumors. The phenotypic expression in this small series of 34 female cases of DH appeared to be highly variable, however, analyzing the cancer incidence in DH at age 70 he reported a value of 80% for breast cancer and 84% for breast and ovarian.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, analyzing both maternal and paternal lineages we evidenced that the two germinal mutations were respectively inherited one by the mother and one by the father. The double heterozygosity is the presence of pathological mutations in both BRCA1 and BRCA2 genes in the same subject and it is an extremely rare event mostly shown in Ashkenazi Jewish [10]. The BRCA1 NT_5382insC is the most common mutation in Caucasian population from Puglia [1] and in Askenazi in which accounted for 26 (10.1%) of all the BRCA1 founder mutations, appearing in 60% of ovarian cancer and 30% of breast cancer in Ashkenazi population [11].…”

Section: Discussionmentioning

confidence: 99%

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Maternal and paternal lineage double heterozygosity alteration in familial breast cancer: a first case report

Pilato¹,

Summa²,

Danza³

et al. 2010

Breast Cancer Res Treat

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Hereditary breast cancer syndrome was firstly associated with BRCA1 and BRCA2 genes whose mutations confer high risk to develop breast and/or ovarian cancer. Double heterozygosity is a rare condition in which both BRCA1 and BRCA2 mutations are present in a family at the same time.In the current study, a family with double heterozygosity has been reported. Furthermore, for the first time a molecular analysis in both proband lineages, maternal and paternal, has been reported to understand the provenience of both germinal mutations.The case regards a woman that developed breast and ovarian cancer with liver metastasis which presented two mutations, each in the two genes, transmitted from her mother and her father respectively. In this family all available members have been investigated. The concomitantly presence of these peculiar mutations was never reported before suggesting a link with Caucasian population from Southern Italy.

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“…In 2005, Leegte et al 5) presented four double heterozygosity cases and reviewed all published data. Approximately 34 cases with double heterozygosity from 25 different families were included in this report.…”

Section: Discussionmentioning

confidence: 99%

Risk Reducing Surgery in Carriers with Double Heterozygosity for BRCA1 and BRCA2 Mutations

et al. 2012

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cancers, and family history among multiple generations. The prognosis of BRCA associated breast cancer is uncertain. It has been suggested that the prognosis is similar to that of sporadic breast cancer, while others have opined that the prognosis of BRCA asso ciated breast cancer is worse than sporadic cancer. Among the treatment options for BRCA mutation carriers, risk reducing surgery is the most effective. However, this procedure has been rarely performed in Korea. Interestingly, our case showed double heterozygosity for BRCA1 and BRCA2 mutations. The patient was diagnosed with left renal cancer and left breast cancer at 45-years-of-age, 4 years before risk reducing surgery. The patient received left radical nephrectomy and left partial mastectomy with axillary lymph node dissection. After pretest counseling, the patient underwent genetic testing that identified BRCA1 and BRCA2 mutations. After post-test counseling, the patient decided on intensive surveillance. At 49-years-of-age, the patient was newly diagnosed with contralateral breast cancer. Treatment options were discussed once again. We performed bilateral total mastectomy with immediate reconstruction and prophylactic bilateral salpingo-oophorectomy after multidisciplinary discussion. The patient has been satisfied with the results of surgery. We think this procedure is a recommendable treatment option for BRCA mutation carriers.

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Phenotypic expression of double heterozygosity for BRCA1 and BRCA2 germline mutations

Cited by 58 publications

References 31 publications

Double heterozygosity in the BRCA1 and BRCA2 genes in the Jewish population

Double heterozygosity in the BRCA1 and BRCA2 genes in the Jewish population

Maternal and paternal lineage double heterozygosity alteration in familial breast cancer: a first case report

Risk Reducing Surgery in Carriers with Double Heterozygosity for BRCA1 and BRCA2 Mutations

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