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1.  Risk factors for dementia with Lewy bodies 
Neurology  2013;81(9):833-840.
To determine the risk factors associated with dementia with Lewy bodies (DLB).
We identified 147 subjects with DLB and sampled 2 sex- and age-matched cognitively normal control subjects for each case. We also identified an unmatched comparison group of 236 subjects with Alzheimer disease (AD). We evaluated 19 candidate risk factors in the study cohort.
Compared with controls, subjects with DLB were more likely to have a history of anxiety (odds ratio; 95% confidence interval) (7.4; 3.5–16; p < 0.0001), depression (6.0; 3.7–9.5; p < 0.0001), stroke (2.8; 1.3–6.3; p = 0.01), a family history of Parkinson disease (PD) (4.6; 2.5–8.6; p < 0.0001), and carry APOE ε4 alleles (2.2; 1.5–3.3; p < 0.0001), but less likely to have had cancer (0.44; 0.27–0.70; p = 0.0006) or use caffeine (0.29; 0.14–0.57; p < 0.0001) with a similar trend for alcohol (0.65; 0.42–1.0; p = 0.0501). Compared with subjects with AD, subjects with DLB were younger (72.5 vs 74.9 years, p = 0.021) and more likely to be male (odds ratio; 95% confidence interval) (5.3; 3.3–8.5; p < 0.0001), have a history of depression (4.3; 2.4–7.5; p < 0.0001), be more educated (2.5; 1.1–5.6; p = 0.031), have a positive family history of PD (5.0; 2.4–10; p < 0.0001), have no APOE ε4 alleles (0.61; 0.40–0.93; p = 0.02), and to have had an oophorectomy before age 45 years (7.6; 1.5–39; p = 0.015).
DLB risk factors are an amalgam of those for AD and PD. Smoking and education, which have opposing risk effects on AD and PD, are not risk factors for DLB; however, depression and low caffeine intake, both risk factors for AD and PD, increase risk of DLB more strongly than in either.
PMCID: PMC3908463  PMID: 23892702
2.  Assessing the Temporal Relationship Between Cognition and Gait: Slow Gait Predicts Cognitive Decline in the Mayo Clinic Study of Aging 
The association between gait speed and cognition has been reported; however, there is limited knowledge about the temporal associations between gait slowing and cognitive decline among cognitively normal individuals.
The Mayo Clinic Study of Aging is a population-based study of Olmsted County, Minnesota, United States, residents aged 70–89 years. This analysis included 1,478 cognitively normal participants who were evaluated every 15 months with a nurse visit, neurologic evaluation, and neuropsychological testing. The neuropsychological battery used nine tests to compute domain-specific (memory, language, executive function, and visuospatial skills) and global cognitive z-scores. Timed gait speed (m/s) was assessed over 25 feet (7.6 meters) at a usual pace. Using mixed models, we examined baseline gait speed (continuous and in quartiles) as a predictor of cognitive decline and baseline cognition as a predictor of gait speed changes controlling for demographics and medical conditions.
Cross-sectionally, faster gait speed was associated with better performance in memory, executive function, and global cognition. Both cognitive scores and gait speed declined over time. A faster gait speed at baseline was associated with less cognitive decline across all domain-specific and global scores. These results were slightly attenuated after excluding persons with incident mild cognitive impairment or dementia. By contrast, baseline cognition was not associated with changes in gait speed.
Our study suggests that slow gait precedes cognitive decline. Gait speed may be useful as a reliable, easily attainable, and noninvasive risk factor for cognitive decline.
PMCID: PMC3712358  PMID: 23250002
Gait speed; Cognition; Longitudinal; Cohort study.
3.  Criteria for Mild Cognitive Impairment Due to Alzheimer’s Disease in the Community 
Annals of neurology  2013;74(2):199-208.
The newly proposed National Institute on Aging-Alzheimer’s Association (NIA-AA) criteria for mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) suggest a combination of clinical features and biomarker measures, but their performance in the community is not known.
The Mayo Clinic Study of Aging (MCSA) is a population-based longitudinal study of non-demented subjects in Olmsted County, Minnesota. A sample of 154 MCI subjects from the MCSA was compared to a sample of 58 amnestic MCI subjects from the Alzheimer’s Disease Neuroimaging Initiative 1 (ADNI 1) to assess the applicability of the criteria in both settings and to assess their outcomes.
In the MCSA, 14% and in ADNI 1 16% of subjects were biomarker negative. In addition, 14% of the MCSA and 12% of ADNI 1 subjects had evidence for amyloid deposition only, while 43% of MCSA and 55% of ADNI 1 subjects had evidence for amyloid deposition plus neurodegeneration (MRI atrophy, FDG PET hypometabolism or both). However, a considerable number of subjects had biomarkers inconsistent with the proposed AD model, e.g., 29% of MCSA subjects and 17% of the ADNI 1 subjects had evidence for neurodegeneration without amyloid deposition. These subjects may not be on an AD pathway. Neurodegeneration appears to be a key factor in predicting progression relative to amyloid deposition alone.
The NIA-AA criteria apply to most MCI subjects in both the community and clinical trials settings however, a sizeable proportion of subjects had conflicting biomarkers which may be very important and need to be explored.
PMCID: PMC3804562  PMID: 23686697
4.  Rates of β-amyloid accumulation are independent of hippocampal neurodegeneration 
Neurology  2014;82(18):1605-1612.
To test the hypotheses predicted in a hypothetical model of Alzheimer disease (AD) biomarkers that rates of β-amyloid (Aβ) accumulation on PET imaging are not related to hippocampal neurodegeneration whereas rates of neurodegenerative brain atrophy depend on the presence of both amyloid and neurodegeneration in a population-based sample.
A total of 252 cognitively normal (CN) participants from the Mayo Clinic Study of Aging had 2 or more serial visits with both amyloid PET and MRI. Subjects were classified into 4 groups based on baseline positive/negative amyloid PET (A+ or A−) and baseline hippocampal volume (N+ or N−). We compared rates of amyloid accumulation and rates of brain atrophy among the 4 groups.
At baseline, 148 (59%) were amyloid negative and neurodegeneration negative (A−N−), 29 (12%) amyloid negative and neurodegeneration positive (A−N+), 56 (22%) amyloid positive and neurodegeneration negative (A+N−), and 19 (8%) amyloid positive and neurodegeneration positive (A+N+). High rates of Aβ accumulation were found in those with abnormal amyloid at baseline and were not influenced by hippocampal neurodegeneration at baseline. In contrast, rates of brain atrophy were greatest in A+N+.
We describe a 2-feature biomarker approach to classifying elderly CN subjects that is complementary to the National Institute on Aging–Alzheimer's Association preclinical staging criteria. Our results support 2 key concepts in a model of the temporal evolution of AD biomarkers. First, the rate of Aβ accumulation is not influenced by neurodegeneration and thus may be a biologically independent process. Second, Aβ pathophysiology increases or catalyzes neurodegeneration.
PMCID: PMC4013810  PMID: 24706010
5.  Brain β-amyloid load approaches a plateau 
Neurology  2013;80(10):890-896.
To model the temporal trajectory of β-amyloid accumulation using serial amyloid PET imaging.
Participants, aged 70–92 years, were enrolled in either the Mayo Clinic Study of Aging (n = 246) or the Mayo Alzheimer's Disease Research Center (n = 14). All underwent 2 or more serial amyloid PET examinations. There were 205 participants classified as cognitively normal and 55 as cognitively impaired (47 mild cognitive impairment and 8 Alzheimer dementia). We measured baseline amyloid PET-relative standardized uptake values (SUVR) and, for each participant, estimated a slope representing their annual amyloid accumulation rate. We then fit regression models to predict the rate of amyloid accumulation given baseline amyloid SUVR, and evaluated age, sex, clinical group, and APOE as covariates. Finally, we integrated the amyloid accumulation rate vs baseline amyloid PET SUVR association to an amyloid PET SUVR vs time association.
Rates of amyloid accumulation were low at low baseline SUVR. Rates increased to a maximum at baseline SUVR around 2.0, above which rates declined—reaching zero at baseline SUVR above 2.7. The rate of amyloid accumulation as a function of baseline SUVR had an inverted U shape. Integration produced a sigmoid curve relating amyloid PET SUVR to time. The average estimated time required to travel from an SUVR of 1.5–2.5 is approximately 15 years.
This roughly 15-year interval where the slope of the amyloid SUVR vs time curve is greatest and roughly linear represents a large therapeutic window for secondary preventive interventions.
PMCID: PMC3653215  PMID: 23446680
6.  Update on hypothetical model of Alzheimer’s disease biomarkers 
Lancet neurology  2013;12(2):207-216.
In 2010, the authors published a hypothetical model of the major biomarkers of Alzheimer’s disease (AD). The model was received with interest because we described the temporal evolution of AD biomarkers in relation to each other and to the onset and progression of clinical symptoms. In the interim, evidence has accumulated that supports the major assumptions of this model. Evidence has also appeared that challenges some of the assumptions underlying our original model. Recent evidence has allowed us to modify our original model. Refinements include indexing subjects by time rather than clinical symptom severity; incorporating inter-subject variability in cognitive response to the progression of AD pathophysiology; modifications of the specific temporal ordering of some biomarkers; and, recognition that the two major proteinopathies underlying AD biomarker changes, Aβ and tau, may be initiated independently in late onset AD where we hypothesize that an incident Aβopathy can accelerate an antecedent tauopathy.
