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1.
Niger Med J ; 65(3): 376-386, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39022568

RESUMO

Retained intra-abdominal foreign bodies are rare and most occur following abdominal or gynaecological surgery. Sponges are the most retained foreign body. The foreign bodies range from surgical instruments, including abdominal pads and gauze to artery forceps; to a pen cap. Retained objects can also be self-inserted. The authors report a case series on the outcome of retained foreign bodies in the intra-abdominal cavity managed in the general surgery service of the University College Hospital, Ibadan over 12-years.

2.
Hum Mol Genet ; 33(8): 687-697, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38263910

RESUMO

BACKGROUND: Expansion of genome-wide association studies across population groups is needed to improve our understanding of shared and unique genetic contributions to breast cancer. We performed association and replication studies guided by a priori linkage findings from African ancestry (AA) relative pairs. METHODS: We performed fixed-effect inverse-variance weighted meta-analysis under three significant AA breast cancer linkage peaks (3q26-27, 12q22-23, and 16q21-22) in 9241 AA cases and 10 193 AA controls. We examined associations with overall breast cancer as well as estrogen receptor (ER)-positive and negative subtypes (193,132 SNPs). We replicated associations in the African-ancestry Breast Cancer Genetic Consortium (AABCG). RESULTS: In AA women, we identified two associations on chr12q for overall breast cancer (rs1420647, OR = 1.15, p = 2.50×10-6; rs12322371, OR = 1.14, p = 3.15×10-6), and one for ER-negative breast cancer (rs77006600, OR = 1.67, p = 3.51×10-6). On chr3, we identified two associations with ER-negative disease (rs184090918, OR = 3.70, p = 1.23×10-5; rs76959804, OR = 3.57, p = 1.77×10-5) and on chr16q we identified an association with ER-negative disease (rs34147411, OR = 1.62, p = 8.82×10-6). In the replication study, the chr3 associations were significant and effect sizes were larger (rs184090918, OR: 6.66, 95% CI: 1.43, 31.01; rs76959804, OR: 5.24, 95% CI: 1.70, 16.16). CONCLUSION: The two chr3 SNPs are upstream to open chromatin ENSR00000710716, a regulatory feature that is actively regulated in mammary tissues, providing evidence that variants in this chr3 region may have a regulatory role in our target organ. Our study provides support for breast cancer variant discovery using prioritization based on linkage evidence.


Assuntos
População Negra , Neoplasias da Mama , Predisposição Genética para Doença , Feminino , Humanos , População Negra/genética , Neoplasias da Mama/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único
3.
Hum Mol Genet ; 31(18): 3133-3143, 2022 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-35554533

RESUMO

Polygenic risk scores (PRSs) are useful for predicting breast cancer risk, but the prediction accuracy of existing PRSs in women of African ancestry (AA) remains relatively low. We aim to develop optimal PRSs for the prediction of overall and estrogen receptor (ER) subtype-specific breast cancer risk in AA women. The AA dataset comprised 9235 cases and 10 184 controls from four genome-wide association study (GWAS) consortia and a GWAS study in Ghana. We randomly divided samples into training and validation sets. We built PRSs using individual-level AA data by a forward stepwise logistic regression and then developed joint PRSs that combined (1) the PRSs built in the AA training dataset and (2) a 313-variant PRS previously developed in women of European ancestry. PRSs were evaluated in the AA validation set. For overall breast cancer, the odds ratio per standard deviation of the joint PRS in the validation set was 1.34 [95% confidence interval (CI): 1.27-1.42] with the area under receiver operating characteristic curve (AUC) of 0.581. Compared with women with average risk (40th-60th PRS percentile), women in the top decile of the PRS had a 1.98-fold increased risk (95% CI: 1.63-2.39). For PRSs of ER-positive and ER-negative breast cancer, the AUCs were 0.608 and 0.576, respectively. Compared with existing methods, the proposed joint PRSs can improve prediction of breast cancer risk in AA women.


