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1.
Clin Cancer Res ; 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31409615

RESUMO

PURPOSE: Invasive lobular carcinoma (ILC) is a subtype of breast cancer accounting for 10% of breast tumors. The majority of patients are treated with endocrine therapy; however, endocrine resistance is common in estrogen receptor-positive breast cancer and new therapeutic strategies are needed. Bromodomain and extraterminal inhibitors (BETi) are effective in diverse types of breast cancer but they have not yet been assessed in ILC. EXPERIMENTAL DESIGN: We assessed whether targeting the BET proteins with JQ1 could serve as an effective therapeutic strategy in ILC in both 2D and 3D models. We used dynamic BH3 profiling and RNA-sequencing (RNA-seq) to identify transcriptional reprograming enabling resistance to JQ1-induced apoptosis. As part of the RATHER study, we obtained copy-number alterations and RNA-seq on 61 ILC patient samples. RESULTS: Certain ILC cell lines were sensitive to JQ1, while others were intrinsically resistant to JQ1-induced apoptosis. JQ1 treatment led to an enhanced dependence on antiapoptotic proteins and a transcriptional rewiring inducing fibroblast growth factor receptor 1 (FGFR1). This increase in FGFR1 was also evident in invasive ductal carcinoma (IDC) cell lines. The combination of JQ1 and FGFR1 inhibitors was highly effective at inhibiting growth in both 2D and 3D models of ILC and IDC. Interestingly, we found in the RATHER cohort of 61 ILC patients that 20% had FGFR1 amplification and we showed that high BRD3 mRNA expression was associated with poor survival specifically in ILC. CONCLUSIONS: We provide evidence that BETi either alone or in combination with FGFR1 inhibitors or BH3 mimetics may be a useful therapeutic strategy for recurrent ILC patients.

2.
Sci Transl Med ; 11(504)2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391323

RESUMO

Longitudinal analysis of circulating tumor DNA (ctDNA) has shown promise for monitoring treatment response. However, most current methods lack adequate sensitivity for residual disease detection during or after completion of treatment in patients with nonmetastatic cancer. To address this gap and to improve sensitivity for minute quantities of residual tumor DNA in plasma, we have developed targeted digital sequencing (TARDIS) for multiplexed analysis of patient-specific cancer mutations. In reference samples, by simultaneously analyzing 8 to 16 known mutations, TARDIS achieved 91 and 53% sensitivity at mutant allele fractions (AFs) of 3 in 104 and 3 in 105, respectively, with 96% specificity, using input DNA equivalent to a single tube of blood. We successfully analyzed up to 115 mutations per patient in 80 plasma samples from 33 women with stage I to III breast cancer. Before treatment, TARDIS detected ctDNA in all patients with 0.11% median AF. After completion of neoadjuvant therapy, ctDNA concentrations were lower in patients who achieved pathological complete response (pathCR) compared to patients with residual disease (median AFs, 0.003 and 0.017%, respectively, P = 0.0057, AUC = 0.83). In addition, patients with pathCR showed a larger decrease in ctDNA concentrations during neoadjuvant therapy. These results demonstrate high accuracy for assessment of molecular response and residual disease during neoadjuvant therapy using ctDNA analysis. TARDIS has achieved up to 100-fold improvement beyond the current limit of ctDNA detection using clinically relevant blood volumes, demonstrating that personalized ctDNA tracking could enable individualized clinical management of patients with cancer treated with curative intent.

3.
Nat Commun ; 10(1): 2433, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31147552

RESUMO

The original version of this Article omitted from the Author Contributions statement that 'R.S. and J.G.R contributed equally to this work.' This has been corrected in both the PDF and HTML versions of the Article.