PMCID: PMC3622225  PMID: 23332364
7.  Amyloid-first and neurodegeneration-first profiles characterize incident amyloid PET positivity 
Neurology  2013;81(20):1732-1740.
To estimate the incidence of and to characterize cognitive and imaging findings associated with incident amyloid PET positivity.
Cognitively normal (CN) participants in the Mayo Clinic Study of Aging who had 2 or more serial imaging assessments, which included amyloid PET, FDG-PET, and MRI at each time point, were eligible for analysis (n = 207). Twelve subjects with Alzheimer disease dementia were included for comparison.
Of the 123 CN participants who were amyloid-negative at baseline, 26 met criteria for incident amyloid PET positivity. Compared to the 69 subjects who remained stable amyloid-negative, on average these 26 did not differ on any imaging, demographic, or cognitive variables except amyloid PET (by definition) and task-free functional connectivity, which at baseline was greater in the incident amyloid-positive group. Eleven of the 26 incident amyloid-positive subjects had abnormal hippocampal volume, FDG-PET, or both at baseline.
The incidence of amyloid PET positivity is approximately 13% per year among CN participants over age 70 sampled from a population-based cohort. In 15/26 (58%), incident amyloid positivity occurred prior to abnormalities in FDG-PET and hippocampal volume. However, 11/26 (42%) incident amyloid-positive subjects had evidence of neurodegeneration prior to incident amyloid positivity. These 11 could be subjects with combinations of preexisting non-Alzheimer pathophysiologies and tau-mediated neurodegeneration who newly entered the amyloid pathway. Our findings suggest that both “amyloid-first” and “neurodegeneration-first” biomarker profile pathways to preclinical AD exist.
PMCID: PMC3821718  PMID: 24132377
8.  Evaluation of chromosome 6p22 as a breast cancer risk modifier locus in a follow-up study of BRCA2 mutation carriers 
Several common germline variants identified through genome-wide association studies of breast cancer risk in the general population have recently been shown to be associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. When combined, these variants can identify marked differences in the absolute risk of developing breast cancer for mutation carriers, suggesting that additional modifier loci may further enhance individual risk assessment for BRCA1 and BRCA2 mutation carriers. Recently, a common variant on 6p22 (rs9393597) was found to be associated with increased breast cancer risk for BRCA2 mutation carriers [Hazard ratio (HR)=1.55, 95% CI 1.25–1.92, p=6.0×10−5]. This observation was based on data from GWAS studies in which, despite statistical correction for multiple comparisons, the possibility of false discovery remains a concern. Here we report on an analysis of this variant in an additional 6,165 BRCA1 and 3,900 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). In this replication analysis, rs9393597 was not associated with breast cancer risk for BRCA2 mutation carriers [HR=1.09, 95% CI 0.96–1.24, p=0.18]. No association with ovarian cancer risk for BRCA1 or BRCA2 mutation carriers or with breast cancer risk for BRCA1 mutation carriers was observed. This follow-up study suggests that, contrary to our initial report, this variant is not associated with breast cancer risk among individuals with germline BRCA2 mutations.
PMCID: PMC3482828  PMID: 23011509
BRCA1; BRCA2; genetic modifier; association study
9.  ApoE and Quality of Life in Nonagenarians 
ApoE ε4 is associated with adverse health conditions that negatively impact the quality of life (QOL). The relationship between ApoE ε4 and QOL has not been explored in the oldest old. Our study aimed to examine ApoE in the oldest old, and explore its association with QOL.
Cross-sectional cohort study.
A medium sized community in Olmsted County, Minnesota, USA.
90–99 year old individuals living independently or in long term care environments.
We collected demographic information and measured cognitive function (Short Test of Mental Status [STMS], Mini-Mental State Examination [MMSE], Mattis Dementia Rating Scale [DRS]), QOL (Linear Analogue Self Assessment [LASA]) and ApoE distribution. Subjects were classified as cognitively normal, mild cognitive impairment (MCI), dementia (DEM), or dementia with stroke and/or parkinsonism (DEMSP). Regression model was used to assess the predictors of QOL.
121 subjects (45 cognitively normal, 13 MCI, 34 DEM, 29 DEMSP) aged 90–99,106 (87.6 %) females, were included. Frequency of ApoE ε3 allele was highest [194 (80.2%): ε2/3 18, ε3/3 77, ε3/4 22] followed by ApoE ε4 [25 (10.3%): ε2/4 3, ε3/4 22] and ApoE ε2 [23 (9.5%; ε2/2 1, ε2/3 18, ε2/4 3]. None of the subjects carried ApoE ε4/4 genotype. QOL was similar between ApoE ε4 carrier and non-carriers. Physical well-being, emotional well-being, intellectual well-being, social connectedness and coping ability were positively associated with QOL, whereas male gender, DEMSP, pain frequency and pain severity were negatively associated.
The most common ApoE in the oldest old was ε3/3 genotype and ε3 allele. No association was found between ApoE ε4 and QOL. However, those with high physical, emotional and intellectual well being, social connectedness and coping ability had the highest overall QOL.
PMCID: PMC3461124  PMID: 22863665
Well being; oldest old; apolipoprotein E
10.  BRCA2 localization to the midbody by Filamin A regulates CEP55 signaling and completion of cytokinesis 
Developmental cell  2012;23(1):137-152.
Disruption of the BRCA2 tumor suppressor is associated with structural and numerical chromosomal defects. The numerical abnormalities in BRCA2 deficient cells may partly result from aberrations in cell division caused by disruption of BRCA2 during cytokinesis. Here we show that BRCA2 is a component of the midbody that is recruited through an interaction with Filamin A actin-binding protein. At the midbody BRCA2 influences the recruitment of endosomal sorting complex required for transport (ESCRT) associated proteins, Alix and Tsg101, and formation of CEP55-Alix and CEP55-Tsg101 complexes during abscission. Disruption of these BRCA2 interactions by cancer associated mutations results in increased cytokinetic defects but has no effect on BRCA2-dependent homologous recombination repair of DNA damage. These findings identify a specific role for BRCA2 in the regulation of midbody structure and function, separate from DNA damage repair, that may explain in part the whole-chromosomal instability in BRCA2-deficient tumors.
PMCID: PMC3419138  PMID: 22771033
Cytokinesis; BRCA2; Midbody; Filamin A
11.  Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk 
Couch, Fergus J. | Wang, Xianshu | McGuffog, Lesley | Lee, Andrew | Olswold, Curtis | Kuchenbaecker, Karoline B. | Soucy, Penny | Fredericksen, Zachary | Barrowdale, Daniel | Dennis, Joe | Gaudet, Mia M. | Dicks, Ed | Kosel, Matthew | Healey, Sue | Sinilnikova, Olga M. | Lee, Adam | Bacot, François | Vincent, Daniel | Hogervorst, Frans B. L. | Peock, Susan | Stoppa-Lyonnet, Dominique | Jakubowska, Anna | Investigators, kConFab | Radice, Paolo | Schmutzler, Rita Katharina | Domchek, Susan M. | Piedmonte, Marion | Singer, Christian F. | Friedman, Eitan | Thomassen, Mads | Hansen, Thomas V. O. | Neuhausen, Susan L. | Szabo, Csilla I. | Blanco, Ignacio | Greene, Mark H. | Karlan, Beth Y. | Garber, Judy | Phelan, Catherine M. | Weitzel, Jeffrey N. | Montagna, Marco | Olah, Edith | Andrulis, Irene L. | Godwin, Andrew K. | Yannoukakos, Drakoulis | Goldgar, David E. | Caldes, Trinidad | Nevanlinna, Heli | Osorio, Ana | Terry, Mary Beth | Daly, Mary B. | van Rensburg, Elizabeth J. | Hamann, Ute | Ramus, Susan J. | Ewart Toland, Amanda | Caligo, Maria A. | Olopade, Olufunmilayo I. | Tung, Nadine | Claes, Kathleen | Beattie, Mary S. | Southey, Melissa C. | Imyanitov, Evgeny N. | Tischkowitz, Marc | Janavicius, Ramunas | John, Esther