The Icelandic founder mutation BRCA2 999del5: analysis of expression

Mikaelsdottir, Evgenia; Valgeirsdóttir, Sigrı́dur; Eyfjörd, Jórunn E.; Rafnar, Thorunn

doi:10.1186/bcr785

Cited by 42 publications

(28 citation statements)

References 21 publications

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“…In this study BRCA2 mutations were more frequent than BRCA1 mutations, although it should be taken into account that a high proportion of families are carrying the BRCA2 c.8764_8765delAG founder mutation. Mutations in BRCA2 gene have been detected in up to 40% of male breast cancers in Iceland [39]; in our isolated population, we detected a BRCA2 mutation in 1/14 (7%) men with breast cancer with a frequency similar to that reported for male breast cancers in USA (4%) [40]. Again, these findings suggest that other environmental and/or genetic factors are contributing to the susceptibility to male breast cancer in Sardinia.…”

Section: Discussionsupporting

confidence: 81%

A role of BRCA1 and BRCA2germline mutations in breast cancer susceptibility within Sardinian population

Palomba

Loi

Uras³

et al. 2009

BMC Cancer

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BackgroundIn recent years, numerous studies have assessed the prevalence of germline mutations in BRCA1 and BRCA2 genes in various cohorts. We here extensively investigated the prevalence and geographical distribution of BRCA1-2 mutations in the entire genetically-homogeneous Sardinian population. The occurrence of phenotypic characteristics which may be predictive for the presence of BRCA1-2 germline mutations was also evaluated.MethodsThree hundred and forty-eight breast cancer patients presenting a familial recurrence of invasive breast or ovarian carcinoma with at least two affected family members were screened for BRCA1-2 mutations by DHPLC analysis and DNA sequencing. Association of BRCA1 and BRCA2 mutational status with clinical and pathological parameters was evaluated by Pearson's Chi-Squared test.Results and ConclusionOverall, 8 BRCA1 and 5 BRCA2 deleterious mutations were detected in 35/348 (10%) families; majority (23/35;66%) of mutations was found in BRCA2 gene. The geographical distribution of BRCA1-2 mutations was related to three specific large areas of Sardinia, reflecting its ancient history: a) the Northern area, linguistically different from the rest of the island (where a BRCA2 c.8764_8765delAG mutation with founder effect was predominant); b) the Middle area, land of the ancient Sardinian population (where BRCA2 mutations are still more common than BRCA1 mutations); and c) the South-Western area, with many Phoenician and Carthaginian locations (where BRCA1 mutations are prevalent). We also found that phenotypic features such as high tumor grading and lack of expression of estrogen/progesterone receptors together with age at diagnosis and presence of ovarian cancer in the family may be predictive for the presence of BRCA1-2 germline mutations.

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Section: Discussionsupporting

confidence: 81%

A role of BRCA1 and BRCA2germline mutations in breast cancer susceptibility within Sardinian population

Palomba

Loi

Uras³

et al. 2009

BMC Cancer

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“…These mutations first occurred as common ancestors in a specific group of people and then spread as the population expanded, eg, the BRCA1 185delAG and 5382insC mutations and BRCA2 6174delT mutation in the Jewish population, 27 the BRCA2 999del5 mutation in the Icelandic population, 28 the BRCA1 R71G mutation in the Spanish population, 29 , 30 the BRCA1 4184del4 and BRCA2 2157delG mutations in the English population, 31 and the BRCA2 S2834X and 5802del4 mutations in the Japanese population. 32 In mutation screening of these populations, screening for founder mutations should be done first.…”

Section: Brca1 and Brca2mentioning

confidence: 99%

Hereditary Breast Cancer in the Han Chinese Population

Cao

Wang

2013

Journal of Epidemiology

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Breast cancer is the most common malignancy among women and has a strong genetic background. So far, 13 breast cancer susceptibility genes of high or moderate penetrance have been identified. This review summarizes findings on these genes in Han Chinese. BRCA1 and BRCA2 are the 2 most important susceptibility genes. They have a relatively low mutation rate, and the most frequent sites of mutation are in exon 11. Frameshift mutations are the main type of mutation. Founder mutations may also exist, and BRCA-associated breast cancer has specific clinicopathologic characteristics. TP53 and PALB2 are relatively rare susceptibility genes. The relationship between the other 9 genes and breast cancer has not been fully elucidated. At present, the mutation spectrum for these susceptibility genes is not well understood in the Chinese population, and there are few reports on prognosis and clinical intervention in high-risk populations. Therefore, the true value of genetic counseling for breast cancer has yet to be realized. This article reviews studies of hereditary breast cancer in the Han Chinese population, highlights potential inadequacies, and provides a foundation for genetic counseling for breast cancer in China.

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“…Class 1 mutations include loss of function mutations caused by reduced transcript and protein levels due to nonsense-mediated decay (NMD) and/or degradation or instability of truncated proteins [50-52], translation re-initiation but no production of stable protein [53], or the absence of expression caused by deletion of transcription regulatory regions. Class 2 mutations comprise mutations expected to generate stable mutant proteins: missense mutations, in-frame deletions/insertions and truncating mutations with premature stop codons occurring in the last exon and thus not triggering NMD.…”

Section: Methodsmentioning

confidence: 99%

The Leu33Pro polymorphism in the ITGB3 gene does not modify BRCA1/2-associated breast or ovarian cancer risks: results from a multicenter study among 15,542 BRCA1 and BRCA2 mutation carriers

Jakubowska

Rozkrut

Antoniou

et al. 2009

Breast Cancer Res Treat

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Integrins containing the β3 subunit are key players in tumor growth and metastasis. A functional Leu33Pro polymorphism (rs5918) in the β3 subunit of the integrin gene (ITGB3) has previously been suggested to act as a modifier of ovarian cancer risk in Polish BRCA1 mutation carriers. To investigate the association further, we genotyped 9,998 BRCA1 and 5,544 BRCA2 mutation carriers from 34 studies from the Consortium of Investigators of Modifiers of BRCA1/2 for the ITGB3 Leu33Pro polymorphism. Data were analysed within a Cox-proportional hazards framework using a retrospective likelihood approach. There was marginal evidence that the ITGB3 polymorphism was associated with an increased risk of ovarian cancer for BRCA1 mutation carriers (per-allele Hazard Ratio (HR) 1.11, 95% CI 1.00–1.23, p-trend 0.05). However, when the original Polish study was excluded from the analysis, the polymorphism was no longer significantly associated with ovarian cancer risk (HR 1.07, 95% CI 0.96–1.19, p-trend 0.25). There was no evidence of an association with ovarian cancer risk for BRCA2 mutation carriers (HR 1.09, 95% CI 0.89–1.32). The polymorphism was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers. The ITGB3 Leu33Pro polymorphism does not modify breast or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.

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The Icelandic founder mutation BRCA2 999del5: analysis of expression

Cited by 42 publications

References 21 publications

A role of BRCA1 and BRCA2germline mutations in breast cancer susceptibility within Sardinian population

A role of BRCA1 and BRCA2germline mutations in breast cancer susceptibility within Sardinian population

Hereditary Breast Cancer in the Han Chinese Population

The Leu33Pro polymorphism in the ITGB3 gene does not modify BRCA1/2-associated breast or ovarian cancer risks: results from a multicenter study among 15,542 BRCA1 and BRCA2 mutation carriers

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