4.
Cell Rep ; 27(9): 2690-2708.e10, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31141692

RESUMO

The detailed molecular characterization of lethal cancers is a prerequisite to understanding resistance to therapy and escape from cancer immunoediting. We performed extensive multi-platform profiling of multi-regional metastases in autopsies from 10 patients with therapy-resistant breast cancer. The integrated genomic and immune landscapes show that metastases propagate and evolve as communities of clones, reveal their predicted neo-antigen landscapes, and show that they can accumulate HLA loss of heterozygosity (LOH). The data further identify variable tumor microenvironments and reveal, through analyses of T cell receptor repertoires, that adaptive immune responses appear to co-evolve with the metastatic genomes. These findings reveal in fine detail the landscapes of lethal metastatic breast cancer.

5.
Nature ; 567(7748): 399-404, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30867590

RESUMO

The rates and routes of lethal systemic spread in breast cancer are poorly understood owing to a lack of molecularly characterized patient cohorts with long-term, detailed follow-up data. Long-term follow-up is especially important for those with oestrogen-receptor (ER)-positive breast cancers, which can recur up to two decades after initial diagnosis1-6. It is therefore essential to identify patients who have a high risk of late relapse7-9. Here we present a statistical framework that models distinct disease stages (locoregional recurrence, distant recurrence, breast-cancer-related death and death from other causes) and competing risks of mortality from breast cancer, while yielding individual risk-of-recurrence predictions. We apply this model to 3,240 patients with breast cancer, including 1,980 for whom molecular data are available, and delineate spatiotemporal patterns of relapse across different categories of molecular information (namely immunohistochemical subtypes; PAM50 subtypes, which are based on gene-expression patterns10,11; and integrative or IntClust subtypes, which are based on patterns of genomic copy-number alterations and gene expression12,13). We identify four late-recurring integrative subtypes, comprising about one quarter (26%) of tumours that are both positive for ER and negative for human epidermal growth factor receptor 2, each with characteristic tumour-driving alterations in genomic copy number and a high risk of recurrence (mean 47-62%) up to 20 years after diagnosis. We also define a subgroup of triple-negative breast cancers in which cancer rarely recurs after five years, and a separate subgroup in which patients remain at risk. Use of the integrative subtypes improves the prediction of late, distant relapse beyond what is possible with clinical covariates (nodal status, tumour size, tumour grade and immunohistochemical subtype). These findings highlight opportunities for improved patient stratification and biomarker-driven clinical trials.


Assuntos
Neoplasias da Mama/classificação , Neoplasias da Mama/genética , Recidiva Local de Neoplasia/classificação , Recidiva Local de Neoplasia/genética , Receptores Estrogênicos/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Progressão da Doença , Feminino , Humanos , Modelos Biológicos , Metástase Neoplásica/genética , Recidiva Local de Neoplasia/patologia , Especificidade de Órgãos , Prognóstico , Receptor ErbB-2/deficiência , Receptor ErbB-2/genética , Receptores Estrogênicos/análise , Receptores Estrogênicos/deficiência , Fatores de Tempo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
6.
Cancer Res ; 79(10): 2619-2633, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30885980

RESUMO

The PDLIM2 protein regulates stability of transcription factors including NF-κB and STATs in epithelial and hemopoietic cells. PDLIM2 is strongly expressed in certain cancer cell lines that exhibit an epithelial-to-mesenchymal phenotype, and its suppression is sufficient to reverse this phenotype. PDLIM2 supports the epithelial polarity of nontransformed breast cells, suggesting distinct roles in tumor suppression and oncogenesis. To better understand its overall function, we investigated PDLIM2 expression and activity in breast cancer. PDLIM2 protein was present in 60% of tumors diagnosed as triple-negative breast cancer (TNBC), and only 20% of other breast cancer subtypes. High PDLIM2 expression in TNBC was positively correlated with adhesion signaling and ß-catenin activity. Interestingly, PDLIM2 was restricted to the cytoplasm/membrane of TNBC cells and excluded from the nucleus. In breast cell lines, PDLIM2 retention in the cytoplasm was controlled by cell adhesion, and translocation to the nucleus was stimulated by insulin-like growth factor-1 or TGFß. Cytoplasmic PDLIM2 was associated with active ß-catenin and ectopic expression of PDLIM2 was sufficient to increase ß-catenin levels and its transcriptional activity in reporter assays. Suppression of PDLIM2 inhibited tumor growth in vivo, whereas overexpression of PDLIM2 disrupted growth in 3D cultures. These results suggest that PDLIM2 may serve as a predictive biomarker for a large subset of TNBC whose phenotype depends on adhesion-regulated ß-catenin activity and which may be amenable to therapies that target these pathways. SIGNIFICANCE: This study shows that PDLIM2 expression defines a subset of triple-negative breast cancer that may benefit from targeting the ß-catenin and adhesion signaling pathways. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/10/2619/F1.large.jpg.

