| 1. |
- Antoniou, Antonis C., et al.
(författare)
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Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers
- 2011
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 20:16, s. 3304-3321
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Tidskriftsartikel (refereegranskat)abstract
- Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [ hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 x 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 x 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.
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| 2. |
- Aoude, Lauren G., et al.
(författare)
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A BAP1 Mutation in a Danish Family Predisposes to Uveal Melanoma and Other Cancers
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:8
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Tidskriftsartikel (refereegranskat)abstract
- Truncating germline mutations in the tumor suppressor gene BRCA-1 associated protein-1 (BAP1) have been reported in families predisposed to developing a wide range of different cancer types including uveal melanoma and cutaneous melanoma. There has also been an association between amelanotic tumor development and germline BAP1 mutation suggesting a possible phenotypic characteristic of BAP1 mutation carriers. Though there have been many types of cancer associated with germline BAP1 mutation, the full spectrum of disease association is yet to be ascertained. Here we describe a Danish family with predominantly uveal melanoma but also a range of other tumor types including lung, neuroendocrine, stomach, and breast cancer; as well as pigmented skin lesions. Whole-exome sequencing identified a BAP1 splice mutation located at c.581-2A>G, which leads to a premature truncation of BAP1 in an individual with uveal melanoma. This mutation was carried by several other family members with melanoma or various cancers. The finding expands on the growing profile of BAP1 as an important uveal and cutaneous melanoma tumor suppressor gene and implicates its involvement in the development of lung, and stomach cancer.
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| 3. |
- Aoude, Lauren G, et al.
(författare)
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Nonsense Mutations in the Shelterin Complex Genes ACD and TERF2IP in Familial Melanoma.
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 107:2, s. 408-408
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Tidskriftsartikel (refereegranskat)abstract
- The shelterin complex protects chromosomal ends by regulating how the telomerase complex interacts with telomeres. Following the recent finding in familial melanoma of inactivating germline mutations in POT1, encoding a member of the shelterin complex, we searched for mutations in the other five components of the shelterin complex in melanoma families.
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| 4. |
- Moghadasi, Setareh, et al.
(författare)
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The BRCA1 c. 5096G > A p.Arg1699Gln (R1699Q) intermediate risk variant : breast and ovarian cancer risk estimation and recommendations for clinical management from the ENIGMA consortium
- 2018
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Ingår i: Journal of Medical Genetics. - : BMJ PUBLISHING GROUP. - 0022-2593 .- 1468-6244. ; 55:1, s. 15-20
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Tidskriftsartikel (refereegranskat)abstract
- Background: We previously showed that the BRCA1 variant c. 5096G> A p.Arg1699Gln (R1699Q) was associated with an intermediate risk of breast cancer (BC) and ovarian cancer (OC). This study aimed to assess these cancer risks for R1699Q carriers in a larger cohort, including follow-up of previously studied families, to further define cancer risks and to propose adjusted clinical management of female BRCA1* R1699Q carriers.Methods: Data were collected from 129 BRCA1* R1699Q families ascertained internationally by ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) consortium members. A modified segregation analysis was used to calculate BC and OC risks. Relative risks were calculated under both monogenic model and major gene plus polygenic model assumptions.Results: In this cohort the cumulative risk of BC and OC by age 70 years was 20% and 6%, respectively. The relative risk for developing cancer was higher when using a model that included the effects of both the R1699Q variant and a residual polygenic component compared with monogenic model (for BC 3.67 vs 2.83, and for OC 6.41 vs 5.83).Conclusion: O ur results confirm that BRCA1* R1699Q confers an intermediate risk for BC and OC. Breast surveillance for female carriers based on mammogram annually from age 40 is advised. Bilateral salpingooophorectomy should be considered based on family history.
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| 5. |
- Thomassen, Mads, et al.