Assuntos
Neoplasias da Mama , Estudo de Associação Genômica Ampla , Neoplasias da Mama/genética , Feminino , Predisposição Genética para Doença , Humanos , Herança Multifatorial/genética , Receptores de Estrogênio/genética , Fatores de Risco
4.
Nat Commun ; 12(1): 4198, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34234117

RESUMO

Our study describes breast cancer risk loci using a cross-ancestry GWAS approach. We first identify variants that are associated with breast cancer at P < 0.05 from African ancestry GWAS meta-analysis (9241 cases and 10193 controls), then meta-analyze with European ancestry GWAS data (122977 cases and 105974 controls) from the Breast Cancer Association Consortium. The approach identifies four loci for overall breast cancer risk [1p13.3, 5q31.1, 15q24 (two independent signals), and 15q26.3] and two loci for estrogen receptor-negative disease (1q41 and 7q11.23) at genome-wide significance. Four of the index single nucleotide polymorphisms (SNPs) lie within introns of genes (KCNK2, C5orf56, SCAMP2, and SIN3A) and the other index SNPs are located close to GSTM4, AMPD2, CASTOR2, and RP11-168G16.2. Here we present risk loci with consistent direction of associations in African and European descendants. The study suggests that replication across multiple ancestry populations can help improve the understanding of breast cancer genetics and identify causal variants.


Assuntos
População Negra/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença , Locos de Características Quantitativas , População Branca/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Íntrons , Polimorfismo de Nucleotídeo Único
5.
J Natl Cancer Inst ; 113(9): 1168-1176, 2021 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-33769540

RESUMO

BACKGROUND: Polygenic risk scores (PRSs) have been demonstrated to identify women of European, Asian, and Latino ancestry at elevated risk of developing breast cancer (BC). We evaluated the performance of existing PRSs trained in European ancestry populations among women of African ancestry. METHODS: We assembled genotype data for women of African ancestry, including 9241 case subjects and 10 193 control subjects. We evaluated associations of 179- and 313-variant PRSs with overall and subtype-specific BC risk. PRS discriminatory accuracy was assessed using area under the receiver operating characteristic curve. We also evaluated a recalibrated PRS, replacing the index variant with variants in each region that better captured risk in women of African ancestry and estimated lifetime absolute risk of BC in African Americans by PRS category. RESULTS: For overall BC, the odds ratio per SD of the 313-variant PRS (PRS313) was 1.27 (95% confidence interval [CI] = 1.23 to 1.31), with an area under the receiver operating characteristic curve of 0.571 (95% CI = 0.562 to 0.579). Compared with women with average risk (40th-60th PRS percentile), women in the top decile of PRS313 had a 1.54-fold increased risk (95% CI = 1.38-fold to 1.72-fold). By age 85 years, the absolute risk of overall BC was 19.6% for African American women in the top 1% of PRS313 and 6.7% for those in the lowest 1%. The recalibrated PRS did not improve BC risk prediction. CONCLUSION: The PRSs stratify BC risk in women of African ancestry, with attenuated performance compared with that reported in European, Asian, and Latina populations. Future work is needed to improve BC risk stratification for women of African ancestry.


Assuntos
Neoplasias da Mama , Idoso de 80 Anos ou mais , Povo Asiático , População Negra/genética , Neoplasias da Mama/genética , Feminino , Predisposição Genética para Doença , Humanos , Fatores de Risco
6.
Ecancermedicalscience ; 14: 1084, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32863878

RESUMO

INTRODUCTION: Oncologic surgical extirpation, the mainstay of loco-regional disease control in breast cancer, is aimed at achieving negative margins and lymph node clearance. Even though axillary lymph nodal metastasis is a critical index of prognostication, establishing the impact of lymph node ratio (LNR) and adequate surgical margins on disease-specific survivorship would be key to achieving longer survival. This study examines the prognostic role of pN (lymph nodes positive for malignancy), LNR and resection margin on breast cancer survival in a tertiary hospital in Ibadan, Nigeria. METHODS: We conducted a longitudinal cohort study of 225 patients with breast carcinoma, documented clinico-pathologic parameters and 5-year follow up outcomes - distant metastasis and survival. Chi-square test and logistic regression analysis were used to evaluate the interaction of resection margin and proportion of metastatic lymph nodes with patients' survival. The receiver operating characteristic curve was plotted to determine the proportion of metastatic lymph nodes which predicted survival. The survival analysis was done using Kaplan-Meier method. RESULTS: Sixty (26.7%) patients of the patients had positive resection margins, with the most common immuno-histochemical type being Lumina A. 110 (49%) patients had more than 10 axillary lymph nodes harvested. The mean age was 48.6 ± 11.8 years. Tumour size (p = 0.018), histological type (p = 0.015), grade (p = 0.006), resection margin (p = 0.023), number of harvested nodes (p < 0.01), number of metastatic nodes (p < 0.001) and loco-regional recurrence (p < 0.01) are associated with survival. The overall 5-year survival was 65.3%. CONCLUSION: Unfavourable survival outcomes following breast cancer treatment is multifactorial, including the challenges faced in the multimodal treatment protocol received by our patients.