7.
Br J Cancer ; 120(6): 647-657, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30787463

RESUMO

BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). RESULTS: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10-7, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10-7, HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. CONCLUSIONS: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.

8.
Nat Commun ; 10(1): 657, 2019 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-30737380

RESUMO

Genomic changes observed across treatment may result from either clonal evolution or geographically disparate sampling of heterogeneous tumors. Here we use computational modeling based on analysis of fifteen primary breast tumors and find that apparent clonal change between two tumor samples can frequently be explained by pre-treatment heterogeneity, such that at least two regions are necessary to detect treatment-induced clonal shifts. To assess for clonal replacement, we devise a summary statistic based on whole-exome sequencing of a pre-treatment biopsy and multi-region sampling of the post-treatment surgical specimen and apply this measure to five breast tumors treated with neoadjuvant HER2-targeted therapy. Two tumors underwent clonal replacement with treatment, and mathematical modeling indicates these two tumors had resistant subclones prior to treatment and rates of resistance-related genomic changes that were substantially larger than previous estimates. Our results provide a needed framework to incorporate primary tumor heterogeneity in investigating the evolution of resistance.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/terapia , Terapia Neoadjuvante/métodos , Receptor ErbB-2/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Modelos Teóricos , Sequenciamento Completo do Exoma/métodos
9.
Genome Med ; 11(1): 1, 2019 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-30609936

RESUMO

Circulating tumour DNA (ctDNA) detection and monitoring have enormous potential clinical utility in oncology. We describe here a fast, flexible and cost-effective method to profile multiple genes simultaneously in low input cell-free DNA (cfDNA): Next Generation-Targeted Amplicon Sequencing (NG-TAS). We designed a panel of 377 amplicons spanning 20 cancer genes and tested the NG-TAS pipeline using cell-free DNA from two HapMap lymphoblastoid cell lines. NG-TAS consistently detected mutations in cfDNA when mutation allele fraction was > 1%. We applied NG-TAS to a clinical cohort of metastatic breast cancer patients, demonstrating its potential in monitoring the disease. The computational pipeline is available at https://github.com/cclab-brca/NGTAS_pipeline .


Assuntos
Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Análise de Sequência de DNA/métodos , Software , Biomarcadores Tumorais/sangue , Linhagem Celular Tumoral , DNA Tumoral Circulante/sangue , Custos e Análise de Custo , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/economia , Humanos , Mutação , Análise de Sequência de DNA/economia
10.
PET Clin ; 13(3): 325-338, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30100073

RESUMO

Breast cancer is a heterogeneous disease, observed traditionally by morphology and protein expression but, more recently with the advent of modern molecular technologies, at the genomic and transcriptomic level. This review describes the association between the different molecular subtypes with the histologic subtypes of breast cancer alongside some of their major genomic characteristics and illustrates how these subtypes may affect the appearance of tumors on imaging studies. The authors aim to show how molecular stratification can be used to augment traditional methods to improve our understanding of breast cancers and their clinical management.