M. | Kwong, Ava | Diez, Orland | Balmaña, Judith | Barkardottir, Rosa B. | Arun, Banu K. | Rennert, Gad | Teo, Soo-Hwang | Ganz, Patricia A. | Campbell, Ian | van der Hout, Annemarie H. | van Deurzen, Carolien H. M. | Seynaeve, Caroline | Gómez Garcia, Encarna B. | van Leeuwen, Flora E. | Meijers-Heijboer, Hanne E. J. | Gille, Johannes J. P. | Ausems, Margreet G. E. M. | Blok, Marinus J. | Ligtenberg, Marjolijn J. L. | Rookus, Matti A. | Devilee, Peter | Verhoef, Senno | van Os, Theo A. M. | Wijnen, Juul T. | Frost, Debra | Ellis, Steve | Fineberg, Elena | Platte, Radka | Evans, D. Gareth | Izatt, Louise | Eeles, Rosalind A. | Adlard, Julian | Eccles, Diana M. | Cook, Jackie | Brewer, Carole | Douglas, Fiona | Hodgson, Shirley | Morrison, Patrick J. | Side, Lucy E. | Donaldson, Alan | Houghton, Catherine | Rogers, Mark T. | Dorkins, Huw | Eason, Jacqueline | Gregory, Helen | McCann, Emma | Murray, Alex | Calender, Alain | Hardouin, Agnès | Berthet, Pascaline | Delnatte, Capucine | Nogues, Catherine | Lasset, Christine | Houdayer, Claude | Leroux, Dominique | Rouleau, Etienne | Prieur, Fabienne | Damiola, Francesca | Sobol, Hagay | Coupier, Isabelle | Venat-Bouvet, Laurence | Castera, Laurent | Gauthier-Villars, Marion | Léoné, Mélanie | Pujol, Pascal | Mazoyer, Sylvie | Bignon, Yves-Jean | Złowocka-Perłowska, Elżbieta | Gronwald, Jacek | Lubinski, Jan | Durda, Katarzyna | Jaworska, Katarzyna | Huzarski, Tomasz | Spurdle, Amanda B. | Viel, Alessandra | Peissel, Bernard | Bonanni, Bernardo | Melloni, Giulia | Ottini, Laura | Papi, Laura | Varesco, Liliana | Tibiletti, Maria Grazia | Peterlongo, Paolo | Volorio, Sara | Manoukian, Siranoush | Pensotti, Valeria | Arnold, Norbert | Engel, Christoph | Deissler, Helmut | Gadzicki, Dorothea | Gehrig, Andrea | Kast, Karin | Rhiem, Kerstin | Meindl, Alfons | Niederacher, Dieter | Ditsch, Nina | Plendl, Hansjoerg | Preisler-Adams, Sabine | Engert, Stefanie | Sutter, Christian | Varon-Mateeva, Raymonda | Wappenschmidt, Barbara | Weber, Bernhard H. F. | Arver, Brita | Stenmark-Askmalm, Marie | Loman, Niklas | Rosenquist, Richard | Einbeigi, Zakaria | Nathanson, Katherine L. | Rebbeck, Timothy R. | Blank, Stephanie V. | Cohn, David E. | Rodriguez, Gustavo C. | Small, Laurie | Friedlander, Michael | Bae-Jump, Victoria L. | Fink-Retter, Anneliese | Rappaport, Christine | Gschwantler-Kaulich, Daphne | Pfeiler, Georg | Tea, Muy-Kheng | Lindor, Noralane M. | Kaufman, Bella | Shimon Paluch, Shani | Laitman, Yael | Skytte, Anne-Bine | Gerdes, Anne-Marie | Pedersen, Inge Sokilde | Moeller, Sanne Traasdahl | Kruse, Torben A. | Jensen, Uffe Birk | Vijai, Joseph | Sarrel, Kara | Robson, Mark | Kauff, Noah | Mulligan, Anna Marie | Glendon, Gord | Ozcelik, Hilmi | Ejlertsen, Bent | Nielsen, Finn C. | Jønson, Lars | Andersen, Mette K. | Ding, Yuan Chun | Steele, Linda | Foretova, Lenka | Teulé, Alex | Lazaro, Conxi | Brunet, Joan | Pujana, Miquel Angel | Mai, Phuong L. | Loud, Jennifer T. | Walsh, Christine | Lester, Jenny | Orsulic, Sandra | Narod, Steven A. | Herzog, Josef | Sand, Sharon R. | Tognazzo, Silvia | Agata, Simona | Vaszko, Tibor | Weaver, Joellen | Stavropoulou, Alexandra V. | Buys, Saundra S. | Romero, Atocha | de la Hoya, Miguel | Aittomäki, Kristiina | Muranen, Taru A. | Duran, Mercedes | Chung, Wendy K. | Lasa, Adriana | Dorfling, Cecilia M. | Miron, Alexander | Benitez, Javier | Senter, Leigha | Huo, Dezheng | Chan, Salina B. | Sokolenko, Anna P. | Chiquette, Jocelyne | Tihomirova, Laima | Friebel, Tara M. | Agnarsson, Bjarni A. | Lu, Karen H. | Lejbkowicz, Flavio | James, Paul A. | Hall, Per | Dunning, Alison M. | Tessier, Daniel | Cunningham, Julie | Slager, Susan L. | Wang, Chen | Hart, Steven | Stevens, Kristen | Simard, Jacques | Pastinen, Tomi | Pankratz, Vernon S. | Offit, Kenneth | Easton, Douglas F. | Chenevix-Trench, Georgia | Antoniou, Antonis C.
PLoS Genetics  2013;9(3):e1003212.
BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10−8, HR = 1.14, 95% CI: 1.09–1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10−8, HR = 1.27, 95% CI: 1.17–1.38) and 4q32.3 (rs4691139, P = 3.4×10−8, HR = 1.20, 95% CI: 1.17–1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10−4). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%–50% compared to 81%–100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.
Author Summary
BRCA1 mutation carriers have increased and variable risks of breast and ovarian cancer. To identify modifiers of breast and ovarian cancer risk in this population, a multi-stage GWAS of 14,351 BRCA1 mutation carriers was performed. Loci 1q32 and TCF7L2 at 10q25.3 were associated with breast cancer risk, and two loci at 4q32.2 and 17q21.31 were associated with ovarian cancer risk. The 4q32.3 ovarian cancer locus was not associated with ovarian cancer risk in the general population or in BRCA2 carriers and is the first indication of a BRCA1-specific risk locus for either breast or ovarian cancer. Furthermore, modeling the influence of these modifiers on cumulative risk of breast and ovarian cancer in BRCA1 mutation carriers for the first time showed that a wide range of individual absolute risks of each cancer can be estimated. These differences suggest that genetic risk modifiers may be incorporated into the clinical management of BRCA1 mutation carriers.
PMCID: PMC3609646  PMID: 23544013
12.  Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk 
Gaudet, Mia M. | Kuchenbaecker, Karoline B. | Vijai, Joseph | Klein, Robert J. | Kirchhoff, Tomas | McGuffog, Lesley | Barrowdale, Daniel | Dunning, Alison M. | Lee, Andrew | Dennis, Joe | Healey, Sue | Dicks, Ed | Soucy, Penny | Sinilnikova, Olga M. | Pankratz, Vernon S. | Wang, Xianshu | Eldridge, Ronald C. | Tessier, Daniel C. | Vincent, Daniel | Bacot, Francois | Hogervorst, Frans B. L. | Peock, Susan | Stoppa-Lyonnet, Dominique | Peterlongo, Paolo | Schmutzler, Rita K. | Nathanson, Katherine L. | Piedmonte, Marion | Singer, Christian F. | Thomassen, Mads | Hansen, Thomas v. O. | Neuhausen, Susan L. | Blanco, Ignacio | Greene, Mark H. | Garber, Judith | Weitzel, Jeffrey N. | Andrulis, Irene L. | Goldgar, David E. | D'Andrea, Emma | Caldes, Trinidad | Nevanlinna, Heli | Osorio, Ana | van Rensburg, Elizabeth J. | Arason, Adalgeir | Rennert, Gad | van den Ouweland, Ans M. W. | van der Hout, Annemarie H. | Kets, Carolien M. | Aalfs, Cora M. | Wijnen, Juul T. | Ausems, Margreet G. E. M. | Frost, Debra | Ellis, Steve | Fineberg, Elena | Platte, Radka | Evans, D. Gareth | Jacobs, Chris | Adlard, Julian | Tischkowitz, Marc | Porteous, Mary E. | Damiola, Francesca | Golmard, Lisa | Barjhoux, Laure | Longy, Michel | Belotti, Muriel | Ferrer, Sandra Fert | Mazoyer, Sylvie | Spurdle, Amanda B. | Manoukian, Siranoush | Barile, Monica | Genuardi, Maurizio | Arnold, Norbert | Meindl, Alfons | Sutter, Christian | Wappenschmidt, Barbara | Domchek, Susan M. | Pfeiler, Georg | Friedman, Eitan | Jensen, Uffe Birk | Robson, Mark | Shah, Sohela | Lazaro, Conxi | Mai, Phuong L. | Benitez, Javier | Southey, Melissa C. | Schmidt, Marjanka K. | Fasching, Peter A. | Peto, Julian | Humphreys, Manjeet K. | Wang, Qin | Michailidou, Kyriaki | Sawyer, Elinor J. | Burwinkel, Barbara | Guénel, Pascal | Bojesen, Stig E. | Milne, Roger L. | Brenner, Hermann | Lochmann, Magdalena | Aittomäki, Kristiina | Dörk, Thilo | Margolin, Sara | Mannermaa, Arto | Lambrechts, Diether | Chang-Claude, Jenny | Radice, Paolo | Giles, Graham G. | Haiman, Christopher A. | Winqvist, Robert | Devillee, Peter | García-Closas, Montserrat | Schoof, Nils | Hooning, Maartje J. | Cox, Angela | Pharoah, Paul D. P. | Jakubowska, Anna | Orr, Nick | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Hall, Per | Couch, Fergus J. | Simard, Jacques | Altshuler, David | Easton, Douglas F. | Chenevix-Trench, Georgia | Antoniou, Antonis C. | Offit, Kenneth
PLoS Genetics  2013;9(3):e1003173.
Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80–0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.