7.
JCO Glob Oncol ; 6: 387-394, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32125900

RESUMO

PURPOSE: Breast cancer is the most common cancer among women, and in low- to middle-income countries late-stage diagnosis contributes to significant mortality. Previous research at the University College Hospital, a tertiary hospital in Ibadan, Nigeria, on social factors contributing to late diagnosis revealed that many patients received inappropriate initial treatment. METHODS: The level of breast cancer knowledge among health practitioners at various levels of the health system was assessed. We developed a tool tailored to local needs to assess knowledge of symptoms, risk factors, treatments, and cultural beliefs. The recruitment included doctors, nurses, and pharmacists in public hospitals, physicians and pharmacists in private practice, nurses and health care workers from primary health care centers, community birth attendants, and students in a health care field from state schools. RESULTS: A total of 1,061 questionnaires were distributed, and 725 providers responded (68%). Seventy-eight percent were female, and > 90% were Yoruba, the dominant local ethnic group. The majority were Christian, and 18% were Muslim. Median knowledge score was 31 out of 56, and the differences in scores between health care worker types were statistically significant (P < .001). Nearly 60% of the participants believed breast cancer is always deadly. More than 40% of participants believed that keeping money in the bra causes breast cancer, and approximately 10% believed that breast cancer is caused by a spiritual attack. CONCLUSION: Our questionnaire revealed that, even at the tertiary care level, significant gaps in knowledge exist, and knowledge of breast cancer is unacceptably low at the level of community providers. In addition to efforts aimed at strengthening health systems, greater knowledge among community health care workers has the potential to reduce delays in diagnosis for Nigerian patients with breast cancer.


Assuntos
Neoplasias da Mama , Neoplasias da Mama/diagnóstico , Estudos Transversais , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Pessoal de Saúde , Humanos , Nigéria
8.
J Clin Oncol ; 36(28): 2820-2825, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30130155

RESUMO

PURPOSE: Among Nigerian women, breast cancer is diagnosed at later stages, is more frequently triple-negative disease, and is far more frequently fatal than in Europe or the United States. We evaluated the contribution of an inherited predisposition to breast cancer in this population. PATIENTS AND METHODS: Cases were 1,136 women with invasive breast cancer (mean age at diagnosis, 47.5 ± 11.5 years) ascertained in Ibadan, Nigeria. Patients were selected regardless of age at diagnosis, family history, or prior genetic testing. Controls were 997 women without cancer (mean age at interview, 47.0 ± 12.4 years) from the same communities. BROCA panel sequencing was used to identify loss-of-function mutations in known and candidate breast cancer genes. RESULTS: Of 577 patients with information on tumor stage, 86.1% (497) were diagnosed at stage III (241) or IV (256). Of 290 patients with information on tumor hormone receptor status and human epidermal growth factor receptor 2, 45.9% (133) had triple-negative breast cancer. Among all cases, 14.7% (167 of 1,136) carried a loss-of-function mutation in a breast cancer gene: 7.0% in BRCA1, 4.1% in BRCA2, 1.0% in PALB2, 0.4% in TP53, and 2.1% in any of 10 other genes. Odds ratios were 23.4 (95% CI, 7.4 to 73.9) for BRCA1 and 10.3 (95% CI, 3.7 to 28.5) for BRCA2. Risks were also significantly associated with PALB2 (11 cases, zero controls; P = .002) and TP53 (five cases, zero controls; P = .036). Compared with other patients, BRCA1 mutation carriers were younger ( P < .001) and more likely to have triple-negative breast cancer ( P = .028). CONCLUSION: Among Nigerian women, one in eight cases of invasive breast cancer is a result of inherited mutations in BRCA1, BRCA2, PALB2, or TP53, and breast cancer risks associated with these genes are extremely high. Given limited resources, prevention and early detection services should be especially focused on these highest-risk women.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Predisposição Genética para Doença , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Nigéria/epidemiologia
9.
Mol Carcinog ; 57(10): 1311-1318, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29873413

