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1.
Artigo em Inglês | MEDLINE | ID: mdl-31205070

RESUMO

Loss of immunoreactivity in tissue sections has been shown to occur when slide sections are stored at room temperature for prolonged periods of time. We conducted a systematic investigation to determine the extent of staining loss in various storage conditions to determine an optimal storage method. We investigated 6 antibodies that are commonly used for breast cancer subtyping in research studies with immunohistochemistry (ER, PR, HER2, CK5/6, EGFR, and Ki67) in formalin-fixed paraffin-embedded breast tissue microarrays consisting of 148 patients. Tissue microarrays were sectioned at various time points: fresh, 1 week, 1 month, 6 months, and 12 months before staining. Slides sectioned at each time point were stored in 5 storage conditions: desiccator, paraffin dipped, 4°C, -20°C, and -80°C. Immunohistochemistry scores were assessed over time with McNemar Test and Bowker Test of Symmetry. Desiccator storage was the only storage condition that did not show any loss in immunoreactivity for any antibody or time point in our study. Paraffin coated slides were the most difficult storage method operationally and also showed the most loss in immunoreactivity. Storing sections in a desiccator was the most effective method for minimizing immunoreactivity loss. Cold storage at 4°C is an intermediate option that is not as protective as a desiccator, but offers the advantage of being accessible to virtually all research labs.

2.
Cancer Causes Control ; 30(8): 799-811, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31069578

RESUMO

An important premise of epidemiology is that individuals with the same disease share similar underlying etiologies and clinical outcomes. In the past few decades, our knowledge of disease pathogenesis has improved, and disease classification systems have evolved to the point where no complex disease processes are considered homogenous. As a result, pathology and epidemiology have been integrated into the single, unified field of molecular pathological epidemiology (MPE). Advancing integrative molecular and population-level health sciences and addressing the unique research challenges specific to the field of MPE necessitates assembling experts in diverse fields, including epidemiology, pathology, biostatistics, computational biology, bioinformatics, genomics, immunology, and nutritional and environmental sciences. Integrating these seemingly divergent fields can lead to a greater understanding of pathogenic processes. The International MPE Meeting Series fosters discussion that addresses the specific research questions and challenges in this emerging field. The purpose of the meeting series is to: discuss novel methods to integrate pathology and epidemiology; discuss studies that provide pathogenic insights into population impact; and educate next-generation scientists. Herein, we share the proceedings of the Fourth International MPE Meeting, held in Boston, MA, USA, on 30 May-1 June, 2018. Major themes of this meeting included 'integrated genetic and molecular pathologic epidemiology', 'immunology-MPE', and 'novel disease phenotyping'. The key priority areas for future research identified by meeting attendees included integration of tumor immunology and cancer disparities into epidemiologic studies, further collaboration between computational and population-level scientists to gain new insight on exposure-disease associations, and future pooling projects of studies with comparable data.

3.
Clin Breast Cancer ; 19(4): 225-235.e2, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30928413

RESUMO

INTRODUCTION: GATA3 is a critical transcription factor in maintaining the differentiated state of luminal mammary epithelial cells. We sought to determine the prognostic and predictive roles of GATA3 genotypes for breast cancer. PATIENTS AND METHODS: Twelve single nucleotide polymorphisms (SNPs) were genotyped in 2 breast cancer cohorts, including the SWOG S8897 trial where patients were treated with adjuvant chemotherapy (CAF [cyclophosphamide, doxorubicin, 5-fluorouracil] vs. CMF [cyclophosphamide, methotrexate, 5-fluorouracil]) or untreated, and the observational Pathways Study. RESULTS: In the S8897 trial, rs3802604 and rs568727 were associated with disease-free survival and overall survival in the treated group, regardless of chemotherapy regimen. The GG genotype of rs3802604 conferred poorer overall survival (adjusted hazard ratio, 2.45; 95% confidence interval, 1.48-4.05) and disease-free survival (adjusted hazard ratio, 1.95; 95% confidence interval, 1.27-2.99) compared with the AA genotype. Similar associations were found for rs568727. In contrast, no association with either SNP was found in the untreated group. Subgroup analyses indicated that these 2 SNPs more strongly influenced outcomes in the patients who also received tamoxifen. However, the associations in the subgroup with tamoxifen treatment were not replicated in the Pathways Study, possibly owing to substantial differences between the 2 patient cohorts, such as chemotherapy regimen and length of follow-up. Results from joint analyses across these 2 cohorts were marginally significant, driven by the results in S8897. Bioinformatic analyses support potential functional disruption of the GATA3 SNPs in breast tissue. CONCLUSIONS: The present study provides some evidence for the predictive value of GATA3 genotypes for breast cancer adjuvant therapies. Future replication studies in appropriate patient populations are warranted.

