Cancer Risks for BRCA1 and BRCA2 Mutation Carriers: Results From Prospective Analysis of EMBRACE

Mavaddat, Nasim; Peock, Susan; Frost, Debra; Ellis, Steve; Platte, Radka; Fineberg, Elena; Evans, D. Gareth; Izatt, Louise; Eeles, Rosalind; Adlard, Julian; Davidson, Rosemarie; Eccles, Diana; Cole, Trevor; Cook, Jackie; Brewer, Carole; Tischkowitz, Marc; Douglas, Fiona; Hodgson, Shirley; Walker, Lisa; Porteous, Mary; Morrison, Patrick J.; Side, Lucy; Kennedy, Michael J.; Houghton, Catherine; Donaldson, Alan; Rogers, Mark T.; Dorkins, Huw; Miedzybrodzka, Zosia; Gregory, Helen; Eason, Jacqueline; Barwell, Julian; McCann, Emma; Murray, Alex; Antoniou, Antonis C.; Easton, Douglas F.

doi:10.1093/jnci/djt095

Cited by 807 publications

(610 citation statements)

References 65 publications

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“…When they included only cohorts from 1940 onward, their estimates substantially increased: from 45% to 66% for BRCA1 and 27% to 32% for BRCA2 by age 65. Though based on mainly retrospective data, our breast cancer risk estimates of the carriers in the Netherlands are very similar to those published in a recent prospective study: 60% (95% CI, 44%-75%) for BRCA1 and 55% (95% CI, 41%-70%) for BRCA2 carriers by age 70 (27). However, in this prospective study the peak incidence among BRCA2 carriers was in the age group 40 to 49 years, which is earlier than in the Netherlands.…”

Section: Discussionsupporting

confidence: 84%

Variation in Mutation Spectrum Partly Explains Regional Differences in the Breast Cancer Risk of Female BRCA Mutation Carriers in the Netherlands

Vos

Teixeira

Kolk

et al. 2014

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: We aimed to quantify previously observed relatively high cancer risks in BRCA2 mutation carriers (BRCA2 carriers) older than 60 in the Northern Netherlands, and to analyze whether these could be explained by mutation spectrum or population background risk.Methods: This consecutive cohort study included all known pathogenic BRCA1/2 carriers in the Northern Netherlands (N ¼ 1,050). Carrier and general reference populations were: BRCA1/2 carriers in the rest of the Netherlands (N ¼ 2,013) and the general population in both regions. Regional differences were assessed with HRs and ORs. HRs were adjusted for birth year and mutation spectrum.Results: All BRCA1 carriers and BRCA2 carriers younger than 60 had a significantly lower breast cancer risk in the Northern Netherlands; HRs were 0.66 and 0.64, respectively. Above age 60, the breast cancer risk in BRCA2 carriers in the Northern Netherlands was higher than in the rest of the Netherlands [HR, 3.99; 95% confidence interval (CI), 1.11-14.35]. Adjustment for mutational spectrum changed the HRs for BRCA1, BRCA2 <60, and BRCA2 !60 years by À3%, þ32%, and þ11% to 0.75, 0.50, and 2.61, respectively. There was no difference in background breast cancer incidence between the two regions (OR, 1.03; 95% CI, 0.97-1.09).Conclusions: Differences in mutation spectrum only partly explain the regional differences in breast cancer risk in BRCA2 carriers, and for an even smaller part in BRCA1 carriers.Impact: The increased risk in BRCA2 carriers older than 60 may warrant extension of intensive breast screening beyond age 60. Cancer Epidemiol Biomarkers Prev; 23(11); 2482-91. Ó2014 AACR.

