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  • 1
    Keywords: COHORT ; VARIANTS ; WOMEN ; HEIGHT ; METAANALYSIS ; bias ; ESTROGEN ; GENOME-WIDE ASSOCIATION ; PROGESTERONE-RECEPTOR STATUS ; INOSITOL POLYPHOSPHATES
    Abstract: A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC. Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes-type shrinkage estimator. Six SNPs showed interactions with associated p-values (p(int)) 〈1.1 x 10(-3). None of the observed interactions was significant after accounting for multiple testing. The Bayesian False Discovery Probability was used to rank the findings, which indicated three interactions as being noteworthy at 1% prior probability of interaction. SNP rs6828523 was associated with increased ER-negative BC risk in women 170 cm (OR = 1.22, p = 0.017), but inversely associated with ER-negative BC risk in women 〈160 cm (OR = 0.83, p = 0.039, p(int) = 1.9 x 10(-4)). The inverse association between rs4808801 and overall BC risk was stronger for women who had had four or more pregnancies (OR = 0.85, p = 2.0 x 10(-4)), and absent in women who had had just one (OR = 0.96, p = 0.19, p(int) = 6.1 x 10(-4)). SNP rs11242675 was inversely associated with overall BC risk in never/former smokers (OR = 0.93, p = 2.8 x 10(-5)), but no association was observed in current smokers (OR = 1.07, p = 0.14, p(int) = 3.4 x 10(-4)). In conclusion, recently identified BC susceptibility loci are not strongly modified by established risk factors and the observed potential interactions require confirmation in independent studies. What's new? The recent discovery of 47 susceptibility loci associated with all or estrogen receptor-negative breast cancer provided new opportunities for genetic risk prediction but it remained unclear how exposure levels of environmental (non-genetic) risk factors influenced the risk assessment. In this gene-environment study, the international team examined interactions between the single nucleotide polymorphisms and 13 established environmental risk factors including parity, height and alcohol consumption. Notably, relative risks of breast cancer associated with the susceptibility loci were not strongly modified by environmental risk factors, a finding that, if confirmed, has important implications for the risk assessment in breast cancer.
    Type of Publication: Journal article published
    PubMed ID: 25227710
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  • 2
    Keywords: breast cancer ; Citizen science ; Crowd science ; Crowdsourcing
    Abstract: BACKGROUND: Citizen science, scientific research conducted by non-specialists, has the potential to facilitate biomedical research using available large-scale data, however validating the results is challenging. The Cell Slider is a citizen science project that intends to share images from tumors with the general public, enabling them to score tumor markers independently through an internet-based interface. METHODS: From October 2012 to June 2014, 98,293 Citizen Scientists accessed the Cell Slider web page and scored 180,172 sub-images derived from images of 12,326 tissue microarray cores labeled for estrogen receptor (ER). We evaluated the accuracy of Citizen Scientist's ER classification, and the association between ER status and prognosis by comparing their test performance against trained pathologists. FINDINGS: The area under ROC curve was 0.95 (95% CI 0.94 to 0.96) for cancer cell identification and 0.97 (95% CI 0.96 to 0.97) for ER status. ER positive tumors scored by Citizen Scientists were associated with survival in a similar way to that scored by trained pathologists. Survival probability at 15 years were 0.78 (95% CI 0.76 to 0.80) for ER-positive and 0.72 (95% CI 0.68 to 0.77) for ER-negative tumors based on Citizen Scientists classification. Based on pathologist classification, survival probability was 0.79 (95% CI 0.77 to 0.81) for ER-positive and 0.71 (95% CI 0.67 to 0.74) for ER-negative tumors. The hazard ratio for death was 0.26 (95% CI 0.18 to 0.37) at diagnosis and became greater than one after 6.5 years of follow-up for ER scored by Citizen Scientists, and 0.24 (95% CI 0.18 to 0.33) at diagnosis increasing thereafter to one after 6.7 (95% CI 4.1 to 10.9) years of follow-up for ER scored by pathologists. INTERPRETATION: Crowdsourcing of the general public to classify cancer pathology data for research is viable, engages the public and provides accurate ER data. Crowdsourced classification of research data may offer a valid solution to problems of throughput requiring human input.