4.
Genomics Proteomics Bioinformatics ; 17(2): 211-218, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30959223

RESUMO

As next-generation sequencing (NGS) technology has become widely used to identify genetic causal variants for various diseases and traits, a number of packages for checking NGS data quality have sprung up in public domains. In addition to the quality of sequencing data, sample quality issues, such as gender mismatch, abnormal inbreeding coefficient, cryptic relatedness, and population outliers, can also have fundamental impact on downstream analysis. However, there is a lack of tools specialized in identifying problematic samples from NGS data, often due to the limitation of sample size and variant counts. We developed SeqSQC, a Bioconductor package, to automate and accelerate sample cleaning in NGS data of any scale. SeqSQC is designed for efficient data storage and access, and equipped with interactive plots for intuitive data visualization to expedite the identification of problematic samples. SeqSQC is available at http://bioconductor.org/packages/SeqSQC.

5.
Cancer Med ; 8(4): 1845-1853, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30864286

RESUMO

Young black women are at higher risk of triple-negative breast cancer (TNBC); however, a majority of the genetic studies on cancer predisposition were carried out in White populations. The underrepresentation of minority racial/ethnic populations in cancer genetic studies may have led to disproportionate gaps in our knowledge of cancer predisposition genes in these populations. We surveyed the protein-truncating mutations at the exome-wide scale and in known breast cancer predisposition genes among 170 patients of multiple racial/ethnic groups with early-onset (≤age 50) TNBC from two independent cohorts. Black patients, on average, had a higher number of truncating mutations than Whites at the exome-wide level, but fewer truncating mutations in the panel of known breast cancer genes. White TNBC patients showed a strong enrichment of truncating variants in known breast cancer genes, whereas no such enrichment was found among Black patients. Our findings indicate likely more breast cancer disposition genes yet to be discovered in minority racial/ethnic groups, and the current multigene panels may result in unequal benefits from cancer genetic testing.

6.
Clin Epigenetics ; 11(1): 45, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30867049

RESUMO

BACKGROUND: Little is known about the effects of chemotherapeutic drugs on DNA methylation status of leukocytes, which may be predictive of treatment benefits and toxicities. Based on a prospective national study, we characterize the changes in leukocyte DNA methylome from pre- to post-chemotherapy (approximately 4 months apart) in 93 patients treated for early stage breast cancer and 48 matched non-cancer controls. We further examined significant methylation changes with perceived cognitive impairment, a clinically significant problem related to cancer and chemotherapy. RESULTS: Approximately 4.2% of the CpG sites measured using the Illumina 450K methylation array underwent significant changes after chemotherapy (p < 1e-7), in comparison to a stable DNA methylome in controls. Post-chemotherapy, the estimated relative proportions of B cells and CD4+ T cells were decreased by a median of 100% and 39%, respectively, whereas the proportion of monocytes was increased by a median of 91%. After controlling for leukocyte composition, 568 CpGs from 460 genes were still significantly altered following chemotherapy. With additional adjustment for chemotherapy regimen, cumulative infusions, growth factors, and steroids, changes in four CpGs remained significant, including cg16936953 in VMP1/MIR21, cg01252023 in CORO1B, cg11859398 in SDK1, and cg19956914 in SUMF2. The most significant CpG, cg16936953, was also associated with cognitive decline in breast cancer patients. CONCLUSIONS: Chemotherapy profoundly alters the composition and DNA methylation landscape of leukocytes in breast cancer patients. Our results shed light on the epigenetic response of circulating immune cell populations to cytotoxic chemotherapeutic drugs and provide possible epigenetic links to the degeneration of cognitive function associated with chemotherapy.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Cognição/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Leucócitos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/sangue , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Ilhas de CpG/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Feminino , Humanos , Leucócitos/efeitos dos fármacos , Estadiamento de Neoplasias , Estudos Prospectivos , Resultado do Tratamento
7.
Cancer Causes Control ; 30(2): 187-193, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30656539