RESUMO

Gene expression changes within the Hippo pathway were found to be associated with large tumor size and metastasis in breast cancer. The combined effect of genetic variants in genes of this pathway may have a causal role in breast cancer development. We examined 7086 SNPs that were not highly correlated (r2 < 0.8) in 35 Hippo pathway genes using data from the genome-wide association study of breast cancer from the Root Consortium, which includes 3686 participants of African ancestry from Nigeria, United States of America, and Barbados: 1657 cases (403 estrogen receptor-positive [ER+], 374 ER-) and 2029 controls. Gene-level analyses were conducted using improved AdaJoint test for large-scale genetic association studies adjusting for age, study site and the first four eigenvectors from the principal component analysis. SNP-level analyses were conducted with logistic regression. The Hippo pathway was significantly associated with risk of ER+ breast cancer (pathway-level P = 0.019), with WWC1 (Padj = 0.04) being the leading gene. The pathway-level significance was lost without WWC1 (P = 0.12). rs147106204 in the WWC1 gene was the most statistically significant SNP after gene-level adjustment for multiple comparisons (OR = 0.53, 95%CI = 0.41-0.70, Padj = 0.025). We found evidence of an association between genetic variations in the Hippo pathway and ER+ breast cancer. Moreover, WWC1 was identified as the most important genetic susceptibility locus highlighting the importance of genetic epidemiology studies of breast cancer in understudied populations.


Assuntos
População Negra/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais/genética , Barbados , Neoplasias da Mama/etnologia , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla , Genótipo , Via de Sinalização Hippo , Humanos , Pessoa de Meia-Idade , Nigéria , Receptores de Estrogênio/metabolismo , Estados Unidos
10.
Int J Cancer ; 142(1): 36-43, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28891071

RESUMO

The vitamin D related pathway has been evaluated in carcinogenesis but its genetic contribution remains poorly understood. We examined single-nucleotide polymorphisms (SNPs) in the vitamin D related pathway genes using data from a genome-wide association study (GWAS) of breast cancer in the African Diaspora that included 3,686 participants (1,657 cases). Pathway- and gene-level analyses were conducted using the adaptive rank truncated product test. Odds ratios (OR) and 95% confidence intervals (CI) were estimated at SNP-level. After stringent Bonferroni corrections, we observed no significant association between variants in the vitamin D pathway and breast cancer risk at the pathway-, gene-, or SNP-level. In addition, no association was found for either the reported signals from GWASs of vitamin D related traits, or the SNPs within vitamin D receptor (VDR) binding regions. Furthermore, a decrease in genetically predicted 25(OH)D levels by Mendelian randomization was not associated with breast cancer (p = 0.23). However, an association for breast cancer with the pigment synthesis/metabolism pathway almost approached significance (pathway-level p = 0.08), driven primarily by a nonsense SNP rs41302073 in TYRP1, with an OR of 1.54 (95% CI = 1.24-1.91, padj = 0.007). In conclusion, we found no evidence to support an association between vitamin D status and breast cancer risk in women of African ancestry, suggesting that vitamin D is unlikely to have significant effect on breast carcinogenesis. Interestingly, TYRP1 might be related to breast cancer through a non-vitamin D relevant mechanism but further studies are needed.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Vitamina D/genética , Adulto , População Negra , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
11.
Cancer Epidemiol Biomarkers Prev ; 27(1): 116-118, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29254938

RESUMO

Background: Pancreatic cancer mutation signatures closely resemble breast cancer, suggesting that both cancers may have common predisposition mechanisms that may include commonly inherited SNPs.Methods: We examined 23 genetic variants known to be associated with pancreatic cancer as breast cancer risk factors in the Root genome-wide association study (GWAS; 1,657 cases and 2,029 controls of African diaspora) and GAME-ON/DRIVE GWAS (16,003 cases and 41,335 controls of European ancestry).Results: None of the pancreatic cancer susceptibility variants were individually associated with breast cancer risk after adjustment for multiple testing (at α = 0.002) in the two populations. In Root GWAS, a change by one SD in the polygenic risk score (PRS) was not significantly associated with breast cancer. In addition, we did not observe a trend in the relationship between PRS percentiles and breast cancer risk.Conclusions: The association between reported pancreatic cancer genetic susceptibility variants and breast cancer development in women of African or European ancestry is likely weak, if it does exist.Impact: Known GWAS-derived susceptibility variants of pancreatic cancer do not explain its shared genetic etiology with breast cancer. Cancer Epidemiol Biomarkers Prev; 27(1); 116-8. ©2017 AACR.