    Type of Publication: Journal article published
    PubMed ID: 26288840
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  • 3
  • 4
    Keywords: RISK ; chemotherapy ; MUTATION CARRIERS ; METAANALYSIS ; GENOME-WIDE ASSOCIATION ; CONFER SUSCEPTIBILITY ; CANCER SUSCEPTIBILITY LOCI ; COMMON VARIANTS ; 14Q24.1 RAD51L1 ; IDENTIFIES 3
    Abstract: Invasive lobular breast cancer (ILC) accounts for 10-15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95% CI) for ILC = 1.13 (1.09-1.18), P = 6.0x10(-10); P-het for ILC vs IDC ER+ tumors = 1.8x10(-4)). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P〈0.05. Two SNPs showed significantly stronger associations for ILC than LCIS (rs2981579/10q26/FGFR2, P-het = 0.04 and rs889312/5q11/MAP3K1, P-het = 0.03); and two showed stronger associations for LCIS than ILC (rs6678914/1q32/LGR6, P-het = 0.001 and rs1752911/6q14, P-het = 0.04). In addition, seven of the 75 known loci showed significant differences between ER+ tumors with IDC and ILC histology, three of these showing stronger associations for ILC (rs11249433/1p11, rs2981579/10q26/FGFR2 and rs10995190/10q21/ZNF365) and four associated only with IDC (5p12/rs10941679; rs2588809/14q24/RAD51L1, rs6472903/8q21 and rs1550623/2q31/CDCA7). In conclusion, we have identified one novel lobular breast cancer specific predisposition polymorphism at 7q34, and shown for the first time that common breast cancer polymorphisms predispose to LCIS. We have shown that many of the ER+ breast cancer predisposition loci also predispose to ILC, although there is some heterogeneity between ER+ lobular and ER+ IDC tumors. These data provide evidence for overlapping, but distinct etiological pathways within ER+ breast cancer between morphological subtypes.
    Type of Publication: Journal article published
    PubMed ID: 24743323
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  • 5
  • 6
    Keywords: CELLS ; GROWTH-FACTOR ; SURVIVAL ; DIFFERENTIATION ; COMPLEX ; PHOSPHORYLATION ; PROTEIN-KINASE ; METASTASIS ; chemotherapy ; adenocarcinoma
    Abstract: Background: Annexin A1 (ANXA1) is a protein related with the carcinogenesis process and metastasis formation in many tumors. However, little is known about the prognostic value of ANXA1 in breast cancer. The purpose of this study is to evaluate the association between ANXA1 expression, BRCA1/2 germline carriership, specific tumor subtypes and survival in breast cancer patients. Methods: Clinical-pathological information and follow-up data were collected from nine breast cancer studies from the Breast Cancer Association Consortium (BCAC) (n = 5,752) and from one study of familial breast cancer patients with BRCA1/2 mutations (n = 107). ANXA1 expression was scored based on the percentage of immunohistochemical staining in tumor cells. Survival analyses were performed using a multivariable Cox model. Results: The frequency of ANXA1 positive tumors was higher in familial breast cancer patients with BRCA1/2 mutations than in BCAC patients, with 48.6 % versus 12.4 %, respectively; P 〈 0.0001. ANXA1 was also highly expressed in BCAC tumors that were poorly differentiated, triple negative, EGFR-CK5/6 positive or had developed in patients at a young age. In the first 5 years of follow-up, patients with ANXA1 positive tumors had a worse breast cancer-specific survival (BCSS) than ANXA1 negative (HRadj = 1.35; 95 % CI = 1.05-1.73), but the association weakened after 10 years (HRadj = 1.13; 95 % CI = 0.91-1.40). ANXA1 was a significant independent predictor of survival in HER2+ patients (10-years BCSS: HRadj = 1.70; 95 % CI = 1.17-2.45). Conclusions: ANXA1 is overexpressed in familial breast cancer patients with BRCA1/2 mutations and correlated with poor prognosis features: triple negative and poorly differentiated tumors. ANXA1 might be a biomarker candidate for breast cancer survival prediction in high risk groups such as HER2+ cases.