RESUMO

PURPOSE: Bladder cancer is one of the top five cancers diagnosed in the U.S. with a high recurrence rate, and also one of the most expensive cancers to treat over the life-course. However, there are few observational, prospective studies of bladder cancer survivors. METHODS: The Bladder Cancer Epidemiology, Wellness, and Lifestyle Study (Be-Well Study) is a National Cancer Institute-funded, multi-center prospective cohort study of non-muscle-invasive bladder cancer (NMIBC) patients (Stage Ta, T1, Tis) enrolled from the Kaiser Permanente Northern California (KPNC) and Southern California (KPSC) health care systems, with genotyping and biomarker assays performed at Roswell Park Comprehensive Cancer Center. The goal is to investigate diet and lifestyle factors in recurrence and progression of NMIBC, with genetic profiles considered, and to build a resource for future NMIBC studies. RESULTS: Recruitment began in February 2015. As of 30 June 2018, 1,281 patients completed the baseline interview (774 KPNC, 511 KPSC) with a recruitment rate of 54%, of whom 77% were male and 23% female, and 80% White, 6% Black, 8% Hispanic, 5% Asian, and 2% other race/ethnicity. Most patients were diagnosed with Ta (69%) or T1 (27%) tumors. Urine and blood specimens were collected from 67% and 73% of consented patients at baseline, respectively. To date, 599 and 261 patients have completed the 12- and 24-month follow-up questionnaires, respectively, with additional urine and saliva collection. CONCLUSIONS: The Be-Well Study will be able to answer novel questions related to diet, other lifestyle, and genetic factors and their relationship to recurrence and progression among early-stage bladder cancer patients.


Assuntos
Recidiva Local de Neoplasia/epidemiologia , Neoplasias da Bexiga Urinária/epidemiologia , Idoso , Idoso de 80 Anos ou mais , California/epidemiologia , Sobreviventes de Câncer , Dieta , Progressão da Doença , Feminino , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/prevenção & controle , Estudos Prospectivos , Neoplasias da Bexiga Urinária/genética
8.
Artigo em Inglês | MEDLINE | ID: mdl-30387004

RESUMO

PURPOSE: In post-menopausal women, high body mass index (BMI) is an established breast cancer risk factor and is associated with worse breast cancer prognosis. We assessed the associations between BMI and gene expression of both breast tumor and adjacent tissue in estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) diseases to help elucidate the mechanisms linking obesity with breast cancer biology in 519 post-menopausal women from the Nurses' Health Study (NHS) and NHSII. METHODS: Differential gene expression was analyzed separately in ER+ and ER- disease both comparing overweight (BMI ≥ 25 to < 30) or obese (BMI ≥ 30) women to women with normal BMI (BMI < 25), and per 5 kg/m2 increase in BMI. Analyses controlled for age and year of diagnosis, physical activity, alcohol consumption, and hormone therapy use. Gene set enrichment analyses were performed and validated among a subset of post-menopausal cases in The Cancer Genome Atlas (for tumor) and Polish Breast Cancer Study (for tumor-adjacent). RESULTS: No gene was differentially expressed by BMI (FDR < 0.05). BMI was significantly associated with increased cellular proliferation pathways, particularly in ER+ tumors, and increased inflammation pathways in ER- tumor and ER- tumor-adjacent tissues (FDR < 0.05). High BMI was associated with upregulation of genes involved in epithelial-mesenchymal transition in ER+ tumor-adjacent tissues. CONCLUSIONS: This study provides insights into molecular mechanisms of BMI influencing post-menopausal breast cancer biology. Tumor and tumor-adjacent tissues provide independent information about potential mechanisms.