Assuntos
Neoplasias da Mama/genética , Neoplasias Pancreáticas/genética , Biomarcadores Tumorais/genética , População Negra/estatística & dados numéricos , Neoplasias da Mama/etnologia , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Neoplasias Pancreáticas/etnologia , Fatores de Risco , População Branca/estatística & dados numéricos
12.
NPJ Breast Cancer ; 3: 5, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28649645

RESUMO

A coding region polymorphism exists in the TP53 gene (Pro47Ser; rs1800371) in individuals of African descent, which reduces p53 tumor suppressor function in a mouse model. It has been unclear whether this functionally significant polymorphism alters cancer risk in humans. This analysis included 6907 women with breast cancer and 7644 controls from the AMBER, ROOT, and AABC consortia. We used multivariable logistic regression to estimate associations between the TP53 Pro47Ser allele and overall breast cancer risk. Because polymorphisms in TP53 tend to be associated with cancer risk in pre-menopausal women, we also limited our analyses to this population in the AMBER and ROOT consortia, where menopausal status was known, and conducted a fixed effects meta-analysis. In an analysis of all women in the AMBER, ROOT, and AABC consortia, we found no evidence for association of the Pro47Ser variant with breast cancer risk. However, when we restricted our analysis to only pre-menopausal women from the AMBER and ROOT consortia, there was a per allele odds ratio of 1.72 (95% confidence interval 1.08-2.76; p-value = 0.023). Although the Pro47Ser variant was not associated with overall breast cancer risk, it may increase risk among pre-menopausal women of African ancestry. Following up on more studies in human populations may better elucidate the role of this variant in breast cancer etiology. However, because of the low frequency of the polymorphism in women of African ancestry, its impact at a population level may be minimal.

13.
Carcinogenesis ; 38(8): 789-796, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28582508

RESUMO

Functional studies have elucidated the role of the mammalian target of rapamycin (mTOR) pathway in breast carcinogenesis, but to date, there is a paucity of data on its contribution to breast cancer risk in women of African ancestry. We examined 47628 SNPs in 61 mTOR pathway genes in the genome wide association study of breast cancer in the African Diaspora study (The Root consortium), which included 3686 participants (1657 cases). Pathway- and gene-level analyses were conducted using the adaptive rank truncated product (ARTP) test for 10994 SNPs that were not highly correlated (r2 < 0.8). Odds ratio (OR) and 95% confidence interval (CI) were estimated with logistic regression for each single-nucleotide polymorphism. The mTOR pathway was significantly associated with overall and estrogen receptor-negative (ER-) breast cancer risk (P = 0.003 and 0.03, respectively). PRKAG3 (Padj = 0.0018) and RPS6KA3 (Padj = 0.061) were the leading genes for the associations with overall breast cancer risk and ER- breast cancer risk, respectively. rs190843378 in PRKAG3 was statistically significant after gene-level adjustment for multiple comparisons (OR = 0.50 for each T allele, 95% CI = 0.38-0.66, Padj = 3.6E-05), with a statistical power of 0.914. These results provide new insights on the biological relevance of the mTOR pathway in breast cancer progression and underscore the need for more genetic epidemiology studies of breast cancer in the African Diaspora.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Neoplasias da Mama/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Serina-Treonina Quinases TOR/genética , Alelos , População Negra/genética , Neoplasias da Mama/patologia , Carcinogênese/genética , Carcinogênese/patologia , Receptor alfa de Estrogênio/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único , Transdução de Sinais
14.
Cancer Epidemiol Biomarkers Prev ; 26(7): 1016-1026, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28377418

RESUMO

Background: Genome-wide association studies have identified approximately 100 common genetic variants associated with breast cancer risk, the majority of which were discovered in women of European ancestry. Because of different patterns of linkage disequilibrium, many of these genetic markers may not represent signals in populations of African ancestry.Methods: We tested 74 breast cancer risk variants and conducted fine-mapping of these susceptibility regions in 6,522 breast cancer cases and 7,643 controls of African ancestry from three genetic consortia (AABC, AMBER, and ROOT).Results: Fifty-four of the 74 variants (73%) were found to have ORs that were directionally consistent with those previously reported, of which 12 were nominally statistically significant (P < 0.05). Through fine-mapping, in six regions (3p24, 12p11, 14q13, 16q12/FTO, 16q23, 19p13), we observed seven markers that better represent the underlying risk variant for overall breast cancer or breast cancer subtypes, whereas in another two regions (11q13, 16q12/TOX3), we identified suggestive evidence of signals that are independent of the reported index variant. Overlapping chromatin features and regulatory elements suggest that many of the risk alleles lie in regions with biological functionality.Conclusions: Through fine-mapping of known susceptibility regions, we have revealed alleles that better characterize breast cancer risk in women of African ancestry.Impact: The risk alleles identified represent genetic markers for modeling and stratifying breast cancer risk in women of African ancestry. Cancer Epidemiol Biomarkers Prev; 26(7); 1016-26. ©2017 AACR.