    Type of Publication: Journal article published
    PubMed ID: 26137966
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  • 7
    Abstract: TP53 overexpression is indicative of somatic TP53 mutations and associates with aggressive tumors and poor prognosis in breast cancer. We utilized a two-stage SNP association study to detect variants associated with breast cancer survival in a TP53-dependent manner. Initially, a genome-wide study (n = 575 cases) was conducted to discover candidate SNPs for genotyping and validation in the Breast Cancer Association Consortium (BCAC). The SNPs were then tested for interaction with tumor TP53 status (n = 4,610) and anthracycline treatment (n = 17,828). For SNPs interacting with anthracycline treatment, siRNA knockdown experiments were carried out to validate candidate genes.In the test for interaction between SNP genotype and TP53 status, we identified one locus, represented by rs10916264 (p(interaction) = 3.44 x 10-5; FDR-adjusted p = 0.0011) in estrogen receptor (ER) positive cases. The rs10916264 AA genotype associated with worse survival among cases with ER-positive, TP53-positive tumors (hazard ratio [HR] 2.36, 95% confidence interval [C.I] 1.45 - 3.82). This is a cis-eQTL locus for FBXO28 and TP53BP2; expression levels of these genes were associated with patient survival specifically in ER-positive, TP53-mutated tumors. Additionally, the SNP rs798755 was associated with survival in interaction with anthracycline treatment (p(interaction) = 9.57 x 10-5, FDR-adjusted p = 0.0130). RNAi-based depletion of a predicted regulatory target gene, FAM53A, indicated that this gene can modulate doxorubicin sensitivity in breast cancer cell lines.If confirmed in independent data sets, these results may be of clinical relevance in the development of prognostic and predictive marker panels for breast cancer.
    Type of Publication: Journal article published
    PubMed ID: 28179588
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  • 8
    Keywords: CANCER ; EXPRESSION ; RISK ; GENE ; SUSCEPTIBILITY ; breast cancer ; PATTERNS ; risk factors ; ESTROGEN-RECEPTOR ; ALLELES ; GENOME-WIDE ASSOCIATION ; CONFER SUSCEPTIBILITY ; COMMON VARIANTS ; PROGESTERONE-RECEPTOR ; BRCA2 MUTATION CARRIERS ; Risk prediction
    Abstract: Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations with ER+ than ER- tumors for six of the eight loci identified in GWAS: rs2981582 (10q26) (P-heterogeneity = 6.1 x 10(-18)), rs3803662 (16q12) (P = 3.7 x 10(-5)), rs13281615 (8q24) (P = 0.002), rs13387042 (2q35) (P = 0.006), rs4973768 (3p24) (P = 0.003) and rs6504950 (17q23) (P = 0.002). The two candidate loci, CASP8 (rs1045485, rs17468277) and TGFB1 (rs1982073), were most strongly related with the risk of PR negative tumors (P = 5.1 x 10(-6) and P = 4.1 x 10(-4), respectively), as previously suggested. Four of the eight loci identified in GWAS were associated with triple negative tumors (P 〈= 0.016): rs3803662 (16q12), rs889312 (5q11), rs3817198 (11p15) and rs13387042 (2q35); however, only two of them (16q12 and 2q35) were associated with tumors with the core basal phenotype (P 〈= 0.002). These analyses are consistent with different biological origins of breast cancers, and indicate that tumor stratification might help in the identification and characterization of novel risk factors for breast cancer subtypes. This may eventually result in further improvements in prevention, early detection and treatment
    Type of Publication: Journal article published
    PubMed ID: 21596841
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  • 9
    Publication Date: 2018-06-26
    Description: Recent studies have reported germline CDH1 mutations in cases of lobular breast cancer (LBC) not associated with the classical hereditary diffuse gastric cancer syndrome. A multidisciplinary workgroup discussed genetic susceptibility, pathophysiology and clinical management of hereditary LBC (HLBC). The team has established the clinical criteria for CDH1 screening and results’ interpretation, and created consensus guidelines regarding genetic counselling, breast surveillance and imaging techniques, clinicopathological findings, psychological and decisional support, as well as prophylactic surgery and plastic reconstruction. Based on a review of current evidence for the identification of HLBC cases/families, CDH1 genetic testing is recommended in patients fulfilling the following criteria: (A) bilateral LBC with or without family history of LBC, with age at onset 〈50 years, and (B) unilateral LBC with family history of LBC, with age at onset 〈45 years. In CDH1 asymptomatic mutant carriers, breast surveillance with clinical examination, yearly mammography, contrast-enhanced breast MRI and breast ultrasonography (US) with 6-month interval between the US and the MRI should be implemented as a first approach. In selected cases with personal history, family history of LBC and CDH1 mutations, prophylactic mastectomy could be discussed with an integrative group of clinical experts. Psychodecisional support also plays a pivotal role in the management of individuals with or without CDH1 germline alterations. Ultimately, the definition of a specific protocol for CDH1 genetic screening and ongoing coordinated management of patients with HLBC is crucial for the effective surveillance and early detection of LBC.