9.
Breast Cancer Res ; 20(1): 146, 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30486865

RESUMO

BACKGROUND: The pathophysiology of chemotherapy-induced peripheral neuropathy (CIPN) is not well understood. Currently, dose reduction is the only recommendation for alleviating symptoms, often leading to premature treatment cessation. The primary aim of this analysis was to determine the association between components of diet during taxane treatment for breast cancer and change in CIPN symptoms over treatment. METHODS: Women with stage II or III invasive breast cancer were enrolled into an ancillary study to the North American Breast Cancer Intergroup phase III trial (S0221) led by the Southwest Oncology Group (SWOG). Questionnaires including a food frequency questionnaire and the Functional Assessment of Cancer Treatment Gynecologic Oncology Group-Neurotoxicity were administered to assess diet and neuropathic conditions at baseline and during chemotherapy. Ordinal regression was used to estimate odds ratios (ORs) for associations between various food groups and change in neuropathy score (< 10%, 10-30%, > 30%) (n = 900). RESULTS: The odds of worse neuropathy decreased by 21% for each increase in tertile of grain consumption (OR = 0.79, 95% CI 0.66-0.94, p = 0.009). We also observed a nominal 19% increase with higher consumption of citrus fruits (OR = 1.19, 95% CI 1.01-1.40, p = 0.05). CONCLUSIONS: Distinguishing between those who experienced a moderate and a severe change in neuropathy, we found that citrus fruit and grain consumption may play a role in the severity of symptoms. Since there are no existing dietary recommendations for the management of CIPN, further research is needed to investigate whether there may be certain foods that could worsen or alleviate neuropathy symptoms associated with treatment for breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03413761 . Registered retrospectively on 29 January 2018.

10.
Artigo em Inglês | MEDLINE | ID: mdl-30488344

RESUMO

PURPOSE: The association of recreational physical activity (RPA) with mortality is well established only for breast and colon cancers and few studies have evaluated relationships for exercising before and after diagnosis, across multiple disease sites. We examined the joint associations of pre- and post- diagnosis RPA with mortality in a cohort of 5,807 patients enrolled in the Data Bank and BioRepository at Roswell Park. METHODS: Patients were classified into one of four activity categories (habitually active, increased activity after diagnosis, decreased activity after diagnosis, habitually inactive). Cox proportional hazards models were used to estimate the associations of activity status with mortality. RESULTS: In comparison to patients who were habitually inactive, habitually active patients experienced a 39% decreased hazard of all-cause mortality (HR = 0.61, 95% CI 0.54-0.69) and a 36% decreased hazard of cancer-specific mortality (HR = 0.64, 95% CI 0.56-0.73). Previously inactive patients who began exercising after diagnosis experienced a 28% decreased hazard of all-cause (HR = 0.72, 95% CI 0.59-0.89) and cancer-specific mortality (HR = 0.72, 95% CI 0.57-0.91) in comparison to patients who remained inactive. Patients engaging in 3-4 sessions/week experienced the greatest survival advantages, but 1-2 sessions/week also yielded significant survival advantages in comparison to inactivity. CONCLUSION: Low-to-moderate frequency pre- and post-diagnosis RPA was associated with significantly decreased mortality in patients diagnosed with a variety of malignancies. These observations solidify the clinical and public health importance of the message that some regular activity is better than inactivity, which is particularly encouraging, given that cancer survivors can be overwhelmed by current daily physical activity recommendations.