Author Summary
Women who carry BRCA2 mutations have an increased risk of breast cancer that varies widely. To identify common genetic variants that modify the breast cancer risk associated with BRCA2 mutations, we have built upon our previous work in which we examined genetic variants across the genome in relation to breast cancer risk among BRCA2 mutation carriers. Using a custom genotyping platform with 211,155 genetic variants known as single nucleotide polymorphisms (SNPs), we genotyped 3,881 women who had breast cancer and 4,330 women without breast cancer, which represents the largest possible, international collection of BRCA2 mutation carriers. We identified that a SNP located at 6p24 in the genome was associated with lower risk of breast cancer. Importantly, this SNP was not associated with breast cancer in BRCA1 mutation carriers or in a general population of women, indicating that the breast cancer association with this SNP might be specific to BRCA2 mutation carriers. Combining this BRCA2-specific SNP with 13 other breast cancer risk SNPs also known to modify risk in BRCA2 mutation carriers, we were able to derive a risk prediction model that could be useful in helping women with BRCA2 mutations weigh their risk-reduction strategy options.
PMCID: PMC3609647  PMID: 23544012
13.  A non-synonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers 
Ding, Yuan C. | McGuffog, Lesley | Healey, Sue | Friedman, Eitan | Laitman, Yael | Shani-Shimon–Paluch,  | Kaufman, Bella | Liljegren, Annelie | Lindblom, Annika | Olsson, Håkan | Kristoffersson, Ulf | Stenmark-Askmalm, Marie | Melin, Beatrice | Domchek, Susan M. | Nathanson, Katherine L. | Rebbeck, Timothy R. | Jakubowska, Anna | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Gronwald, Jacek | Huzarski, Tomasz | Cybulski, Cezary | Byrski, Tomasz | Osorio, Ana | Cajal, Teresa Ramóny | Stavropoulou, Alexandra V | Benítez, Javier | Hamann, Ute | Rookus, Matti | Aalfs, Cora M. | de Lange, Judith L. | Meijers-Heijboer, Hanne E.J. | Oosterwijk, Jan C. | van Asperen, Christi J. | García, Encarna B. Gómez | Hoogerbrugge, Nicoline | Jager, Agnes | van der Luijt, Rob B. | Easton, Douglas F. | Peock, Susan | Frost, Debra | Ellis, Steve D. | Platte, Radka | Fineberg, Elena | Evans, D. Gareth | Lalloo, Fiona | Izatt, Louise | Eeles, Ros | Adlard, Julian | Davidson, Rosemarie | Eccles, Diana | Cole, Trevor | Cook, Jackie | Brewer, Carole | Tischkowitz, Marc | Godwin, Andrew K. | Pathak, Harsh | Stoppa-Lyonnet, Dominique | Sinilnikova, Olga M. | Mazoyer, Sylvie | Barjhoux, Laure | Léoné, Mélanie | Gauthier-Villars, Marion | Caux-Moncoutier, Virginie | de Pauw, Antoine | Hardouin, Agnès | Berthet, Pascaline | Dreyfus, Hélène | Ferrer, Sandra Fert | Collonge-Rame, Marie-Agnès | Sokolowska, Johanna | Buys, Saundra | Daly, Mary | Miron, Alex | Terry, Mary Beth | Chung, Wendy | John, Esther M | Southey, Melissa | Goldgar, David | Singer, Christian F | Maria, Muy-Kheng Tea | Gschwantler-Kaulich, Daphne | Fink-Retter, Anneliese | Hansen, Thomas v. O. | Ejlertsen, Bent | Johannsson, Oskar Th. | Offit, Kenneth | Sarrel, Kara | Gaudet, Mia M. | Vijai, Joseph | Robson, Mark | Piedmonte, Marion R | Andrews, Lesley | Cohn, David | DeMars, Leslie R. | DiSilvestro, Paul | Rodriguez, Gustavo | Toland, Amanda Ewart | Montagna, Marco | Agata, Simona | Imyanitov, Evgeny | Isaacs, Claudine | Janavicius, Ramunas | Lazaro, Conxi | Blanco, Ignacio | Ramus, Susan J | Sucheston, Lara | Karlan, Beth Y. | Gross, Jenny | Ganz, Patricia A. | Beattie, Mary S. | Schmutzler, Rita K. | Wappenschmidt, Barbara | Meindl, Alfons | Arnold, Norbert | Niederacher, Dieter | Preisler-Adams, Sabine | Gadzicki, Dorotehea | Varon-Mateeva, Raymonda | Deissler, Helmut | Gehrig, Andrea | Sutter, Christian | Kast, Karin | Nevanlinna, Heli | Aittomäki, Kristiina | Simard, Jacques | Spurdle, Amanda B. | Beesley, Jonathan | Chen, Xiaoqing | Tomlinson, Gail E. | Weitzel, Jeffrey | Garber, Judy E. | Olopade, Olufunmilayo I. | Rubinstein, Wendy S. | Tung, Nadine | Blum, Joanne L. | Narod, Steven A. | Brummel, Sean | Gillen, Daniel L. | Lindor, Noralane | Fredericksen, Zachary | Pankratz, Vernon S. | Couch, Fergus J. | Radice, Paolo | Peterlongo, Paolo | Greene, Mark H. | Loud, Jennifer T. | Mai, Phuong L. | Andrulis, Irene L. | Glendon, Gord | Ozcelik, Hilmi | Gerdes, Anne-Marie | Thomassen, Mads | Jensen, Uffe Birk | Skytte, Anne-Bine | Caligo, Maria A. | Lee, Andrew | Chenevix-Trench, Georgia | Antoniou, Antonis C | Neuhausen, Susan L.
We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers.
IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers.
Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 [Hazard ratio (HR) = 1.43; 95% CI: 1.06–1.92; p = 0.019] and BRCA2 mutation carriers (HR=2.21; 95% CI: 1.39–3.52, p=0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class 2 mutations than class 1 (mutations (class 2 HR=1.86, 95% CI: 1.28–2.70; class 1 HR=0.86, 95%CI:0.69–1.09; p-for difference=0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class 2 mutation carriers (HR = 2.42; p = 0.03).
The IRS1 Gly972Arg SNP, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class 2 mutation carriers.
These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.
PMCID: PMC3415567  PMID: 22729394
Breast cancer; Ovarian cancer; BRCA1 and BRCA2 mutation carriers; insulin receptor substrate 1; Insulin-like growth factor /insulin (IGF/INS) signaling
14.  Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers 
Antoniou, Antonis C | Kartsonaki, Christiana | Sinilnikova, Olga M. | Soucy, Penny | McGuffog, Lesley | Healey, Sue | Lee, Andrew | Peterlongo, Paolo | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Cattaneo, Elisa | Barile, Monica | Pensotti, Valeria | Pasini, Barbara | Dolcetti, Riccardo | Giannini, Giuseppe | Laura Putignano, Anna | Varesco, Liliana | Radice, Paolo | Mai, Phuong L. | Greene, Mark H. | Andrulis, Irene L. | Glendon, Gord | Ozcelik, Hilmi | Thomassen, Mads | Gerdes, Anne-Marie | Kruse, Torben A. | Birk Jensen, Uffe | Crüger, Dorthe G. | Caligo, Maria A. | Laitman, Yael | Milgrom, Roni | Kaufman, Bella | Paluch-Shimon, Shani | Friedman, Eitan | Loman, Niklas | Harbst, Katja | Lindblom, Annika | Arver, Brita | Ehrencrona, Hans | Melin, Beatrice | Nathanson, Katherine L. | Domchek, Susan M. | Rebbeck, Timothy | Jakubowska, Ania | Lubinski, Jan | Gronwald, Jacek | Huzarski, Tomasz | Byrski, Tomasz | Cybulski, Cezary | Gorski, Bohdan | Osorio, Ana | Ramón y Cajal, Teresa | Fostira, Florentia | Andrés, Raquel | Benitez, Javier | Hamann, Ute | Hogervorst, Frans B. | Rookus, Matti A. | Hooning, Maartje J. | Nelen, Marcel R. | van der Luijt, Rob B. | van Os, Theo A.M. | van Asperen, Christi J. | Devilee, Peter | Meijers-Heijboer, Hanne E.J. | Gómez Garcia, Encarna B. | Peock, Susan | Cook, Margaret | Frost, Debra | Platte, Radka | Leyland, Jean | Gareth Evans, D. | Lalloo, Fiona | Eeles, Ros | Izatt, Louise | Adlard, Julian | Davidson, Rosemarie | Eccles, Diana | Ong, Kai-ren | Cook, Jackie | Douglas, Fiona | Paterson, Joan | John Kennedy, M. | Miedzybrodzka, Zosia | Godwin, Andrew | Stoppa-Lyonnet, Dominique | Buecher, Bruno | Belotti, Muriel | Tirapo, Carole | Mazoyer, Sylvie | Barjhoux, Laure | Lasset, Christine | Leroux, Dominique | Faivre, Laurence | Bronner, Myriam | Prieur, Fabienne | Nogues, Catherine | Rouleau, Etienne | Pujol, Pascal | Coupier, Isabelle | Frénay, Marc | Hopper, John L. | Daly, Mary B. | Terry, Mary B. | John, Esther M. | Buys, Saundra S. | Yassin, Yosuf | Miron, Alexander | Goldgar, David | Singer, Christian F. | Tea, Muy-Kheng | Pfeiler, Georg | Catharina Dressler, Anne | Hansen, Thomas v.O. | Jønson, Lars | Ejlertsen, Bent | Bjork Barkardottir, Rosa | Kirchhoff, Tomas | Offit, Kenneth | Piedmonte, Marion | Rodriguez, Gustavo | Small, Laurie | Boggess, John | Blank, Stephanie | Basil, Jack | Azodi, Masoud | Ewart Toland, Amanda | Montagna, Marco | Tognazzo, Silvia | Agata, Simona | Imyanitov, Evgeny | Janavicius, Ramunas | Lazaro, Conxi | Blanco, Ignacio | Pharoah, Paul D.P. | Sucheston, Lara | Karlan, Beth Y. | Walsh, Christine S. | Olah, Edith | Bozsik, Aniko | Teo, Soo-Hwang | Seldon, Joyce L. | Beattie, Mary S. | van Rensburg, Elizabeth J. | Sluiter, Michelle D. | Diez, Orland | Schmutzler, Rita K. | Wappenschmidt, Barbara | Engel, Christoph | Meindl, Alfons | Ruehl, Ina | Varon-Mateeva, Raymonda | Kast, Karin | Deissler, Helmut | Niederacher, Dieter | Arnold, Norbert | Gadzicki, Dorothea | Schönbuchner, Ines | Caldes, Trinidad | de la Hoya, Miguel | Nevanlinna, Heli | Aittomäki, Kristiina | Dumont, Martine | Chiquette, Jocelyne | Tischkowitz, Marc | Chen, Xiaoqing | Beesley, Jonathan | Spurdle, Amanda B. | Neuhausen, Susan L. | Chun Ding, Yuan | Fredericksen, Zachary | Wang, Xianshu | Pankratz, Vernon S. | Couch, Fergus | Simard, Jacques | Easton, Douglas F. | Chenevix-Trench, Georgia
Human Molecular Genetics  2011;20(16):3304-3321.
