Racial/ethnic disparities in breast cancer mortality continue to widen but genomic studies rarely interrogate breast cancer in diverse populations. Through genome, exome, and RNA sequencing, we examined the molecular features of breast cancers using 194 patients from Nigeria and 1037 patients from The Cancer Genome Atlas (TCGA). Relative to Black and White cohorts in TCGA, Nigerian HR + /HER2 − tumors are characterized by increased homologous recombination deficiency signature, pervasive TP53 mutations, and greater structural variation—indicating aggressive biology. GATA3 mutations are also more frequent in Nigerians regardless of subtype. Higher proportions of APOBEC-mediated substitutions strongly associate with PIK3CA and CDH1 mutations, which are underrepresented in Nigerians and Blacks. PLK2, KDM6A, and B2M are also identified as previously unreported significantly mutated genes in breast cancer. This dataset provides novel insights into potential molecular mechanisms underlying outcome disparities and lay a foundation for deployment of precision therapeutics in underserved populations.
There is an urgent need for novel noninvasive prognostic biomarkers for monitoring the recurrence of breast cancer. The purpose of this study is to identify circulating microRNAs that can predict breast cancer recurrence. We conducted a microRNA profiling experiment in serum samples from 48 breast cancer patients using Exiqon miRCURY microRNA RT-PCR panels. Significantly differentiated miRNAs for recurrence in the discovery profiling were further validated in an independent set of sera from 20 patients with breast cancer recurrences and 22 patients without recurrences. We identified seven miRNAs that were differentially expressed between breast cancer patients with and without recurrences, including four miRNAs upregulated (miR-21-5p, miR-375, miR-205-5p, and miR-194-5p) and three miRNAs downregulated (miR-382-5p, miR-376c-3p, and miR-411-5p) for recurrent patients. Using penalized logistic regression, we built a 7-miRNA signature for breast cancer recurrence, which had an excellent discriminating capacity (concordance index=0.914). This signature was significantly associated with recurrence after adjusting for known prognostic factors, and it was applicable to both hormone-receptor positive (concordance index=0.890) and triple-negative breast cancers (concordance index=0.942). We also found the 7-miRNA signature were reliably measured across different runs of PCR experiments (intra-class correlation coefficient=0.780) and the signature was significantly higher in breast cancer patients with recurrence than healthy controls (p=1.1×10−5). In conclusion, circulating miRNAs are promising biomarkers and the signature may be developed into a minimally invasive multi-marker blood test for continuously monitoring the recurrence of breast cancer. It should be further validated for different subtypes of breast cancers in longitudinal studies.
Objectives: Paucity of data on populations of African Ancestry in clinical trials continues to limit our ability to design and implement innovative solutions to narrow the breast cancer survival gap amongst Africans, African Americans, and European Americans. We have developed a cross-continent research infrastructure to examine the spectrum of genomic alterations in breast tumors from West Africa and subsequently, to compare them to tumors from African American women and women of European Ancestry in The Cancer Genome Atlas (TCGA) database. Methods: Consecutive women with breast cancer presenting for treatment at the University College Hospital, Ibadan and at Lagos State University Teaching Hospital, Lagos, Nigeria gave informed consent and were recruited to the West African Breast Cancer Study (WABCS) between 2013-2016. Tumor-normal pairs were subjected to exome and/or high-depth (90x) genome sequencing. High confidence somatic mutations (substitutions, insertions/deletions and structural variants) were obtained by using multiple variant callers. Furthermore, 1,089 exomic and 80 genomic breast tumor-normal pairs from TCGA were harmonized with WABCS samples, resulting in a cohort of 147 West Africans (147 exome; 40 genome), 154 African Americans (154 exome; 31 genome), and 776 Caucasians (776 exome; 43 genome). Results: Across the exomes, genes commonly altered in breast cancer in TCGA are also altered in women of African ancestry, but the mutational spectrum is quite different, demonstrating overrepresentation of tumors with aggressive phenotypes. Overall, TP53 (65%), ERBB2 (27%), and GATA3 (17%) showed statistically significant higher alteration frequencies in West Africans and African Americans. In contrast, PIK3CA (24%) was less frequently mutated. Of note, GATA3 mutation was statistically significantly more frequent in Nigerians (39%) and African Americans (16.7%) compared to Caucasians (10.5%), in ER-positive cancers. Analysis on Structural Variants (SV), on the other hand, has shown that the genome-wide SV counts among three populations are comparable in ER-negative cancers, while Nigerians have significantly more SV counts compared to African Americans (P=0.0013) or European Americans (P=2.9x10-5) in ER-positive cancers. Similarly, genome-wide substitution patterns in ER+ and ER- cancers varied widely by race/ethnicity. In ER- cases, West Africans carried the highest proportion of canonical APOBEC-associated substitutions, particularly C>T transitions. Conversely, European Americans with ER+ disease showed a higher proportion of C>T than both West Africans (Welch t-test P = 0.044) and African Americans (Welch t-test P = 0.011). Mutation signature analyses highlighted multiple APOBEC signatures, with notable contribution differences across ancestry and ER status. A signature likely corresponding to DNA damage repair correlated with the proportion of genetic ancestry, being most prevalent in European Americans and least common in Nigerians, particularly in ER-negative cancers, with African Americans showing a degree of this signature's contribution in between the two populations (linear model adjusted for age, P=1.0x10-10). Conclusions: Overall, our data suggests mutation spectra differences in across race/ethnicity and geography. Identification of molecular characteristics such as higher rates of HER2 enriched tumors and higher rates of GATA3 mutations in ER positive tumors are beginning to reveal the genomic basis of race-associated phenotypes and outcomes in breast cancer. Population differences in frequency and spectrum of mutations should now inform the design of innovative clinical trials that improve health equity and accelerate Precision Oncology care in diverse populations. Citation Format: Olopade OI, Pitt JJ, Riester M, Odetunde A, Yoshimatsu T, Labrot E, Ademola A, Sanni A, Okedere B, Mahan S, Nwosu I, Leary R, Ajani M, Johnson RS, Sveen E, Zheng Y, Wang S, Fitzgerald DJ, Grundstad J, Tuteja J, Clayton W, Khramtsova G, Oludara M, Omodele F, Benson O, Adeoye A, Morhason-Bello O, Ogundiran T, Babalola C, Popoola A, Morrissey M, Chen L, Huo D, Falusi A, Winckler W, Obafunwa J, Papoutsakis D, Ojengbede O, White KP, Ibrahim N, Oluwasola O, Barretina J. Comparative analysis of the genomic landscape of breast cancers from women of African and European ancestry [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr PD8-05.
Management of rapid patient deterioration requires prompt recognition and swift response by bedside nurses and specially trained personnel, who successfully intervene to improve patient outcomes. Timely recognition and activation of rapid response mechanisms requires prudent nursing care. When patient needs and nurse competencies are unbalanced, patient outcomes decline and nurse confidence diminishes. This article offers a brief background of rapid response, including the supporting theoretical framework. Also discussed are barriers to nursing action that result in synergistic imbalance, including: bedside nurse competence to recognize patient deterioration and activate rapid response systems; bedside nurse clinical judgment, interdisciplinary teamwork; and organizational culture. The article includes implications for practice aims to address identified barriers and improve patient outcomes.
The original version of this Article contained an error in the author affiliations. The affiliation of Kevin P. White with Tempus Labs, Inc. Chicago, IL, USA was inadvertently omitted. This has now been corrected in both the PDF and HTML versions of the Article.
