| 1. |
- Maxwell, Christopher A., et al.
(författare)
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Interplay between BRCA1 and RHAMM Regulates Epithelial Apicobasal Polarization and May Influence Risk of Breast Cancer
- 2011
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Ingår i: PLoS Biology. - : Public Library of Science (PLoS). - 1545-7885 .- 1544-9173. ; 9:11
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Tidskriftsartikel (refereegranskat)abstract
- Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04 (95% CI 0.94-1.16), p(trend) = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.
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| 2. |
- Kirchhoff, Tomas, et al.
(författare)
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Breast cancer risk and 6q22.33 : combined results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2
- 2012
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Ingår i: PLOS ONE. - : Public library of science. - 1932-6203. ; 7:6
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Tidskriftsartikel (refereegranskat)abstract
- Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p = <0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95%CI 0.80-1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.
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| 3. |
- Vuorela, Mikko, et al.
(författare)
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Further evidence for the contribution of the RAD51C gene in hereditary breast and ovarian cancer susceptibility.
- 2011
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Ingår i: Breast cancer research and treatment. - : Springer Science and Business Media LLC. - 1573-7217 .- 0167-6806. ; 130:3, s. 1003-1010
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Tidskriftsartikel (refereegranskat)abstract
- RAD51C, a RAD51 paralogue involved in homologous recombination, is a recently established Fanconi anemia and breast cancer predisposing factor. In the initial report, RAD51C mutations were shown to confer a high risk for both breast and ovarian tumors, but most of the replication studies published so far have failed to identify any additional susceptibility alleles. Here, we report a full mutation screening of the RAD51C gene in 147 Finnish familial breast cancer cases and in 232 unselected ovarian cancer cases originating from Finland and Sweden. In addition, in order to resolve whether common RAD51C SNPs are risk factors for breast cancer, we genotyped five tagging single nucleotide polymorphisms, rs12946522, rs304270, rs304283, rs17222691, and rs28363312, all located within the gene, from 993 Finnish breast cancer cases and 871 controls for cancer associated variants. Whereas, none of the studied common SNPs associated with breast cancer susceptibility, mutation analysis revealed two clearly pathogenic alterations. RAD51C c.-13_14del27 was observed in one familial breast cancer case and c.774delT in one unselected ovarian cancer case, thus confirming that RAD51C mutations are implicated in breast and ovarian cancer predisposition, although their overall frequency seems to be low. Independent identification of the very recently reported RAD51C c.774delT mutation in yet another patient originating from Sweden suggests that it might be a recurrent mutation in that population and should be studied further. The reliable estimation of the clinical implications of carrying a defective RAD51C allele still requires the identification of additional mutation positive families.
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| 4. |
- Wachenfeldt, Anna von
(författare)
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Familial breast cancer : risk populations and their surveillance
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Women carrying mutations in either BRCA 1 or BRCA2 have a lifetime risk of breast cancer of 80%. As little is known about the risk of other malignancies, apart from ovarian/tubal cancer in mutation carriers, the importance of other malignancies in a family with several cases of breast cancer is hard to evaluate. Women at high risk of breast cancer due to family history are offered genetic counselling and surveillance. Whether women looking for oncogenetic counselling are, in terms of socioeconomic status and health-related quality of life, comparable with women in general is not known. Mammography is a widely used screening method to detect breast cancer and has proven to reduce breast cancer mortality in women older than 50 years. The sensitivity of the method is much lower in women with dense breast and in general young women tend to have denser breast than older women. Most women under surveillance in virtue of family history of breast cancer are younger than 50, thus in a group where mammography alone has not been proved to be effective as a single screening method there is a need for other surveillance methods in women at risk of hereditary breast cancer. We identified 803 BRCA 1/2-negative families with two or more cases of breast cancer and at least one additional malignancy. The observed proportion of different non-breast cancer in the study families was compared with the percentage distribution of non-breast cancer tumours in Sweden. Tumours in endometrium were seen in a significantly larger proportion in the study group than in the general population and could not be explained by previously known syndromes or other explanations for being overrepresented. Thus we suggest that endometrial carcinoma and breast cancer constitute a new breast cancer syndrome. In a cross-sectional study aiming to characterize health-related quality of life and socioeconomic status among all healthy women who had ever visited the Oncogenetic Clinic, Department of Oncology, Södersjukhuset in 1998 – 2004, 306 women consented to participate (82.5%). Significantly more women in the study group were cohabiting (74.2 vs. 43.8%), had the highest education level, (56.7 vs. 39.6%) and had the highest household income (36.9 vs. 12.9 %) as compared to the reference population in the same catchment area. Study subjects reported significantly lower levels of health-related quality of life for subscales related to mental health and for general health compared to normative data, but similar levels on subscales related to physical health. Six-hundred-and-thirty-two women (94%) from one counselling clinic consented to participate in a study aiming to find the most sensitive method to detect breast cancer in women with a familiar risk of the disease. Every woman underwent yearly, and blinded to the other methods, mammography, ultrasound and clinical breast exam. This first report describes the study design and the procedure, and the study cohort regarding hereditary pattern and sociodemographics. Further, the associations between breast density, BMI and other breast-cancer risk factors are elucidated. High breast density was associated with low BMI and young age. However, high density was not associated with increasing risk of breast cancer. Ultrasound and clinical breast examination caused substantially more work-up than MG. The number of detected cancers did not differ from the expected numbers. However, it is too early to draw any conclusion about the sensitivity of the three different modalities..
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