11.
Lancet Gastroenterol Hepatol ; 3(7): 489-498, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29706558

RESUMO

BACKGROUND: Germline pathogenic variants in the E-cadherin gene (CDH1) are strongly associated with the development of hereditary diffuse gastric cancer. There is a paucity of data to guide risk assessment and management of families with hereditary diffuse gastric cancer that do not carry a CDH1 pathogenic variant, making it difficult to make informed decisions about surveillance and risk-reducing surgery. We aimed to identify new candidate genes associated with predisposition to hereditary diffuse gastric cancer in affected families without pathogenic CDH1 variants. METHODS: We did whole-exome sequencing on DNA extracted from the blood of 39 individuals (28 individuals diagnosed with hereditary diffuse gastric cancer and 11 unaffected first-degree relatives) in 22 families without pathogenic CDH1 variants. Genes with loss-of-function variants were prioritised using gene-interaction analysis to identify clusters of genes that could be involved in predisposition to hereditary diffuse gastric cancer. FINDINGS: Protein-affecting germline variants were identified in probands from six families with hereditary diffuse gastric cancer; variants were found in genes known to predispose to cancer and in lesser-studied DNA repair genes. A frameshift deletion in PALB2 was found in one member of a family with a history of gastric and breast cancer. Two different MSH2 variants were identified in two unrelated affected individuals, including one frameshift insertion and one previously described start-codon loss. One family had a unique combination of variants in the DNA repair genes ATR and NBN. Two variants in the DNA repair gene RECQL5 were identified in two unrelated families: one missense variant and a splice-acceptor variant. INTERPRETATION: The results of this study suggest a role for the known cancer predisposition gene PALB2 in families with hereditary diffuse gastric cancer and no detected pathogenic CDH1 variants. We also identified new candidate genes associated with disease risk in these families. FUNDING: UK Medical Research Council (Sackler programme), European Research Council under the European Union's Seventh Framework Programme (2007-13), National Institute for Health Research Cambridge Biomedical Research Centre, Experimental Cancer Medicine Centres, and Cancer Research UK.

12.
J Pathol ; 245(4): 456-467, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29774524

RESUMO

Although mutational inactivation of E-cadherin (CDH1) is the main driver of invasive lobular breast cancer (ILC), approximately 10-15% of all ILCs retain membrane-localized E-cadherin despite the presence of an apparent non-cohesive and invasive lobular growth pattern. Given that ILC is dependent on constitutive actomyosin contraction for tumor development and progression, we used a combination of cell systems and in vivo experiments to investigate the consequences of α-catenin (CTNNA1) loss in the regulation of anchorage independence of non-invasive breast carcinoma. We found that inactivating somatic CTNNA1 mutations in human breast cancer correlated with lobular and mixed ducto-lobular phenotypes. Further, inducible loss of α-catenin in mouse and human E-cadherin-expressing breast cancer cells led to atypical localization of E-cadherin, a rounded cell morphology, and anoikis resistance. Pharmacological inhibition experiments subsequently revealed that, similar to E-cadherin-mutant ILC, anoikis resistance induced by α-catenin loss was dependent on Rho/Rock-dependent actomyosin contractility. Finally, using a transplantation-based conditional mouse model, we demonstrate that inducible inactivation of α-catenin instigates acquisition of lobular features and invasive behavior. We therefore suggest that α-catenin represents a bona fide tumor suppressor for the development of lobular-type breast cancer and as such provides an alternative event to E-cadherin inactivation, adherens junction (AJ) dysfunction, and subsequent constitutive actomyosin contraction. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

13.
Cell ; 173(6): 1398-1412.e22, 2018 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-29731168

RESUMO

Noncoding mutations in cancer genomes are frequent but challenging to interpret. PVT1 encodes an oncogenic lncRNA, but recurrent translocations and deletions in human cancers suggest alternative mechanisms. Here, we show that the PVT1 promoter has a tumor-suppressor function that is independent of PVT1 lncRNA. CRISPR interference of PVT1 promoter enhances breast cancer cell competition and growth in vivo. The promoters of the PVT1 and the MYC oncogenes, located 55 kb apart on chromosome 8q24, compete for engagement with four intragenic enhancers in the PVT1 locus, thereby allowing the PVT1 promoter to regulate pause release of MYC transcription. PVT1 undergoes developmentally regulated monoallelic expression, and the PVT1 promoter inhibits MYC expression only from the same chromosome via promoter competition. Cancer genome sequencing identifies recurrent mutations encompassing the human PVT1 promoter, and genome editing verified that PVT1 promoter mutation promotes cancer cell growth. These results highlight regulatory sequences of lncRNA genes as potential disease-associated DNA elements.