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Section: Discussionsupporting

confidence: 84%

Variation in Mutation Spectrum Partly Explains Regional Differences in the Breast Cancer Risk of Female BRCA Mutation Carriers in the Netherlands

Vos

Teixeira

Kolk

et al. 2014

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…Risks for breast cancer for women with a mutation in the BRCA1 gene have been reported to range from 44 to 87% by the age of 70 years. 27,28 While we do not know the exact risk figures reported to Ms Jolie by her genetic counselor, we do know that she chose to report an 87% risk in her commentary. As this work was on awareness and recall of celebrity revelations, we focused on a range (80-90%) close to the specific risk provided in Ms Jolie's New York Times piece.…”

Section: Discussionmentioning

confidence: 99%

The Angelina effect: immediate reach, grasp, and impact of going public

Borzekowski

Guan

Smith

et al. 2014

Genetics in Medicine

134

111

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Results: While three of four Americans were aware of Angelina Jolie's double mastectomy, fewer than 10% of respondents had the information necessary to accurately interpret Ms Jolie's risk of developing cancer relative to a woman unaffected by the BRCA gene mutation. Awareness of the Angelina Jolie story was not associated with improved understanding. Conclusion:While celebrities can bring heightened awareness to health issues, there is a need for these messages to be accompanied by more purposeful communication efforts to assist the public in understanding and using the complex diagnostic and treatment information that these stories convey.Genet Med advance online publication 19 December 2013

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“…20 Tumors associated with mutations, chromosomal translocations or mutations in tumor suppressor genes such as breast cancer susceptibility genes 1 and 2 undergo rapid tumorigenesis, 21 and such tumors are generally considered not to require inflammatory stimuli. However, our results in an osteosarcoma model indicate that inflammation is required for tumorigenesis even in mutation-induced tumors.…”

Section: Discussionmentioning

confidence: 99%

TNFα promotes osteosarcoma progression by maintaining tumor cells in an undifferentiated state

et al. 2013

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Chronic inflammation is frequently associated with tumorigenesis in elderly people. By contrast, young people without chronic inflammation often develop tumors considered independent of chronic inflammation but driven instead by mutations. Thus, whether inflammation has a significant role in tumor progression in tumors driven by mutations remains largely unknown. Here we show that TNFa is required for the tumorigenesis of osteosarcoma, the most common tumor in children and adolescents. We show that transplantation of AX osteosarcoma cells, which harbor mutations driving c-Myc overexpression and Ink4a-deficiency, in wildtype mice promotes lethal tumorigenesis accompanied by ectopic bone formation and multiple metastases, phenotypes seen in osteosarcoma patients. Such tumorigenesis was completely abrogated in TNFa-deficient mice. AX cells have the capacity to undergo osteoblastic differentiation; however, that activity was significantly inhibited by TNFa treatment, suggesting that TNFa maintains AX cells in an undifferentiated state. TNFa inhibition of AX cell osteoblastic differentiation occurred through ERK activation, and a pharmacological TNFa inhibitor effectively inhibited both AX cell tumorigenesis and increased osteoblastic gene expression and increased survival of tumor-bearing mice. Lethal tumorigenesis of AX cells was also abrogated in IL-1a/IL-1b doubly deficient mice. We found that both TNFa and IL-1 maintained AX cells in an undifferentiated state via ERK activation. Thus, inflammatory cytokines are required to promote tumorigenesis even in mutation-induced tumors, and TNFa/IL-1 and ERK may represent therapeutic targets for osteosarcoma.

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Cancer Risks for BRCA1 and BRCA2 Mutation Carriers: Results From Prospective Analysis of EMBRACE

Cited by 807 publications

References 65 publications

Variation in Mutation Spectrum Partly Explains Regional Differences in the Breast Cancer Risk of Female BRCA Mutation Carriers in the Netherlands

Variation in Mutation Spectrum Partly Explains Regional Differences in the Breast Cancer Risk of Female BRCA Mutation Carriers in the Netherlands

The Angelina effect: immediate reach, grasp, and impact of going public

TNFα promotes osteosarcoma progression by maintaining tumor cells in an undifferentiated state

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