Assuntos
Biomarcadores Tumorais/genética , Negro ou Afro-Americano/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença , Alelos , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Mapeamento Cromossômico , Feminino , Loci Gênicos , Humanos , Polimorfismo de Nucleotídeo Único , Receptores de Estrogênio/metabolismo , Fatores de Risco
15.
Hum Genet ; 135(10): 1145-59, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27380242

RESUMO

MicroRNAs (miRNA) regulate breast biology by binding to specific RNA sequences, leading to RNA degradation and inhibition of translation of their target genes. While germline genetic variations may disrupt some of these interactions between miRNAs and their targets, studies assessing the relationship between genetic variations in the miRNA network and breast cancer risk are still limited, particularly among women of African ancestry. We systematically put together a list of 822 and 10,468 genetic variants among primary miRNA sequences and 38 genes in the miRNA biogenesis pathway, respectively; and examined their association with breast cancer risk in the ROOT consortium which includes women of African ancestry. Findings were replicated in an independent consortium. Logistic regression was used to estimate the odds ratio (OR) and 95 % confidence intervals (CI). For overall breast cancer risk, three single-nucleotide polymorphisms (SNPs) in miRNA biogenesis genes DROSHA rs78393591 (OR = 0.69, 95 % CI: 0.55-0.88, P = 0.003), ESR1 rs523736 (OR = 0.88, 95 % CI: 0.82-0.95, P = 3.99 × 10(-4)), and ZCCHC11 rs114101502 (OR = 1.33, 95 % CI: 1.11-1.59, P = 0.002), and one SNP in primary miRNA sequence (rs116159732 in miR-6826, OR = 0.74, 95 % CI: 0.63-0.89, P = 0.001) were found to have significant associations in both discovery and validation phases. In a subgroup analysis, two SNPs were associated with risk of estrogen receptor (ER)-negative breast cancer, and three SNPs were associated with risk of ER-positive breast cancer. Several variants in miRNA and miRNA biogenesis pathway genes were associated with breast cancer risk. Risk associations varied by ER status, suggesting potential new mechanisms in etiology.


Assuntos
Neoplasias da Mama/genética , Proteínas de Ligação a DNA/genética , Receptor alfa de Estrogênio/genética , MicroRNAs/genética , Ribonuclease III/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , População Negra , Neoplasias da Mama/patologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , MicroRNAs/biossíntese , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
16.
Hum Mol Genet ; 25(21): 4835-4846, 2016 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28171663

RESUMO

Multiple breast cancer loci have been identified in previous genome-wide association studies, but they were mainly conducted in populations of European ancestry. Women of African ancestry are more likely to have young-onset and oestrogen receptor (ER) negative breast cancer for reasons that are unknown and understudied. To identify genetic risk factors for breast cancer in women of African descent, we conducted a meta-analysis of two genome-wide association studies of breast cancer; one study consists of 1,657 cases and 2,029 controls genotyped with Illumina's HumanOmni2.5 BeadChip and the other study included 3,016 cases and 2,745 controls genotyped using Illumina Human1M-Duo BeadChip. The top 18,376 single nucleotide polymorphisms (SNP) from the meta-analysis were replicated in the third study that consists of 1,984 African Americans cases and 2,939 controls. We found that SNP rs13074711, 26.5 Kb upstream of TNFSF10 at 3q26.21, was significantly associated with risk of oestrogen receptor (ER)-negative breast cancer (odds ratio [OR]=1.29, 95% CI: 1.18-1.40; P = 1.8 × 10 − 8). Functional annotations suggest that the TNFSF10 gene may be involved in breast cancer aetiology, but further functional experiments are needed. In addition, we confirmed SNP rs10069690 was the best indicator for ER-negative breast cancer at 5p15.33 (OR = 1.30; P = 2.4 × 10 − 10) and identified rs12998806 as the best indicator for ER-positive breast cancer at 2q35 (OR = 1.34; P = 2.2 × 10 − 8) for women of African ancestry. These findings demonstrated additional susceptibility alleles for breast cancer can be revealed in diverse populations and have important public health implications in building race/ethnicity-specific risk prediction model for breast cancer.


Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 3/genética , Negro ou Afro-Americano/genética , Alelos , População Negra/genética , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Loci Gênicos , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Polimorfismo de Nucleotídeo Único/genética , Receptores de Estrogênio/genética , Fatores de Risco , Ligante Indutor de Apoptose Relacionado a TNF/genética , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo
17.
BMC Med Ethics ; 15: 38, 2014 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-24885380

RESUMO

BACKGROUND: Studies on informed consent to medical research conducted in low or middle-income settings have increased, including empirical investigations of consent to genetic research. We investigated voluntary participation and comprehension of informed consent among women involved in a genetic epidemiological study on breast cancer in an urban setting of Nigeria comparing women in the case and control groups. METHODS: Surveys were administered in face-to-face interviews with 215 participants following their enrollment in the genetic study (106 patients, 109 controls). Audio-taped in-depth interviews were conducted with a sub-sample of 17 (8%) women who completed the survey. RESULTS: The majority of all participants reported being told that participation in the genetic study was voluntary (97%), that they did not feel pressured to participate in the study (99%), and that they could withdraw from the study (81%). The majority of the breast cancer patients (83%) compared to 58% of women in the control group reported that the study purpose was to learn about the genetic inheritance of breast cancer (OR 3.44; 95% CI =1.66, 7.14, p value = 0.001). Most participants reported being told about study procedures (95%) and study benefits (98%). Sixty-eight percent of the patients, compared to 47% of the control group reported being told about study risks (p-value <0.001). Of the 165 married women, 19% reported asking permission from their husbands to enroll in the breast cancer study; no one sought permission from local elders. In-depth interviews highlight the use of persuasion and negotiation between a wife and her husband regarding study participation. CONCLUSIONS: The global expansion of genetic and genomic research highlights our need to understand informed consent practices for studies in ethnically diverse cultural environments such as Africa. Quantitative and qualitative empirical investigations of the informed consent process for genetic and genomic research will further our knowledge of complex issues associated with communication of information, comprehension, decisional authority and voluntary participation. In the future, the development and testing of innovative strategies to promote voluntary participation and comprehension of the goals of genomic research will contribute to our understanding of strategies that enhance the consent process.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Compreensão , Pesquisa em Genética , Consentimento Livre e Esclarecido , Consentimento do Representante Legal/estatística & dados numéricos , Adulto , População Negra , Neoplasias da Mama/psicologia , Feminino , Predisposição Genética para Doença , Pesquisa em Genética/ética , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Consentimento Livre e Esclarecido/ética , Masculino , Epidemiologia Molecular , Nigéria/epidemiologia , Nigéria/etnologia , Seleção de Pacientes , Recusa de Participação/etnologia , Inquéritos e Questionários , Consentimento do Representante Legal/ética
18.
BMC Surg ; 13: 59, 2013 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-24354443

RESUMO

BACKGROUND: Modified radical mastectomy remains the standard therapeutic surgical operation for breast cancer in most parts of the world. This retrospective study reviews mastectomy for management of breast cancer in a surgical oncology division over a ten year period. METHODS: We reviewed the case records of consecutive breast cancer patients who underwent mastectomy at the Surgical Oncology Division, University College Hospital (UCH) Ibadan between November 1999 and October 2009. RESULTS: Of the 1226 newly diagnosed breast cancer patients over the study period, 431 (35.2%) patients underwent mastectomy making an average of 43 mastectomies per year. Most patients were young women, premenopausal, had invasive ductal carcinoma and underwent modified radical mastectomy as the definitive surgical treatment. Prior to mastectomy, locally advanced tumors were down staged in about half of the patients that received neo-adjuvant combination chemotherapy. Surgical complication rate was low. The most frequent operative complication was seroma collection in six percent of patients. The average hospital stay was ten days and most patients were followed up at the surgical outpatients department for about two years post-surgery. CONCLUSIONS: There was low rate of mastectomy in this cohort which could partly be attributable to late presentation of many patients with inoperable local or metastatic tumors necessitating only palliative or terminal care. Tumor down-staging with neo-adjuvant chemotherapy enhanced surgical loco-regional tumor control in some patients. The overall morbidity and the rates of postoperative events were minimal. Long-term post-operative out-patients follow-up was not achieved as many patients were lost to follow up after two years of mastectomy.