14.
Exp Mol Pathol ; 104(3): 161-169, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29608913

RESUMO

Pathology archives with linked clinical data are an invaluable resource for translational research, with the limitation that most cancer samples are formalin-fixed paraffin-embedded (FFPE) tissues. Therefore, FFPE tissues are an important resource for genomic profiling studies but are under-utilised due to the low amount and quality of extracted nucleic acids. We profiled the copy number landscape of 356 breast cancer patients using DNA extracted FFPE tissues by shallow whole genome sequencing. We generated a total of 491 sequencing libraries from 2 kits and obtained data from 98.4% of libraries with 86.4% being of good quality. We generated libraries from as low as 3.8 ng of input DNA and found that the success was independent of input DNA amount and quality, processing site and age of the fixed tissues. Since copy number alterations (CNA) play a major role in breast cancer, it is imperative that we are able to use FFPE archives and we have shown in this study that sWGS is a robust method to do such profiling.


Assuntos
Neoplasias da Mama/genética , Variações do Número de Cópias de DNA , DNA/análise , Formaldeído/química , Inclusão em Parafina/métodos , Fixação de Tecidos/métodos , Sequenciamento Completo do Genoma/métodos , Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Estudos de Casos e Controles , DNA/genética , Feminino , Perfilação da Expressão Gênica , Genômica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Invasividade Neoplásica , Análise de Sequência de DNA
15.
NPJ Breast Cancer ; 4: 5, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29532008

RESUMO

The integration of genomic and transcriptomic profiles of 2000 breast tumours from the METABRIC [Molecular Taxonomy of Breast Cancer International Consortium] cohort revealed ten subtypes, termed integrative clusters (IntClust/s), characterised by distinct genomic drivers. Central histopathology (N = 1643) review was undertaken to explore the relationship between these ten molecular subtypes and traditional clinicopathological features. IntClust subtypes were significantly associated with histological type, tumour grade, receptor status, and lymphocytic infiltration (p < 0.0001). Lymph node status and Nottingham Prognostic Index [NPI] categories were also significantly associated with IntClust subtype. IntClust 3 was enriched for tubular and lobular carcinomas, the latter largely accounting for the association with CDH1 mutations in this cluster. Mucinous carcinomas were not present in IntClusts 5 or 10, but did not show an association with any of the remaining IntClusts. In contrast, medullary-like cancers were associated with IntClust 10 (15/26). Hormone receptor-positive tumours were scattered across all IntClusts. IntClust 5 was dominated by HER2 positivity (127/151), including both hormone receptor-positive (60/72) and hormone receptor-negative tumours (67/77). Triple-negative tumours comprised the majority of IntClust 10 (132/159) and around a quarter of IntClust 4 (52/217). Whilst the ten IntClust subtypes of breast cancer show characteristic patterns of association with traditional clinicopathological variables, no IntClust can be adequately identified by these variables alone. Hence, the addition of genomic stratification has the potential to enhance the biological relevance of the current clinical evaluation and facilitate genome-guided therapeutic strategies.