    Print ISSN: 0022-2593
    Electronic ISSN: 1468-6244
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 10
    Publication Date: 2012-04-24
    Description: The elucidation of breast cancer subgroups and their molecular drivers requires integrated views of the genome and transcriptome from representative numbers of patients. We present an integrated analysis of copy number and gene expression in a discovery and validation set of 997 and 995 primary breast tumours, respectively, with long-term clinical follow-up. Inherited variants (copy number variants and single nucleotide polymorphisms) and acquired somatic copy number aberrations (CNAs) were associated with expression in ~40% of genes, with the landscape dominated by cis- and trans-acting CNAs. By delineating expression outlier genes driven in cis by CNAs, we identified putative cancer genes, including deletions in PPP2R2A, MTAP and MAP2K4. Unsupervised analysis of paired DNA-RNA profiles revealed novel subgroups with distinct clinical outcomes, which reproduced in the validation cohort. These include a high-risk, oestrogen-receptor-positive 11q13/14 cis-acting subgroup and a favourable prognosis subgroup devoid of CNAs. Trans-acting aberration hotspots were found to modulate subgroup-specific gene networks, including a TCR deletion-mediated adaptive immune response in the 'CNA-devoid' subgroup and a basal-specific chromosome 5 deletion-associated mitotic network. Our results provide a novel molecular stratification of the breast cancer population, derived from the impact of somatic CNAs on the transcriptome.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3440846/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3440846/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Curtis, Christina -- Shah, Sohrab P -- Chin, Suet-Feung -- Turashvili, Gulisa -- Rueda, Oscar M -- Dunning, Mark J -- Speed, Doug -- Lynch, Andy G -- Samarajiwa, Shamith -- Yuan, Yinyin -- Graf, Stefan -- Ha, Gavin -- Haffari, Gholamreza -- Bashashati, Ali -- Russell, Roslin -- McKinney, Steven -- METABRIC Group -- Langerod, Anita -- Green, Andrew -- Provenzano, Elena -- Wishart, Gordon -- Pinder, Sarah -- Watson, Peter -- Markowetz, Florian -- Murphy, Leigh -- Ellis, Ian -- Purushotham, Arnie -- Borresen-Dale, Anne-Lise -- Brenton, James D -- Tavare, Simon -- Caldas, Carlos -- Aparicio, Samuel -- A7199/Cancer Research UK/United Kingdom -- P50HG02790/HG/NHGRI NIH HHS/ -- Cancer Research UK/United Kingdom -- England -- Nature. 2012 Apr 18;486(7403):346-52. doi: 10.1038/nature10983.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22522925" target="_blank"〉PubMed〈/a〉
    Keywords: Breast Neoplasms/classification/diagnosis/*genetics/*pathology ; DNA Copy Number Variations/*genetics ; Female ; *Gene Expression Profiling ; *Gene Expression Regulation, Neoplastic ; Gene Regulatory Networks/genetics ; Genes, Neoplasm/genetics ; Genome, Human/*genetics ; Genomics ; Humans ; Kaplan-Meier Estimate ; MAP Kinase Kinase 4/genetics ; Polymorphism, Single Nucleotide/genetics ; Prognosis ; Protein Phosphatase 2/genetics ; Treatment Outcome
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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