Assuntos
Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/cirurgia , Mastectomia Radical Modificada , Adulto , Neoplasias da Mama Masculina/cirurgia , Países em Desenvolvimento , Feminino , Seguimentos , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Mastectomia Radical Modificada/estatística & dados numéricos , Pessoa de Meia-Idade , Nigéria , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Resultado do Tratamento
19.
Breast J ; 19(5): 470-7, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23865786

RESUMO

The majority of clinical trials of neo-adjuvant therapy for breast cancer have been conducted in resource-rich countries. We chose Nigeria, a resource-poor country, as the major site for a phase II feasibility open-label multicenter clinical trial designed to evaluate the efficacy, safety, and tolerability of neo-adjuvant capecitabine in locally advanced breast cancer (LABC). Planned treatment consisted of 24 weeks of capecitabine at a dose of 1,000 mg/m(2) twice daily (2,000 mg/m(2) total per day). The primary endpoints were overall, partial, complete clinical response rate (OCR, PCR, CCR) and complete pathologic response (cPR). A total of 16 patients were recruited from August 2007 to April 2010. The study was terminated early as a result of slow accrual. After the first three cycles of therapy, PCR were seen in five of 16 patients (31%; 95% CI 11-59%). Of the remaining 11 patients, eight had no response (NR) or stable disease (SD), and three had progressive disease (PD). Seven patients proceeded with further therapy of which had SD. OCR at the end of eight cycles was 44% (95% CI 20-70%). Clinical response and radiologic response by ultrasonomammography were highly concordant (spearman correlation 0.70). The most common adverse effect was Grade 1 hand-foot syndrome, which was seen in 75% of patients. Despite several limitations, we successfully carried out this phase II feasibility study of neo-adjuvant capecitabine for LABC in Nigeria. Capecitabine monotherapy showed good overall response rates with minimal toxicity and further studies are warranted.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Terapia Neoadjuvante , Adulto , Idoso , Capecitabina , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Estudos de Viabilidade , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Pessoa de Meia-Idade , Nigéria
20.
Carcinogenesis ; 34(7): 1520-8, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23475944

RESUMO

Numerous single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility have been identified by genome-wide association studies (GWAS). However, these SNPs were primarily discovered and validated in women of European and Asian ancestry. Because linkage disequilibrium is ancestry-dependent and heterogeneous among racial/ethnic populations, we evaluated common genetic variants at 22 GWAS-identified breast cancer susceptibility loci in a pooled sample of 1502 breast cancer cases and 1378 controls of African ancestry. None of the 22 GWAS index SNPs could be validated, challenging the direct generalizability of breast cancer risk variants identified in Caucasians or Asians to other populations. Novel breast cancer risk variants for women of African ancestry were identified in regions including 5p12 (odds ratio [OR] = 1.40, 95% confidence interval [CI] = 1.11-1.76; P = 0.004), 5q11.2 (OR = 1.22, 95% CI = 1.09-1.36; P = 0.00053) and 10p15.1 (OR = 1.22, 95% CI = 1.08-1.38; P = 0.0015). We also found positive association signals in three regions (6q25.1, 10q26.13 and 16q12.1-q12.2) previously confirmed by fine mapping in women of African ancestry. In addition, polygenic model indicated that eight best markers in this study, compared with 22 GWAS-identified SNPs, could better predict breast cancer risk in women of African ancestry (per-allele OR = 1.21, 95% CI = 1.16-1.27; P = 9.7 × 10(-16)). Our results demonstrate that fine mapping is a powerful approach to better characterize the breast cancer risk alleles in diverse populations. Future studies and new GWAS in women of African ancestry hold promise to discover additional variants for breast cancer susceptibility with clinical implications throughout the African diaspora.


Assuntos
Biomarcadores Tumorais/metabolismo , População Negra/genética , Neoplasias da Mama/genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Adulto , Alelos , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Mapeamento Cromossômico/métodos , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 16/metabolismo , Cromossomos Humanos Par 6/genética , Cromossomos Humanos Par 6/metabolismo , Intervalos de Confiança , Feminino , Humanos , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único
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