16.
BMC Genomics ; 19(1): 19, 2018 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-29304755

RESUMO

BACKGROUND: Patient-Derived Tumour Xenografts (PDTXs) have emerged as the pre-clinical models that best represent clinical tumour diversity and intra-tumour heterogeneity. The molecular characterization of PDTXs using High-Throughput Sequencing (HTS) is essential; however, the presence of mouse stroma is challenging for HTS data analysis. Indeed, the high homology between the two genomes results in a proportion of mouse reads being mapped as human. RESULTS: In this study we generated Whole Exome Sequencing (WES), Reduced Representation Bisulfite Sequencing (RRBS) and RNA sequencing (RNA-seq) data from samples with known mixtures of mouse and human DNA or RNA and from a cohort of human breast cancers and their derived PDTXs. We show that using an In silico Combined human-mouse Reference Genome (ICRG) for alignment discriminates between human and mouse reads with up to 99.9% accuracy and decreases the number of false positive somatic mutations caused by misalignment by >99.9%. We also derived a model to estimate the human DNA content in independent PDTX samples. For RNA-seq and RRBS data analysis, the use of the ICRG allows dissecting computationally the transcriptome and methylome of human tumour cells and mouse stroma. In a direct comparison with previously reported approaches, our method showed similar or higher accuracy while requiring significantly less computing time. CONCLUSIONS: The computational pipeline we describe here is a valuable tool for the molecular analysis of PDTXs as well as any other mixture of DNA or RNA species.


Assuntos
Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Perfilação da Expressão Gênica , Humanos , Camundongos , Mutação , Alinhamento de Sequência , Análise de Sequência de DNA , Análise de Sequência de RNA
17.
Int J Epidemiol ; 46(6): 1814-1822, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29232439

RESUMO

Background: There is increasing evidence that elevated body mass index (BMI) is associated with reduced survival for women with breast cancer. However, the underlying reasons remain unclear. We conducted a Mendelian randomization analysis to investigate a possible causal role of BMI in survival from breast cancer. Methods: We used individual-level data from six large breast cancer case-cohorts including a total of 36 210 individuals (2475 events) of European ancestry. We created a BMI genetic risk score (GRS) based on genotypes at 94 known BMI-associated genetic variants. Association between the BMI genetic score and breast cancer survival was analysed by Cox regression for each study separately. Study-specific hazard ratios were pooled using fixed-effect meta-analysis. Results: BMI genetic score was found to be associated with reduced breast cancer-specific survival for estrogen receptor (ER)-positive cases [hazard ratio (HR) = 1.11, per one-unit increment of GRS, 95% confidence interval (CI) 1.01-1.22, P = 0.03). We observed no association for ER-negative cases (HR = 1.00, per one-unit increment of GRS, 95% CI 0.89-1.13, P = 0.95). Conclusions: Our findings suggest a causal effect of increased BMI on reduced breast cancer survival for ER-positive breast cancer. There is no evidence of a causal effect of higher BMI on survival for ER-negative breast cancer cases.


Assuntos
Índice de Massa Corporal , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Receptores Estrogênicos/genética , Causalidade , Europa (Continente)/epidemiologia , Feminino , Variação Genética , Humanos , Análise da Randomização Mendeliana , Metanálise como Assunto , Polimorfismo de Nucleotídeo Único , Medição de Risco , Fatores de Risco , Análise de Sobrevida
18.
Breast Cancer Res ; 19(1): 99, 2017 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-28851423

RESUMO

BACKGROUND: Patients with BRCA1-like tumors correlate with improved response to DNA double-strand break-inducing therapy. A gene expression-based classifier was developed to distinguish between BRCA1-like and non-BRCA1-like tumors. We hypothesized that these tumors may also be more sensitive to PARP inhibitors than standard treatments. METHODS: A diagnostic gene expression signature (BRCA1ness) was developed using a centroid model with 128 triple-negative breast cancer samples from the EU FP7 RATHER project. This BRCA1ness signature was then tested in HER2-negative patients (n = 116) from the I-SPY 2 TRIAL who received an oral PARP inhibitor veliparib in combination with carboplatin (V-C), or standard chemotherapy alone. We assessed the association between BRCA1ness and pathologic complete response in the V-C and control arms alone using Fisher's exact test, and the relative performance between arms (biomarker × treatment interaction, likelihood ratio p < 0.05) using a logistic model and adjusting for hormone receptor status (HR). RESULTS: We developed a gene expression signature to identify BRCA1-like status. In the I-SPY 2 neoadjuvant setting the BRCA1ness signature associated significantly with response to V-C (p = 0.03), but not in the control arm (p = 0.45). We identified a significant interaction between BRCA1ness and V-C (p = 0.023) after correcting for HR. CONCLUSIONS: A genomic-based BRCA1-like signature was successfully translated to an expression-based signature (BRC1Aness). In the I-SPY 2 neoadjuvant setting, we determined that the BRCA1ness signature is capable of predicting benefit of V-C added to standard chemotherapy compared to standard chemotherapy alone. TRIAL REGISTRATION: I-SPY 2 TRIAL beginning December 31, 2009: Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer (I-SPY 2), NCT01042379 .