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 (r2 = 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 × 10−9 for rs2046210; HR = 1.28, 95% CI: 1.18–1.40, P-trend = 1.3 × 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.
PMCID: PMC3652640  PMID: 21593217
15.  Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) 
Mavaddat, Nasim | Barrowdale, Daniel | Andrulis, Irene L. | Domchek, Susan M. | Eccles, Diana | Nevanlinna, Heli | Ramus, Susan J. | Spurdle, Amanda | Robson, Mark | Sherman, Mark | Mulligan, Anna Marie | Couch, Fergus J. | Engel, Christoph | McGuffog, Lesley | Healey, Sue | Sinilnikova, Olga M. | Southey, Melissa C. | Terry, Mary Beth | Goldgar, David | O’Malley, Frances | John, Esther M. | Janavicius, Ramunas | Tihomirova, Laima | Hansen, Thomas v O | Nielsen, Finn C. | Osorio, Ana | Stavropoulou, Alexandra | Benítez, Javier | Manoukian, Siranoush | Peissel, Bernard | Barile, Monica | Volorio, Sara | Pasini, Barbara | Dolcetti, Riccardo | Putignano, Anna Laura | Ottini, Laura | Radice, Paolo | Hamann, Ute | Rashid, Muhammad U. | Hogervorst, Frans B. | Kriege, Mieke | van der Luijt, Rob B. | Peock, Susan | Frost, Debra | Evans, D. Gareth | Brewer, Carole | Walker, Lisa | Rogers, Mark T. | Side, Lucy E. | Houghton, Catherine | Weaver, JoEllen | Godwin, Andrew K. | Schmutzler, Rita K. | Wappenschmidt, Barbara | Meindl, Alfons | Kast, Karin | Arnold, Norbert | Niederacher, Dieter | Sutter, Christian | Deissler, Helmut | Gadzicki, Doroteha | Preisler-Adams, Sabine | Varon-Mateeva, Raymonda | Schönbuchner, Ines | Gevensleben, Heidrun | Stoppa-Lyonnet, Dominique | Belotti, Muriel | Barjhoux, Laure | Isaacs, Claudine | Peshkin, Beth N. | Caldes, Trinidad | de al Hoya, Miguel | Cañadas, Carmen | Heikkinen, Tuomas | Heikkilä, Päivi | Aittomäki, Kristiina | Blanco, Ignacio | Lazaro, Conxi | Brunet, Joan | Agnarsson, Bjarni A. | Arason, Adalgeir | Barkardottir, Rosa B. | Dumont, Martine | Simard, Jacques | Montagna, Marco | Agata, Simona | D’Andrea, Emma | Yan, Max | Fox, Stephen | Rebbeck, Timothy R. | Rubinstein, Wendy | Tung, Nadine | Garber, Judy E. | Wang, Xianshu | Fredericksen, Zachary | Pankratz, Vernon S. | Lindor, Noralane M. | Szabo, Csilla | Offit, Kenneth | Sakr, Rita | Gaudet, Mia M. | Singer, Christian F. | Tea, Muy-Kheng | Rappaport, Christine | Mai, Phuong L. | Greene, Mark H. | Sokolenko, Anna | Imyanitov, Evgeny | Toland, Amanda Ewart | Senter, Leigha | Sweet, Kevin | Thomassen, Mads | Gerdes, Anne-Marie | Kruse, Torben | Caligo, Maria | Aretini, Paolo | Rantala, Johanna | von Wachenfeld, Anna | Henriksson, Karin | Steele, Linda | Neuhausen, Susan L. | Nussbaum, Bob | Beattie, Mary | Odunsi, Kunle | Sucheston, Lara | Gayther, Simon A | Nathanson, Kate | Gross, Jenny | Walsh, Christine | Karlan, Beth | Chenevix-Trench, Georgia | Easton, Douglas F. | Antoniou, Antonis C.
Previous small studies found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization.
We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian and contralateral breast cancers.
There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (p-trend=1.2×10−5) but increased with age at diagnosis among BRCA2 carriers (p-trend=6.8×10−6). The proportion of triple negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histological grade than ER-positive tumors (Grade 3 vs. Grade 1, p=1.2×10−13 for BRCA1 and p=0.001 for BRCA2). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status (ER-positive odds ratio (OR) for BRCA2=9.4, 95%CI:7.0-12.6 and PR-positive OR=1.7, 95%CI:1.3-2.3, under joint analysis). Lobular tumors were more likely to be BRCA2-related (OR for BRCA2=3.3, 95%CI:2.4-4.4, p=4.4×10−14), and medullary tumors BRCA1-related (OR for BRCA2=0.25, 95%CI:0.18-0.35, p=2.3×10−15). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (p=0.0004 for BRCA1; p=0.002 for BRCA2). There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous:67%; mucinous:1%; endometriod:12%; clear-cell:2%).
Pathology characteristics of BRCA1 and BRCA2 tumors may be useful for improving risk prediction algorithms and informing clinical strategies for screening and prophylaxis.
PMCID: PMC3272407  PMID: 22144499
pathology; breast; BRCA1; BRCA2; contralateral
16.  Transforming CSF Aβ42 measures into calculated Pittsburgh Compound B (PIBcalc) units of brain Aβ amyloid 
PIB PET and CSF Aβ42 demonstrate a highly significant inverse correlation. Both are presumed to measure brain Aβ amyloid load. Our objectives were to develop a method to transform CSF Aβ42 measures into calculated PIB measures (PIBcalc) of Aβ amyloid load, and to partially validate the method in an independent sample of subjects.
Forty-one ADNI subjects underwent PIB PET imaging and lumbar puncture (LP) at the same time. This sample, referred to as the “training” sample (9 cognitively normal (CN), 22 MCI, and 10 AD), was used to develop a regression model by which CSF Aβ42 (with APOE ε4 genotype as a covariate) was transformed into units of PIB PET (PIBcalc). An independent “supporting” sample of 362 (105 CN, 164 MCI, 93AD) ADNI subjects who underwent LP but not PIB PET imaging had their CSF Aβ42 values converted to PIBcalc. These values were compared to the overall PIB PET distribution found in the ADNI subjects (n = 102).
A linear regression model demonstrates good prediction of actual PIB PET from CSF Aβ42 measures obtained in the training sample (R2 = 0.77, P<0.001). PIBcalc data (derived from CSF Aβ42) in the supporting sample of 362 ADNI subjects who underwent LP but not PIB PET imaging demonstrates group-wise distributions that are highly consistent with the larger ADNI PIB PET distribution and with published PIB PET imaging studies.
Although the precise parameters of this model are specific for the ADNI sample, we conclude that CSF Aβ42 can be transformed into calculated PIB (PIBcalc) measures of Aβ amyloid load. Brain Aβ amyloid load can be ascertained at baseline in therapeutic or observational studies by either CSF or amyloid PET imaging and the data can be pooled using well-established multiple imputation techniques that account for the uncertainty in a CSF-based calculated PIB value.