(författare)
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A BRCA2 mutation incorrectly mapped in the original BRCA2 reference sequence, is a common West Danish founder mutation disrupting mRNA splicing
- 2011
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Ingår i: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 1573-7217 .- 0167-6806. ; 128:1, s. 179-185
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Tidskriftsartikel (refereegranskat)abstract
- Inherited mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose carriers to breast and ovarian cancer. The authors have identified a mutation in BRCA2, 7845+1G > A (c.7617+1G > A), not previously regarded as deleterious because of incorrect mapping of the splice junction in the originally published genomic reference sequence. This reference sequence is generally used in many laboratories and it maps the mutation 16 base pairs inside intron 15. However, according to the recent reference sequences the mutation is located in the consensus donor splice sequence. By reverse transcriptase analysis, loss of exon 15 in the final transcript interrupting the open reading frame was demonstrated. Furthermore, the mutation segregates with a cancer phenotype in 18 Danish families. By genetic analysis of more than 3,500 Danish breast/ovarian cancer risk families, the mutation was identified as the most common BRCA2 mutation in West Denmark, while it is rare in Central and East Denmark and not identified in South Sweden. Haplotype analysis using dense SNP arrays indicated a common founder of the mutation approximately 1,500 years ago.
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| 6. |
- Thomassen, Mads, et al.
(författare)
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BRCA1 and BRCA2 mutations in Danish families with hereditary breast and/or ovarian cancer
- 2008
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Ingår i: Acta Oncologica. - : Informa UK Limited. - 1651-226X .- 0284-186X. ; 47:4, s. 772-777
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Tidskriftsartikel (refereegranskat)abstract
- A national study of BRCA1 and BRCA2 mutations in Danish HBOC (Hereditary Breast Ovarian Cancer) families revealed a total number of 322 mutation positive families, 206 (64%) BRCA1 and 116 (36%) BRCA2 positive families from a population of 5.5 million inhabitants. Seven hundred and twenty six mutation positive individuals were identified: 402 female BRCAl carriers, 79 male BRCAl carriers, 213 female BRCA2 carriers, and 32 male BRCA2 carriers by April 2006. Most of the mutations were frame shift or nonsense mutations, while large genomic rearrangements were rare. Most mutations were only identified in one family. A few mutations were detected repeatedly. In BRCAl the most common mutations were: 2594delC in 32 families (16%), 3438G > T in 19 families (9%), 5382insC in 16 families (8%), 3829delT in 11 families (5%). In BRCA2 the most common mutations were: 6601delA in 13 families (11%), 1538del4 in 12 families (10%), 6714del4 in 10 families (9%). There was a tendency towards a higher frequency of BRCA2 mutations in West Denmark compared to East Denmark. The frequencies of specific BRCA1 and BRCA2 mutations were slightly different in the two regions. The mutations occurring in West Denmark have also been observed in other Scandinavian countries whereas the mutations occurring in East Denmark were more often reported from other European countries and the Baltic countries. The pattern of mutation distributions are comparable with observations from other Scandinavian and European studies and indicate that the Danish BRCAl and BRCA2 mutations are a mixture of Scandinavian mutations and other European mutations including two of the Ashkenazi mutations. Even though a tendency towards founder mutations was observed most mutations were only detected once. Based on these observations we recommend that the mutation screening strategy of the BRCA1 and BRCA2 genes in Danish HBOC families comprises full screening of both genes including analysis for large genomic rearrangements.
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| 7. |
- Wadt, Karin A W, et al.
(författare)
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Molecular characterization of melanoma cases in denmark suspected of genetic predisposition.
- 2015
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:3
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Tidskriftsartikel (refereegranskat)abstract
- Both environmental and host factors influence risk of cutaneous melanoma (CM), and worldwide, the incidence varies depending on constitutional determinants of skin type and pigmentation, latitude, and patterns of sun exposure. We performed genetic analysis of CDKN2A, CDK4, BAP1, MC1R, and MITFp.E318K in Danish high-risk melanoma cases and found CDKN2A germline mutations in 11.3% of CM families with three or more affected individuals, including four previously undescribed mutations. Rare mutations were also seen in CDK4 and BAP1, while MC1R variants were common, occurring at more than twice the frequency compared to Danish controls. The MITF p.E318K variant similarly occurred at an approximately three-fold higher frequency in melanoma cases than controls. To conclude, we propose that mutation screening of CDKN2A and CDK4 in Denmark should predominantly be performed in families with at least 3 cases of CM. In addition, we recommend that testing of BAP1 should not be conducted routinely in CM families but should be reserved for families with CM and uveal melanoma, or mesothelioma.
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