11.
Carcinogenesis ; 2018 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-30321299

RESUMO

Breast cancer is a heterogeneous disease, characterized by molecularly and phenotypically distinct tumor subtypes, linked to disparate clinical outcomes. American women of African ancestry (AA) are more likely than those of European ancestry (EA) to be diagnosed with aggressive, estrogen receptor negative (ER-) or triple negative (TN) breast cancer, and to die of this disease. However, the underlying causes of AA predisposition to ER-/TN breast cancer are still largely unknown. In this study, we performed high-throughput whole-genome miRNA expression profiling in breast tissue samples from both AA and EA women. A number of differentially expressed miRNAs, i.e., DEmiRs defined as >2-fold change in expression and FDR<0.05, were identified as up- or down-regulated by tumor ER status or by ancestry. We found that among 102 ER subtype-related DEmiRs identified in breast tumors, the majority of these DEmiRs were race-specific, with only 23 DEmiRs shared in tumors from both AAs and EAs; this finding indicates that there are unique subsets of miRNAs differentially expressed between ER- and ER+ tumors within AAs versus EAs. Our overall results support the notion that miRNA expression patterns may differ not only by tumor subtype but by ancestry, indicating differences in tumor biology and heterogeneity of breast cancer between AAs and EAs. These results will provide the basis for further functional analysis to elucidate biological differences between AAs and EAs and to help develop targeted treatment strategies to reduce disparities in breast cancer.

12.
PLoS Genet ; 14(6): e1007368, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29879116

RESUMO

Selection pressure due to exposure to infectious pathogens endemic to Africa may explain distinct genetic variations in immune response genes. However, the impact of those genetic variations on human immunity remains understudied, especially within the context of modern lifestyles and living environments, which are drastically different from early humans in sub Saharan Africa. There are few data on population differences in constitutional immune environment, where genetic ancestry and environment are likely two primary sources of variation. In a study integrating genetic, molecular and epidemiologic data, we examined population differences in plasma levels of 14 cytokines involved in innate and adaptive immunity, including those implicated in chronic inflammation, and possible contributing factors to such differences, in 914 AA and 855 EA women. We observed significant differences in 7 cytokines, including higher plasma levels of CCL2, CCL11, IL4 and IL10 in EAs and higher levels of IL1RA and IFNα2 in AAs. Analyses of a wide range of demographic and lifestyle factors showed significant impact, with age, education level, obesity, smoking, and alcohol intake, accounting for some, but not all, observed population differences for the cytokines examined. Levels of two pro-inflammatory chemokines, CCL2 and CCL11, were strongly associated with percent of African ancestry among AAs. Through admixture mapping, the signal was pinpointed to local ancestry at 1q23, with fine-mapping analysis refined to the Duffy-null allele of rs2814778. In AA women, this variant was a major determinant of systemic levels of CCL2 (p = 1.1e-58) and CCL11 (p = 2.2e-110), accounting for 19% and 40% of the phenotypic variance, respectively. Our data reveal strong ancestral footprints in inflammatory chemokine regulation. The Duffy-null allele may indicate a loss of the buffering function for chemokine levels. The substantial immune differences by ancestry may have broad implications to health disparities between AA and EA populations.