PMCID: PMC3060961  PMID: 21282074
Alzheimer's disease; Pittsburgh Compound B; amyloid imaging; Aβ amyloid; cerebrospinal fluid; Alzheimer's disease biomarkers
17.  Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers 
Antoniou, Antonis C | Kuchenbaecker, Karoline B | Soucy, Penny | Beesley, Jonathan | Chen, Xiaoqing | McGuffog, Lesley | Lee, Andrew | Barrowdale, Daniel | Healey, Sue | Sinilnikova, Olga M | Caligo, Maria A | Loman, Niklas | Harbst, Katja | Lindblom, Annika | Arver, Brita | Rosenquist, Richard | Karlsson, Per | Nathanson, Kate | Domchek, Susan | Rebbeck, Tim | Jakubowska, Anna | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Złowowcka-Perłowska, Elżbieta | Osorio, Ana | Durán, Mercedes | Andrés, Raquel | Benítez, Javier | Hamann, Ute | Hogervorst, Frans B | van Os , Theo A | Verhoef, Senno | Meijers-Heijboer, Hanne EJ | Wijnen, Juul | Gómez Garcia, Encarna B | Ligtenberg, Marjolijn J | Kriege, Mieke | Collée, J Margriet | Ausems, Margreet GEM | Oosterwijk, Jan C | Peock, Susan | Frost, Debra | Ellis, Steve D | Platte, Radka | Fineberg, Elena | Evans, D Gareth | Lalloo, Fiona | Jacobs, Chris | Eeles, Ros | Adlard, Julian | Davidson, Rosemarie | Cole, Trevor | Cook, Jackie | Paterson, Joan | Douglas, Fiona | Brewer, Carole | Hodgson, Shirley | Morrison, Patrick J | Walker, Lisa | Rogers, Mark T | Donaldson, Alan | Dorkins, Huw | Godwin, Andrew K | Bove, Betsy | Stoppa-Lyonnet, Dominique | Houdayer, Claude | Buecher, Bruno | de Pauw, Antoine | Mazoyer, Sylvie | Calender, Alain | Léoné, Mélanie | Bressac- de Paillerets, Brigitte | Caron, Olivier | Sobol, Hagay | Frenay, Marc | Prieur, Fabienne | Ferrer, Sandra Fert | Mortemousque, Isabelle | Buys, Saundra | Daly, Mary | Miron, Alexander | Terry, Mary Beth | Hopper, John L | John, Esther M | Southey, Melissa | Goldgar, David | Singer, Christian F | Fink-Retter, Anneliese | Tea, Muy-Kheng | Kaulich, Daphne Geschwantler | Hansen, Thomas VO | Nielsen, Finn C | Barkardottir, Rosa B | Gaudet, Mia | Kirchhoff, Tomas | Joseph, Vijai | Dutra-Clarke, Ana | Offit, Kenneth | Piedmonte, Marion | Kirk, Judy | Cohn, David | Hurteau, Jean | Byron, John | Fiorica, James | Toland, Amanda E | Montagna, Marco | Oliani, Cristina | Imyanitov, Evgeny | Isaacs, Claudine | Tihomirova, Laima | Blanco, Ignacio | Lazaro, Conxi | Teulé, Alex | Valle, J Del | Gayther, Simon A | Odunsi, Kunle | Gross, Jenny | Karlan, Beth Y | Olah, Edith | Teo, Soo-Hwang | Ganz, Patricia A | Beattie, Mary S | Dorfling, Cecelia M | van Rensburg, Elizabeth Jansen | Diez, Orland | Kwong, Ava | Schmutzler, Rita K | Wappenschmidt, Barbara | Engel, Christoph | Meindl, Alfons | Ditsch, Nina | Arnold, Norbert | Heidemann, Simone | Niederacher, Dieter | Preisler-Adams, Sabine | Gadzicki, Dorothea | Varon-Mateeva, Raymonda | Deissler, Helmut | Gehrig, Andrea | Sutter, Christian | Kast, Karin | Fiebig, Britta | Schäfer, Dieter | Caldes, Trinidad | de la Hoya, Miguel | Nevanlinna, Heli | Muranen, Taru A | Lespérance, Bernard | Spurdle, Amanda B | Neuhausen, Susan L | Ding, Yuan C | Wang, Xianshu | Fredericksen, Zachary | Pankratz, Vernon S | Lindor, Noralane M | Peterlongo, Paolo | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Bonanni, Bernardo | Bernard, Loris | Dolcetti, Riccardo | Papi, Laura | Ottini, Laura | Radice, Paolo | Greene, Mark H | Loud, Jennifer T | Andrulis, Irene L | Ozcelik, Hilmi | Mulligan, Anna Marie | Glendon, Gord | Thomassen, Mads | Gerdes, Anne-Marie | Jensen, Uffe B | Skytte, Anne-Bine | Kruse, Torben A | Chenevix-Trench, Georgia | Couch, Fergus J | Simard, Jacques | Easton, Douglas F
Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2).
To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework.
Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 × 10-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 × 10-5, P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df-P = 0.007; rs1292011 2df-P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 × 10-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049).
The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.
PMCID: PMC3496151  PMID: 22348646
18.  Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 
Mulligan, Anna Marie | Couch, Fergus J | Barrowdale, Daniel | Domchek, Susan M | Eccles, Diana | Nevanlinna, Heli | Ramus, Susan J | Robson, Mark | Sherman, Mark | Spurdle, Amanda B | Wappenschmidt, Barbara | Lee, Andrew | McGuffog, Lesley | Healey, Sue | Sinilnikova, Olga M | Janavicius, Ramunas | Hansen, Thomas vO | Nielsen, Finn C | Ejlertsen, Bent | Osorio, Ana | Muñoz-Repeto, Iván | Durán, Mercedes | Godino, Javier | Pertesi, Maroulio | Benítez, Javier | Peterlongo, Paolo | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Cattaneo, Elisa | Bonanni, Bernardo | Viel, Alessandra | Pasini, Barbara | Papi, Laura | Ottini, Laura | Savarese, Antonella | Bernard, Loris | Radice, Paolo | Hamann, Ute | Verheus, Martijn | Meijers-Heijboer, Hanne EJ | Wijnen, Juul | Gómez García, Encarna B | Nelen, Marcel R | Kets, C Marleen | Seynaeve, Caroline | Tilanus-Linthorst, Madeleine MA | van der Luijt, Rob B | Os, Theo van | Rookus, Matti | Frost, Debra | Jones, J Louise | Evans, D Gareth | Lalloo, Fiona | Eeles, Ros | Izatt, Louise | Adlard, Julian | Davidson, Rosemarie | Cook, Jackie | Donaldson, Alan | Dorkins, Huw | Gregory, Helen | Eason, Jacqueline | Houghton, Catherine | Barwell, Julian | Side, Lucy E | McCann, Emma | Murray, Alex | Peock, Susan | Godwin, Andrew K | Schmutzler, Rita K | Rhiem, Kerstin | Engel, Christoph | Meindl, Alfons | Ruehl, Ina | Arnold, Norbert | Niederacher, Dieter | Sutter, Christian | Deissler, Helmut | Gadzicki, Dorothea | Kast, Karin | Preisler-Adams, Sabine | Varon-Mateeva, Raymonda | Schoenbuchner, Ines | Fiebig, Britta | Heinritz, Wolfram | Schäfer, Dieter | Gevensleben, Heidrun | Caux-Moncoutier, Virginie | Fassy-Colcombet, Marion | Cornelis, François | Mazoyer, Sylvie | Léoné, Mélanie | Boutry-Kryza, Nadia | Hardouin, Agnès | Berthet, Pascaline | Muller, Danièle | Fricker, Jean-Pierre | Mortemousque, Isabelle | Pujol, Pascal | Coupier, Isabelle | Lebrun, Marine | Kientz, Caroline | Longy, Michel | Sevenet, Nicolas | Stoppa-Lyonnet, Dominique | Isaacs, Claudine | Caldes, Trinidad | de la Hoya, Miguel | Heikkinen, Tuomas | Aittomäki, Kristiina | Blanco, Ignacio | Lazaro, Conxi | Barkardottir, Rosa B | Soucy, Penny | Dumont, Martine | Simard, Jacques | Montagna, Marco | Tognazzo, Silvia | D'Andrea, Emma | Fox, Stephen | Yan, Max | Rebbeck, Tim | Olopade, Olufunmilayo I | Weitzel, Jeffrey N | Lynch, Henry T | Ganz, Patricia A | Tomlinson, Gail E | Wang, Xianshu | Fredericksen, Zachary | Pankratz, Vernon S | Lindor, Noralane M | Szabo, Csilla | Offit, Kenneth | Sakr, Rita | Gaudet, Mia | Bhatia, Jasmine | Kauff, Noah | Singer, Christian F | Tea, Muy-Kheng | Gschwantler-Kaulich, Daphne | Fink-Retter, Anneliese | Mai, Phuong L | Greene, Mark H | Imyanitov, Evgeny | O'Malley, Frances P | Ozcelik, Hilmi | Glendon, Gordon | Toland, Amanda E | Gerdes, Anne-Marie | Thomassen, Mads | Kruse, Torben A | Jensen, Uffe Birk | Skytte, Anne-Bine | Caligo, Maria A | Soller, Maria | Henriksson, Karin | Wachenfeldt, von Anna | Arver, Brita | Stenmark-Askmalm, Marie | Karlsson, Per | Ding, Yuan Chun | Neuhausen, Susan L | Beattie, Mary | Pharoah, Paul DP | Moysich, Kirsten B | Nathanson, Katherine L | Karlan, Beth Y | Gross, Jenny | John, Esther M | Daly, Mary B | Buys, Saundra M | Southey, Melissa C | Hopper, John L | Terry, Mary Beth | Chung, Wendy | Miron, Alexander F | Goldgar, David | Chenevix-Trench, Georgia | Easton, Douglas F | Andrulis, Irene L | Antoniou, Antonis C
Breast Cancer Research : BCR  2011;13(6):R110.
Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour.
We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach.
The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status.
The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.
PMCID: PMC3326552  PMID: 22053997
19.  Cystic Fibrosis Transmembrane Conductance Regulator Gene Mutation and Lung Cancer Risk 
The cystic fibrosis transmembrane conductance regulator (CFTR) holds an important role in retaining lung function, but its association with lung cancer is unclear. A case-control study was conducted to determine the possible associations of the genetic variants in the CFTR gene with lung cancer risk. Genotypes of a most common deletion ΔF508, one functional SNP, and eight tag SNPs in the CFTR gene were determined in 574 lung cancer patients and 679 controls. A logistic regression model, adjusting for known risk factors, was used to evaluate the association of each variant with lung cancer risk, as confirmation haplotype and sub-haplotype analyses were performed. ΔF508 deletion and genotypes with minor alleles in one tag SNP, rs10487372, and one functional SNP, rs213950, were inversely associated with lung cancer risk. The results of haplotype and sub-haplotype analyses were consistent with single variant analysis, all pointing to deletion ΔF508 being the key variant for significant haplotypes and sub-haplotypes. Individuals with ‘deletion-T’ (ΔF508/rs10487372) haplotype had a 68% reduced risk for lung cancer compared to common haplotype ‘no-deletion-C’ (OR=0.32; 95% CI=0.15–0.68; p=0.01). Genetic variations in the CFTR gene might modulate the risk of lung cancer. This study, for the first time, provides evidence of a protective role of the CFTR deletion carrier in the etiology of lung cancer.
PMCID: PMC2895007  PMID: 20116881
Cystic fibrosis transmembrane conductance regulator; lung cancer; genetic variation
20.  Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction 
Antoniou, Antonis C | Beesley, Jonathan | McGuffog, Lesley | Sinilnikova, Olga M. | Healey, Sue | Neuhausen, Susan L. | Ding, Yuan Chun | Rebbeck, Timothy R. | Weitzel, Jeffrey N. | Lynch, Henry T. | Isaacs, Claudine | Ganz, Patricia A. | Tomlinson, Gail | Olopade, Olufunmilayo I. | Couch, Fergus J. | Wang, Xianshu | Lindor, Noralane M. | Pankratz, Vernon S. | Radice, Paolo | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Barile, Monica | Viel, Alessandra | Allavena, Anna | Dall’Olio, Valentina | Peterlongo, Paolo | Szabo, Csilla I. | Zikan, Michal | Claes, Kathleen | Poppe, Bruce | Foretova, Lenka | Mai, Phuong L. | Greene, Mark H. | Rennert, Gad | Lejbkowicz, Flavio | Glendon, Gord | Ozcelik, Hilmi | Andrulis, Irene L. | Thomassen, Mads | Gerdes, Anne-Marie | Sunde, Lone | Cruger, Dorthe | Jensen, Uffe Birk | Caligo, Maria | Friedman, Eitan | Kaufman, Bella | Laitman, Yael | Milgrom, Roni | Dubrovsky, Maya | Cohen, Shimrit | Borg, Ake | Jernström, Helena | Lindblom, Annika | Rantala, Johanna | Stenmark-Askmalm, Marie | Melin, Beatrice | Nathanson, Kate | Domchek, Susan | Jakubowska, Ania | Lubinski, Jan | Huzarski, Tomasz | Osorio, Ana | Lasa, Adriana | Durán, Mercedes | Tejada, Maria-Isabel | Godino, Javier | Benitez, Javier | Hamann, Ute | Kriege, Mieke | Hoogerbrugge, Nicoline | van der Luijt, Rob B | van Asperen, Christi J | Devilee, Peter | Meijers-Heijboer, E.J. | Blok, Marinus J | Aalfs, Cora M. | Hogervorst, Frans | Rookus, Matti | Cook, Margaret | Oliver, Clare | Frost, Debra | Conroy, Don | Evans, D. Gareth | Lalloo, Fiona | Pichert, Gabriella | Davidson, Rosemarie | Cole, Trevor | Cook, Jackie | Paterson, Joan | Hodgson, Shirley | Morrison, Patrick J. | Porteous, Mary E. | Walker, Lisa | Kennedy, M. John | Dorkins, Huw | Peock, Susan | Godwin, Andrew K. | Stoppa-Lyonnet, Dominique | de Pauw, Antoine | Mazoyer, Sylvie | Bonadona, Valérie | Lasset, Christine | Dreyfus, Hélène | Leroux, Dominique | Hardouin, Agnès | Berthet, Pascaline | Faivre, Laurence | Loustalot, Catherine | Noguchi, Tetsuro | Sobol, Hagay | Rouleau, Etienne | Nogues, Catherine | Frénay, Marc | Vénat-Bouvet, Laurence | Hopper, John L. | Daly, Mary B. | Terry, Mary B. | John, Esther M. | Buys, Saundra S. | Yassin, Yosuf | Miron, Alex | Goldgar, David | Singer, Christian F. | Dressler, Anne Catharina | Gschwantler-Kaulich, Daphne | Pfeiler, Georg | Hansen, Thomas V. O. | Jønson, Lars | Agnarsson, Bjarni A. | Kirchhoff, Tomas | Offit, Kenneth | Devlin, Vincent | Dutra-Clarke, Ana | Piedmonte, Marion | Rodriguez, Gustavo C. | Wakeley, Katie | Boggess, John F. | Basil, Jack | Schwartz, Peter E. | Blank, Stephanie V. | Toland, Amanda Ewart | Montagna, Marco | Casella, Cinzia | Imyanitov, Evgeny | Tihomirova, Laima | Blanco, Ignacio | Lazaro, Conxi | Ramus, Susan J. | Sucheston, Lara | Karlan, Beth Y. | Gross, Jenny | Schmutzler, Rita | Wappenschmidt, Barbara | Engel, Christoph | Meindl, Alfons | Lochmann, Magdalena | Arnold, Norbert | Heidemann, Simone | Varon-Mateeva, Raymonda | Niederacher, Dieter | Sutter, Christian | Deissler, Helmut | Gadzicki, Dorothea | Preisler-Adams, Sabine | Kast, Karin | Schönbuchner, Ines | Caldes, Trinidad | de la Hoya, Miguel | Aittomäki, Kristiina | Nevanlinna, Heli | Simard, Jacques | Spurdle, Amanda B. | Holland, Helene | Chen, Xiaoqing | Platte, Radka | Chenevix-Trench, Georgia | Easton, Douglas F.
Cancer research  2010;70(23):9742-9754.
The known breast cancer (BC) susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1,LSP1 and 2q35 confer increased risks of BC for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of three additional SNPs, rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11 and rs10941679 at 5p12 and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased BC risk for BRCA2 carriers (per-allele Hazard Ratio (HR)=1.10, 95%CI:1.03-1.18, p=0.006 and HR=1.09, 95%CI:1.01-1.19, p=0.03, respectively). Neither SNP was associated with BC risk for BRCA1 carriers and rs6504950 was not associated with BC for either BRCA1 or BRCA2 carriers. Of the nine polymorphisms investigated, seven were associated with BC for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, p-values:7×10−11-0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (p=0.0049, 0.03 respectively). All risk associated polymorphisms appear to interact multiplicatively on BC risk for mutation carriers. Based on the joint genotype distribution of the seven risk associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e. between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing BC by age 80, compared with 42-50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences may be sufficient to influence the clinical management of mutation carriers.
PMCID: PMC2999830  PMID: 21118973
BRCA1; BRCA2; genetic modifier; common variant; genome-wide association study; penetrance; genetic counseling
21.  Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers 
Walker, Logan C | Fredericksen, Zachary S | Wang, Xianshu | Tarrell, Robert | Pankratz, Vernon S | Lindor, Noralane M | Beesley, Jonathan | Healey, Sue | Chen, Xiaoqing | Stoppa-Lyonnet, Dominique | Tirapo, Carole | Giraud, Sophie | Mazoyer, Sylvie | Muller, Danièle | Fricker, Jean-Pierre | Delnatte, Capucine | Schmutzler, Rita K | Wappenschmidt, Barbara | Engel, Christoph | Schönbuchner, Ines | Deissler, Helmut | Meindl, Alfons | Hogervorst, Frans B | Verheus, Martijn | Hooning, Maartje J | van den Ouweland, Ans MW | Nelen, Marcel R | Ausems, Margreet GEM | Aalfs, Cora M | van Asperen, Christi J | Devilee, Peter | Gerrits, Monique M | Waisfisz, Quinten | Szabo, Csilla I | Easton, Douglas F | Peock, Susan | Cook, Margaret | Oliver, Clare T | Frost, Debra | Harrington, Patricia | Evans, D Gareth | Lalloo, Fiona | Eeles, Ros | Izatt, Louise | Chu, Carol | Davidson, Rosemarie | Eccles, Diana | Ong, Kai-Ren | Cook, Jackie | Rebbeck, Tim | Nathanson, Katherine L | Domchek, Susan M | Singer, Christian F | Gschwantler-Kaulich, Daphne | Dressler, Anne-Catharina | Pfeiler, Georg | Godwin, Andrew K | Heikkinen, Tuomas | Nevanlinna, Heli | Agnarsson, Bjarni A | Caligo, Maria Adelaide | Olsson, Håkan | Kristoffersson, Ulf | Liljegren, Annelie | Arver, Brita | Karlsson, Per | Melin, Beatrice | Sinilnikova, Olga M | McGuffog, Lesley | Antoniou, Antonis C | Chenevix-Trench, Georgia | Spurdle, Amanda B | Couch, Fergus J
Breast Cancer Research : BCR  2010;12(6):R102.