Objectives: Of all ethnic/racial groups, age-standardized mortality rate from breast cancer is highest for African American women in the US for reasons that remain understudied. The paucity of genomic studies of breast tumors across the African Diaspora further restricts our understanding of the biology of breast cancer in underserved populations. To gain a better understanding of the genomic landscape of breast cancer in women of African Ancestry, we have developed a cross continent translational research infrastructure to examine the spectrum of genetic alterations in breast tumors from West Africa compared to the spectrum of alterations observed in tumors from African-American and other women who are predominantly white in The Cancer Genome Atlas (TCGA) dataset. Methods: Peripheral blood and breast cancer biopsy tissues were collected from 214 patients enrolled in the West Africa Breast Cancer Study (WABCS) at the University of Ibadan/University College Hospital (UI/UCH) and at Lagos State University Teaching Hospital (LASUTH). Blood DNA as well as breast cancer tissue DNA and RNA were extracted at the Novartis Institutes for Biomedical Research (NIBR), UI/UCH, and LASUTH using a modified protocol of PAXgene Tissue DNA and RNA extraction method. Whole-exome (WES) and transcriptome (RNA-seq) sequencing were performed on the Illumina HiSeq2000 platform at NIBR. Single Nucleotide Variants (SNVs) and insertions/deletions (indels) were called using MuTect and Pindel, while Copy Number Alterations (CNAs) were called using an in-house implementation of the ABSOLUTE method. Observed mutations were compared against those reported in the TCGA dataset. ER, PR and HER2 status were determined by immunohistochemistry (IHC) at UI/UCH, LASUTH and UChicago. Results: WES data for 95 tumors have been analyzed thus far. Genes commonly mutated in breast cancer in TCGA are also mutated in WABCS but the mutational spectrum is vastly different. TP53 (64%), MYC (31%), and GATA3 (26%), showed significantly higher alteration frequencies in WABCS and African Americans. In contrast, PIK3CA (20%), CDH1 (2%), and MAP3K1 (2%) were less frequently mutated in women of African ancestry. In addition to the high proportion with TP53 mutations, the proportion with HER2 positive subtype of 42.1% and triple-negative subtype of 37.9% suggest that tumors with the most aggressive features are overrepresented in breast cancer patients in West Africa. Conclusions: In the first study of its kind, high throughput genomic analysis of the largest cohort of women of African ancestry has uncovered alterations in cancer genes, some of which may be amenable to treatment with targeted therapies. Furthermore, we provide evidence that population differences in frequency and spectrum of mutations should drive the design and deployment of precision medicine initiatives. Only then can we develop innovative interventions to reduce the unacceptably high rates of mortality from breast cancer in underserved and under resourced populations. Citation Format: Olopade OI, Odetunde A, Riester M, Yoshimatsu T, Labrot E, Ademola A, Sanni A, Okedere B, Mahan S, Nwosu I, Leary R, Ajani M, Johnson RS, Sveen E, Zheng Y, Clayton W, Khramtsova G, Oludara M, Omodele F, Benson O, Adeoye A, Morhason-Bello O, Ogundiran T, Babalola C, Popoola A, Morrissey M, Huo D, Falusi A, Winckler W, Obafunwa J, Papoutsakis D, Ojengbede O, Ibrahim N, Oluwasola O, Barretina J. Genomic landscape of breast cancers from women of African ancestry across the diaspora. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-03-17.
Introduction: TNBC has the highest mortality rate amongst all other breast cancer types due to its complex tumor heterogeneity and lack of well-defined molecular targets. It is known that women of African descent are two to three times more likely to develop TNBC compared to women of European ancestry, yet wide-scale genomic studies of African and African American breast tumors are limited. To elucidate genotypes and molecular subtypes associated with the most aggressive forms of breast cancer, we used the PAM50 NanoString platform to reclassify Nigerian (NG), African American (AA) and Caucasian (CA) tumors previously annotated by Immunohistochemistry (IHC), and correlated our findings to their germline genotype data obtained using high-throughput technologies. Methods: RNAs were isolated from formalin-fixed, paraffin embedded (FFPE) tumor tissues using the High Pure Paraffin Kit (Roche) following manufacturer's protocol, and assayed on NanoString nCounter Analysis System using a custom Nano110 (PAM50 + claudin-low & VEGF signatures) probe set. Intrinsic subtyping and gene-expression data were evaluated using R statistical software. All study samples were previously annotated and subtyped by the ER/PR/HER2 IHC classifier. Genotypes were obtained from next generation sequencing or Illumina Human2.5M BeadChip platform using germline DNA from more than 2000 breast cancer cases and 2000 controls were studied. Results: To date, Intrinsic molecular subtyping by Nano110 has been completed on 69 NG, 81 AA and 74 CA tumors. Concordance between IHC and PAM50 was 59%, which is adequate and comparable to previous studies. Basal-like subtype was overrepresented and accounted for nearly 30% of NG and AA cases, compared to 17% in CA cases. HER2-enriched subtype was overrepresented only in NG cases (9%). The proportion with Luminal A tumors were 44% NG, 56% AA and 68% CA, respectively. Conclusions: PAM50 NanoString assay is reliable and high-throughput for molecular subtyping breast cancer using RNA extracted from FFPE tumors. Ongoing work will correlate PAM50 intrinsic subtypes to genotype data. Citation Format: Olayiwola OA, Ogundiran TO, Hardeman A, Yoshimatsu TF, Clayton W, Adeoye A, Ademola A, Ajani MA, Khramtsova G, Grushko TA, Huo D, Zheng Y, Parker J, Perou C, Olopade OI. Genotype-phenotype classification of triple negative breast cancers (TNBC) in women of African descent using the PAM50 NanoString platform and genomic data. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-04-05.
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