Assuntos
Adaptação Biológica/genética , Citocinas/genética , Regulação da Expressão Gênica , Variação Genética , Seleção Genética , Imunidade Adaptativa/genética , Adulto , Grupo com Ancestrais do Continente Africano/genética , Alelos , Evolução Biológica , Citocinas/sangue , Sistema do Grupo Sanguíneo Duffy/genética , Meio Ambiente , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Disparidades nos Níveis de Saúde , Voluntários Saudáveis , Humanos , Imunidade Inata/genética , Pessoa de Meia-Idade
13.
Breast Cancer Res ; 20(1): 45, 2018 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-29871690

RESUMO

BACKGROUND: MicroRNAs (miRNAs) regulate gene expression and influence cancer. Primary transcripts of miRNAs (pri-miRNAs) are poorly annotated and little is known about the role of germline variation in miRNA genes and breast cancer (BC). We sought to identify germline miRNA variants associated with BC risk and tumor subtype among African-American (AA) women. METHODS: Under the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, genotyping and imputed data from four studies on BC in AA women were combined into a final dataset containing 224,188 miRNA gene single nucleotide polymorphisms (SNPs) for 8350 women: 3663 cases and 4687 controls. The primary miRNA sequence was identified for 566 miRNA genes expressed in Encyclopedia of DNA Elements (ENCODE) Tier 1 cell types and human pancreatic islets. Association analysis was conducted using logistic regression for BC status overall and by tumor subtype. RESULTS: A novel BC signal was localized to an 8.6-kb region of 17q25.3 by four SNPs (rs9913477, rs1428882938, rs28585511, and rs7502931) and remained statistically significant after multiple test correction (odds ratio (OR) = 1.44, 95% confidence interval (CI) = 1.26-1.65; p = 3.15 × 10-7; false discovery rate (FDR) = 0.03). These SNPs reside in a genomic location that includes both the predicted primary transcript of the noncoding miRNA gene MIR3065 and the first intron of the gene for brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2). Furthermore, miRNA-associated SNPs on chromosomes 1p32.3, 5q32, and 3p25.1 were the strongest signals for hormone receptor, luminal versus basal-like, and HER2 enrichment status, respectively. A second phase of genotyping (1397 BC cases, 2418 controls) that included two SNPs in the 8.6-kb region was used for validation and meta-analysis. While neither rs4969239 nor rs9913477 was validated, when meta-analyzed with the original dataset their association with BC remained directionally consistent (OR = 1.29, 95% CI = 1.16-1.44 (p = 4.18 × 10-6) and OR = 1.33, 95% CI = 1.17-1.51 (p = 1.6 × 10-5), respectively). CONCLUSION: Germline genetic variation indicates that MIR3065 may play an important role in BC development and heterogeneity among AA women. Further investigation to determine the potential functional effects of these SNPs is warranted. This study contributes to our understanding of BC risk in AA women and highlights the complexity in evaluating variation in gene-dense regions of the human genome.

15.
J Cancer Surviv ; 12(4): 460-468, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29536415

RESUMO

PURPOSE: Self-reported weight, height, and body mass index (BMI) are commonly used in cancer epidemiology studies, but information on the validity of self-reports among cancer survivors is lacking. This study aimed to evaluate the validity of these self-reported measures among African American (AA) breast cancer survivors, known to have high obesity prevalence. METHODS: We compared the self-reported and measured values among 243 participants from the Women's Circle of Health Follow-Up Study (WCHFS), a population-based longitudinal study of AA breast cancer survivors. Multivariable-adjusted linear regressions were used to identify factors associated with reporting errors. We also examined the associations of self-reported and measured BMI with obesity-related health outcomes using multivariable logistic regressions, with hypertension as an example, to evaluate the impact of misreporting. RESULTS: We found that self-reported and measured values were highly correlated among all and when stratified by participants' characteristics (intraclass correlation coefficients ≥ 0.99, 0.84, and 0.96 for weight, height, and BMI, respectively). The agreement between BMI categories (normal, overweight and obese) based on self-reported and measured data was excellent (kappa = 0.81). Women who were older, never smoked, had higher grade tumors, or had greater BMI tended to have overestimated BMI calculated from self-reported weight and height. The BMI-hypertension association was similar using self-reported (OR per 5 kg/m2 increase 1.63; 95% CI 1.27-2.10) and measured BMI (1.58; 95% CI 1.23-2.03). CONCLUSIONS: Self-reported weight, height, and BMI were reasonably accurate in the WCHFS. IMPLICATIONS FOR CANCER SURVIVORS: Our study supports the use of these self-reported values among cancer survivors when direct measurements are not possible.