Current attempts to identify genetic modifiers of BRCA1 and BRCA2 associated risk have focused on a candidate gene approach, based on knowledge of gene functions, or the development of large genome-wide association studies. In this study, we evaluated 24 SNPs tagged to 14 candidate genes derived through a novel approach that analysed gene expression differences to prioritise candidate modifier genes for association studies.
We successfully genotyped 24 SNPs in a cohort of up to 4,724 BRCA1 and 2,693 BRCA2 female mutation carriers from 15 study groups and assessed whether these variants were associated with risk of breast cancer in BRCA1 and BRCA2 mutation carriers.
SNPs in five of the 14 candidate genes showed evidence of association with breast cancer risk for BRCA1 or BRCA2 carriers (P < 0.05). Notably, the minor alleles of two SNPs (rs7166081 and rs3825977) in high linkage disequilibrium (r2 = 0.77), located at the SMAD3 locus (15q22), were each associated with increased breast cancer risk for BRCA2 mutation carriers (relative risk = 1.25, 95% confidence interval = 1.07 to 1.45, Ptrend = 0.004; and relative risk = 1.20, 95% confidence interval = 1.03 to 1.40, Ptrend = 0.018).
This study provides evidence that the SMAD3 gene, which encodes a key regulatory protein in the transforming growth factor beta signalling pathway and is known to interact directly with BRCA2, may contribute to increased risk of breast cancer in BRCA2 mutation carriers. This finding suggests that genes with expression associated with BRCA1 and BRCA2 mutation status are enriched for the presence of common genetic modifiers of breast cancer risk in these populations.
PMCID: PMC3046447  PMID: 21114847
22.  Brain beta-amyloid measures and magnetic resonance imaging atrophy both predict time-to-progression from mild cognitive impairment to Alzheimer’s disease 
Brain  2010;133(11):3336-3348.
Biomarkers of brain Aβ amyloid deposition can be measured either by cerebrospinal fluid Aβ42 or Pittsburgh compound B positron emission tomography imaging. Our objective was to evaluate the ability of Aβ load and neurodegenerative atrophy on magnetic resonance imaging to predict shorter time-to-progression from mild cognitive impairment to Alzheimer’s dementia and to characterize the effect of these biomarkers on the risk of progression as they become increasingly abnormal. A total of 218 subjects with mild cognitive impairment were identified from the Alzheimer’s Disease Neuroimaging Initiative. The primary outcome was time-to-progression to Alzheimer’s dementia. Hippocampal volumes were measured and adjusted for intracranial volume. We used a new method of pooling cerebrospinal fluid Aβ42 and Pittsburgh compound B positron emission tomography measures to produce equivalent measures of brain Aβ load from either source and analysed the results using multiple imputation methods. We performed our analyses in two phases. First, we grouped our subjects into those who were ‘amyloid positive’ (n = 165, with the assumption that Alzheimer's pathology is dominant in this group) and those who were ‘amyloid negative’ (n = 53). In the second phase, we included all 218 subjects with mild cognitive impairment to evaluate the biomarkers in a sample that we assumed to contain a full spectrum of expected pathologies. In a Kaplan–Meier analysis, amyloid positive subjects with mild cognitive impairment were much more likely to progress to dementia within 2 years than amyloid negative subjects with mild cognitive impairment (50 versus 19%). Among amyloid positive subjects with mild cognitive impairment only, hippocampal atrophy predicted shorter time-to-progression (P < 0.001) while Aβ load did not (P = 0.44). In contrast, when all 218 subjects with mild cognitive impairment were combined (amyloid positive and negative), hippocampal atrophy and Aβ load predicted shorter time-to-progression with comparable power (hazard ratio for an inter-quartile difference of 2.6 for both); however, the risk profile was linear throughout the range of hippocampal atrophy values but reached a ceiling at higher values of brain Aβ load. Our results are consistent with a model of Alzheimer’s disease in which Aβ deposition initiates the pathological cascade but is not the direct cause of cognitive impairment as evidenced by the fact that Aβ load severity is decoupled from risk of progression at high levels. In contrast, hippocampal atrophy indicates how far along the neurodegenerative path one is, and hence how close to progressing to dementia. Possible explanations for our finding that many subjects with mild cognitive impairment have intermediate levels of Aβ load include: (i) individual subjects may reach an Aβ load plateau at varying absolute levels; (ii) some subjects may be more biologically susceptible to Aβ than others; and (iii) subjects with mild cognitive impairment with intermediate levels of Aβ may represent individuals with Alzheimer’s disease co-existent with other pathologies.
PMCID: PMC2965425  PMID: 20935035
mild cognitive impairment; amyloid imaging; magnetic resonance imaging; cerebrospinal fluid; Alzheimer’s disease biomarkers
23.  Functional Assays for Classification of BRCA2 Variants of Uncertain Significance 
Cancer research  2008;68(9):3523-3531.
The assessment of the influence of many rare BRCA2 missense mutations on cancer risk has proved difficult. A multifactorial likelihood model that predicts the odds of cancer causality for missense variants is effective, but is limited by the availability of family data. As an alternative, we developed functional assays that measure the influence of missense mutations on the ability of BRCA2 to repair DNA damage by homologous recombination and to control centriole amplification. We evaluated 22 missense mutations from the BRCA2 DNA binding domain (DBD) that were identified in multiple breast cancer families using these assays and compared the results with those from the likelihood model. Thirteen variants inactivated BRCA2 function in at least one assay; two others truncated BRCA2 by aberrant splicing; and seven had no effect on BRCA2 function. Of 10 variants with odds in favor of causality in the likelihood model of 50:1 or more and a posterior probability of pathogenicity of 0.99, eight inactivated BRCA2 function and the other two caused splicing defects. Four variants and four controls displaying odds in favor of neutrality of 50:1 and posterior probabilities of pathogenicity of at least 1 × 10−3 had no effect on function in either assay. The strong correlation between the functional assays and likelihood model data suggests that these functional assays are an excellent method for identifying inactivating missense mutations in the BRCA2 DBD and that the assays may be a useful addition to models that predict the likelihood of cancer in carriers of missense mutations.
PMCID: PMC2936780  PMID: 18451181
24.  No evidence that GATA3 rs570613 SNP modifies breast cancer risk 
GATA-binding protein 3 (GATA3) is a transcription factor that is crucial to mammary gland morphogenesis and differentiation of progenitor cells, and has been suggested to have a tumor suppressor function. The rs570613 single nucleotide polymorphism (SNP) in intron 4 of GATA3 was previously found to be associated with a reduction in breast cancer risk in the Cancer Genetic Markers of Susceptibility project and in pooled analysis of two case-control studies from Norway and Poland (Ptrend =0.004), with some evidence for a stronger association with estrogen receptor (ER) negative tumours [1]. We genotyped GATA3 rs570613 in 6,388 cases and 4,995 controls from the Breast Cancer Association Consortium (BCAC) and 5,617 BRCA1 and BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). We found no association between this SNP and breast cancer risk in BCAC cases overall (ORper-allele = 1.00, 95% CI 0.94 − 1.05), in ER negative BCAC cases (ORper-allele = 1.02, 95% CI 0.91−1.13), in BRCA1 mutation carriers RRper-allele = 0.99, 95% CI 0.90−1.09) or BRCA2 mutation carriers (RRper-allele = 0.93, 95% CI 0.80−1.07). We conclude that there is no evidence that either GATA3 rs570613, or any variant in strong linkage disequilibrium with it, is associated with breast cancer risk in women.
PMCID: PMC2728174  PMID: 19082709
GATA3; breast cancer; polymorphism; BRCA1 and BRCA2; risk
25.  Microcephalin regulates BRCA2 and Rad51-associated DNA double strand break repair 
Cancer research  2009;69(13):5531-5536.
Microcephalin (MCPH1) is a BRCT-domain containing protein involved in the cellular response to DNA damage that has been implicated in autosomal recessive primary microcephaly. MCPH1 is recruited to sites of DNA double strand breaks by phosphorylated histone H2AX (γH2AX) but the mechanism by which MCPH1 contributes to the repair process remains to be determined. Here we show that MCPH1 binds to BRCA2 and regulates the localization of BRCA2 and Rad51 at sites of DNA damage. The interaction occurs through the N-terminus of BRCA2 and the C-terminal BRCT domains of MCPH1. Disruption of the interaction between MCPH1 and BRCA2 has no effect on the ability of BRCA2 to form a complex with Rad51 but is associated with substantially reduced levels of both BRCA2 and Rad51 at sites of DNA double strand breaks. Uncoupling of MCPH1 from BRCA2 also interferes with Rad51 and BRCA2 dependent homologous recombination repair activity. These results suggest that the role of MCPH1 in the DNA damage response is in part associated with the ability to localize BRCA2 to sites of DNA double stand breaks.
PMCID: PMC2706938  PMID: 19549900
Microcephalin; BRCA2; DNA repair; homologous recombination

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