Assuntos
Proteína BRCA1/genética , Biomarcadores Tumorais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Análise por Conglomerados , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Terapia Neoadjuvante , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Sensibilidade e Especificidade , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
19.
Genome Med ; 9(1): 35, 2017 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-28420412

RESUMO

Bioinformatic analysis of genomic sequencing data to identify somatic mutations in cancer samples is far from achieving the required robustness and standardisation. In this study we generated a whole exome sequencing benchmark dataset using the platinum genome sample NA12878 and developed an intersect-then-combine (ITC) approach to increase the accuracy in calling single nucleotide variants (SNVs) and indels in tumour-normal pairs. We evaluated the effect of alignment, base quality recalibration, mutation caller and filtering on sensitivity and false positive rate. The ITC approach increased the sensitivity up to 17.1%, without increasing the false positive rate per megabase (FPR/Mb) and its validity was confirmed in a set of clinical samples.


Assuntos
Biologia Computacional/métodos , Genoma Humano , Mutação , Neoplasias/genética , Análise de Sequência de DNA/métodos , Algoritmos , DNA de Neoplasias , Exoma , Humanos , Mutação INDEL , Polimorfismo de Nucleotídeo Único , Sensibilidade e Especificidade
20.
Cancer Res ; 77(14): 3834-3845, 2017 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-28455421

RESUMO

Triple-negative breast cancer (TNBC) patients commonly exhibit poor prognosis and high relapse after treatment, but there remains a lack of biomarkers and effective targeted therapies for this disease. Here, we report evidence highlighting the cell-cycle-related kinase CDK7 as a driver and candidate therapeutic target in TNBC. Using publicly available transcriptomic data from a collated set of TNBC patients (n = 383) and the METABRIC TNBC dataset (n = 217), we found CDK7 mRNA levels to be correlated with patient prognosis. High CDK7 protein expression was associated with poor prognosis within the RATHER TNBC cohort (n = 109) and the METABRIC TNBC cohort (n = 203). The highly specific CDK7 kinase inhibitors, BS-181 and THZ1, each downregulated CDK7-mediated phosphorylation of RNA polymerase II, indicative of transcriptional inhibition, with THZ1 exhibiting 500-fold greater potency than BS-181. Mechanistic investigations revealed that the survival of MDA-MB-231 TNBC cells relied heavily on the BCL-2/BCL-XL signaling axes in cells. Accordingly, we found that combining the BCL-2/BCL-XL inhibitors ABT-263/ABT199 with the CDK7 inhibitor THZ1 synergized in producing growth inhibition and apoptosis of human TNBC cells. Collectively, our results highlight elevated CDK7 expression as a candidate biomarker of poor prognosis in TNBC, and they offer a preclinical proof of concept for combining CDK7 and BCL-2/BCL-XL inhibitors as a mechanism-based therapeutic strategy to improve TNBC treatment. Cancer Res; 77(14); 3834-45. ©2017 AACR.


Assuntos
Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/biossíntese , Inibidores de Proteínas Quinases/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/enzimologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Quinases Ciclina-Dependentes/genética , Feminino , Humanos , Pessoa de Meia-Idade , Fenilenodiaminas/farmacologia , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Pirazóis/farmacologia , Pirimidinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/genética , Proteína bcl-X/antagonistas & inibidores , Proteína bcl-X/metabolismo
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