16.
Breast Cancer Res ; 20(1): 12, 2018 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-29409530

RESUMO

BACKGROUND: Breast cancer subtype can be classified using standard clinical markers (estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2)), supplemented with additional markers. However, automated biomarker scoring and classification schemes have not been standardized. The aim of this study was to optimize tumor classification using automated methods in order to describe subtype frequency in the African American Breast Cancer Epidemiology and Risk (AMBER) consortium. METHODS: Using immunohistochemistry (IHC), we quantified the expression of ER, PR, HER2, the proliferation marker Ki67, and two basal-like biomarkers, epidermal growth factor receptor (EGFR) and cytokeratin (CK)5/6, in 1381 invasive breast tumors from African American women. RNA-based (prediction analysis of microarray 50 (PAM50)) subtype, available for 574 (42%) cases, was used to optimize classification. Subtype frequency was calculated, and associations between subtype and tumor characteristics were estimated using logistic regression. RESULTS: Relative to ER, PR and HER2 from medical records, central IHC staining and the addition of Ki67 or combined tumor grade improved accuracy for classifying PAM50-based luminal subtypes. Few triple negative cases (< 2%) lacked EGFR and CK5/6 expression, thereby providing little improvement in accuracy for identifying basal-like tumors. Relative to luminal A subtype, all other subtypes had higher combined grade and were larger, and ER-/HER2+ tumors were more often lymph node positive and late stage tumors. The frequency of basal-like tumors was 31%, exceeded only slightly by luminal A tumors (37%). CONCLUSIONS: Our findings indicate that automated IHC-based classification produces tumor subtype frequencies approximating those from PAM50-based classification and highlight high frequency of basal-like and low frequency of luminal A breast cancer in a large study of African American women.

17.
Breast Cancer Res Treat ; 169(3): 407-412, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29417299

RESUMO

Recently, Georgia State University's Centennial Hall was the premier location for the 2017 International Conference on Triple Negative Breast Cancer (TNBC): Illuminating Actionable Biology, which was held from Sept. 18 to 20, 2017, in Atlanta, USA. The conference featured a stellar line-up of domestic and international speakers and diverse participants including TNBC survivors, luminaries in breast cancer research, medical students and fellows, clinicians, translational researchers, epidemiologists, biostatisticians, bioinformaticians, and representatives from the industry. This report distills the burning questions that spiked the event and summarizes key themes, findings, unique opportunities and future directions that emerged from this confluence of thought leaders.

18.
J Natl Cancer Inst ; 110(7): 734-742, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29346580

RESUMO

Background: To what extent steroid hormones contribute to lung cancer in male and female never smokers and smokers is unclear. We examined expression of hormone receptors in lung tumors by sex and smoking. Methods: Patients with primary non-small cell lung cancer were recruited into an Intergroup study in the United States and Canada, led by SWOG (S0424). Tumors from 813 cases (450 women and 363 men) were assayed using immunohistochemistry for estrogen receptor (ER)-α, ER-ß, progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Linear regression was used to examine differences in expression by sex and smoking status. Cox proportional hazard models were used to estimate survival associated with the receptors. All statistical tests were two-sided. Results: In ever smokers, postmenopause and oral contraceptive use were associated with lower nuclear ER-ß (P = .02) and total (nuclear + cytoplasmic) PR expression (P = .02), respectively. Women had lower cytoplasmic ER-α (regression coefficient [ß], or differences in H-scores = -15.8, P = .003) and nuclear ER-ß (ß = -12.8, P = .04) expression than men, adjusting for age, race, and smoking. Ever smokers had both higher cytoplasmic ER-α (ß = 45.0, P < .001) and ER-ß (ß = 25.9, P < .001) but lower total PR (ß = -42.1, P < .001) than never smokers. Higher cytoplasmic ER-α and ER-ß were associated with worse survival (hazard ratio = 1.73, 95% confidence interval [CI] = 1.15 to 2.58, and HR = 1.59, 95% CI = 1.08 to 2.33, respectively; quartiles 4 vs 1). Conclusions: Lower expression of nuclear ER-ß in women supports the estrogen hypothesis in lung cancer etiology. Increasing cytoplasmic ER-α and ER-ß and decreasing PR protein expression may be mechanisms whereby smoking disrupts hormone pathways.

19.
Cancer Epidemiol Biomarkers Prev ; 27(3): 321-330, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29339359

RESUMO

Background: Constitutional immunity shaped by exposure to endemic infectious diseases and parasitic worms in Sub-Saharan Africa may play a role in the etiology of breast cancer among African American (AA) women.Methods: A total of 149,514 gene variants in 433 genes across 45 immune pathways were analyzed in the AMBER consortium among 3,663 breast cancer cases and 4,687 controls. Gene-based pathway analyses were conducted using the adaptive rank truncated product statistic for overall breast cancer risk, and risk by estrogen receptor (ER) status. Unconditional logistic regression analysis was used to estimate ORs and 95% confidence intervals (CIs) for single variants.Results: The top pathways were Interleukin binding (P = 0.01), Biocarta TNFR2 (P = 0.005), and positive regulation of cytokine production (P = 0.024) for overall, ER+, and ER- cancers, respectively. The most significant gene was IL2RB (P = 0.001) for overall cancer, with rs228952 being the top variant identified (OR = 0.85; 95% CI, 0.79-0.92). Only BCL3 contained a significant variant for ER+ breast cancer. Variants in IL2RB, TLR6, IL8, PRKDC, and MAP3K1 were associated with ER- disease. The only genes showing heterogeneity between ER- and ER+ cancers were TRAF1, MAP3K1, and MAPK3 (P ≤ 0.02). We also noted genes associated with autoimmune and atopic disorders.Conclusions: Findings from this study suggest that genetic variants in immune pathways are relevant to breast cancer susceptibility among AA women, both for ER+ and ER- breast cancers.Impact: Results from this study extend our understanding of how inherited genetic variation in immune pathways is relevant to breast cancer susceptibility. Cancer Epidemiol Biomarkers Prev; 27(3); 321-30. ©2018 AACR.

20.
Pharmacogenet Genomics ; 28(2): 49-55, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29278617

RESUMO

OBJECTIVE: Taxane containing chemotherapy extends survival for breast cancer patients. However, taxane-induced peripheral neuropathy (TIPN) cannot be predicted, prevented or effectively treated. Using genome-wide analyses, we sought to identify common risk variants for TIPN. PATIENTS AND METHODS: Women with high-risk breast cancer enrolled in SWOG 0221 were genotyped using the Illumina 1M chip. Genome-wide analyses were performed in relation to ≥grade 3 Common Terminology Criteria for Adverse Events (CTCAE) neuropathy in European and African Americans. Data were meta-analyzed with GW associations of CTCAE ≥grade 3 versus

Assuntos
Neoplasias da Mama/tratamento farmacológico , Hidrocarbonetos Aromáticos com Pontes/efeitos adversos , Predisposição Genética para Doença , Doenças do Sistema Nervoso Periférico/genética , Taxoides/efeitos adversos , Afro-Americanos/genética , Neoplasias da Mama/complicações , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Genômica , Genótipo , Humanos , Doenças do Sistema Nervoso Periférico/patologia , Polimorfismo de Nucleotídeo Único , Taxoides/uso terapêutico
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