Nonsense-Mediated RNA Decay Is a Unique Vulnerability of Cancer Cells Harboring SF3B1 or U2AF1 Mutations.

Nonsense-mediated RNA decay (NMD) is recognized as an RNA surveillance pathway that targets aberrant mRNAs with premature translation termination codons (PTC) for degradation, however, its molecular mechanisms and roles in health and disease remain incompletely understood. In this study, we developed a novel reporter system to accurately measure NMD activity in individual cells. A genome-wide CRISPR-Cas9 knockout screen using this reporter system identified novel NMD-promoting factors, including multiple components of the SF3B complex and other U2 spliceosome factors. Interestingly, cells with mutations in the spliceosome genes SF3B1 and U2AF1, which are commonly found in myelodysplastic syndrome (MDS) and cancers, have overall attenuated NMD activity. Compared with wild-type (WT) cells, SF3B1- and U2AF1-mutant cells were more sensitive to NMD inhibition, a phenotype that is accompanied by elevated DNA replication obstruction, DNA damage, and chromosomal instability. Remarkably, the sensitivity of spliceosome mutant cells to NMD inhibition was rescued by overexpression of RNase H1, which removes R-loops in the genome. Together, these findings shed new light on the functional interplay between NMD and RNA splicing and suggest a novel synthetic lethal strategy for the treatment of MDS and cancers with spliceosome mutations. SIGNIFICANCE: This study has developed a novel NMD reporter system and identified a potential therapeutic approach of targeting the NMD pathway to treat cancer with spliceosome gene mutations.

Factors associated with breast cancer recurrence and survival at Sangre Grande Hospital, Trinidad.

PURPOSE: The aim of this study is to determine the demographic, pathological, and treatment-related factors that predict recurrence and survival in a Trinidadian cohort of breast cancer patients. METHODS: The inclusion criteria for this study were female, over 18 years, and with a primary breast cancer diagnosis confirmed by a biopsy report occurring between 2010 and 2015 at Sangre Grande Hospital, Trinidad. Univariate associations with 5-year recurrence-free survival and 5-year overall survival were calculated using the Kaplan-Meier method for categorical variables and Cox Proportional Hazards for continuous variables. A multivariate model for prediction of recurrence and survival was determined using Cox regression. RESULTS: For the period 2010-2015, 202 records were abstracted. Five-year overall survival and recurrence-free survival rates were found to be 74.3% and 56.4%, respectively. Median times from first suspicious finding to date of biopsy report, date of surgery, and date of chemotherapy were 63 days, 125 days, and 189 days, respectively. In the univariate analysis, age (p = 0.038), stage (p < 0.001), recurrence (p = 0.035), surgery (p = 0.016), ER (p < 0.001) status, PR status (p < 0.001), and subtype (p < 0.001) were significantly associated with survival. Additionally, stage (p = 0.004), N score (p = 0.002), ER (p = 0.028) status, PR (p = 0.018) status, and subtype (p = 0.025) were significantly associated with recurrence. In the Cox multivariate model, Stage 4 was a significant predictor of survival (HR 6.77, 95% CI [0.09-2.49], p = 0.047) and N3 score was a significant predictor of recurrence (HR 4.47, 95% CI [1.29-15.54], p = 0.018). CONCLUSION: This study reports a 5-year breast cancer survival rate of 74.3%, and a recurrence-free survival rate of 56.4% in Trinidad for the period 2010-2015.

Cancer incidence and mortality rates and trends in Trinidad and Tobago.

BACKGROUND: Cancer is the second leading cause of death in the Caribbean, including the islands of Trinidad and Tobago (TT). The population of TT consists of over 1.3 million people with diverse ancestral and sociocultural backgrounds, both of which may influence cancer incidence and mortality. The objective of this study was to examine incidence and mortality patterns and trends in TT. METHODS: Cancer surveillance data on 29,512 incident cancer cases reported to the Dr. Elizabeth Quamina Cancer Registry (population-based cancer registry of TT) between 1995 and 2009 were analyzed. Age-standardized rates, overall and by sex, ancestry, and geography, were reported. RESULTS: The highest incidence and mortality rates were observed for cancers related to reproductive organs in women, namely, breast, cervical, and uterine cancers, and prostate, lung and colorectal cancers among men. Average incidence rates were highest in areas covered by the Tobago Regional Health Authority (TRHA) (188 per 100,000), while average mortality rates were highest in areas covered by the North West Regional Health Authority (108 per 100,000). Nationals of African ancestry exhibited the highest rates of cancer incidence (243 per 100,000) and mortality (156 per 100,000) compared to their counterparts who were of East Indian (incidence, 125 per 100,000; mortality, 66 per 100,000) or mixed ancestry (incidence, 119 per 100,000; mortality, 66 per 100,000). CONCLUSIONS: Our findings highlight the need for national investment to improve the understanding of the epidemiology of cancer in Trinidad and Tobago, and to ultimately guide much needed cancer prevention and control initiatives in the near future.

The burden of prostate cancer in Trinidad and Tobago: one of the highest mortality rates in the world.

PURPOSE: In Trinidad and Tobago (TT), prostate cancer (CaP) is the most commonly diagnosed malignancy and the leading cause of cancer deaths among men. TT currently has one of the highest CaP mortality rates in the world. METHODS: 6,064 incident and 3,704 mortality cases of CaP occurring in TT from January 1995 to 31 December 2009 reported to the Dr. Elizabeth Quamina Cancer population-based cancer registry for TT, were analyzed to examine CaP survival, incidence, and mortality rates and trends by ancestry and geography. RESULTS: The age-standardized CaP incidence and mortality rates (per 100,000) based on the 1960 world-standardized in 2009 were 64.2 and 47.1 per 100,000. The mortality rate in TT increased between 1995 (37.9 per 100,000) and 2009 (79.4 per 100,000), while the rate in the US decreased from 37.3 per 100,000 to 22.1 per 100,000 over the same period. Fewer African ancestry patients received treatment relative to those of Indian and mixed ancestry (45.7%, 60.3%, and 60.9%, respectively). CONCLUSIONS: Notwithstanding the limitations surrounding data quality, our findings highlight the increasing burden of CaP in TT and the need for improved surveillance and standard of care. Our findings highlight the need for optimized models to project cancer rates in developing countries like TT. This study also provides the rationale for targeted screening and optimized treatment for CaP to ameliorate the rates we report.

A rare case of massive lower gastrointestinal bleeding from a ruptured splenic artery aneurysm.

Splenic artery aneurysms (SAAs) are an extremely rare cause of asymptomatic massive lower gastrointestinal bleeding with less than a handful of patients surviving such a presentation. A 24-year-old female presented in shock after multiple episodes of massive rectal bleeding. Imaging revealed a heterogeneous mass arising from the tail of the pancreas eroding into the splenic flexure of the colon. Further episodes of bleeding led to an exploratory laparotomy. Intraoperatively, a suspected neoplastic process arising from the tail of the pancreas with contiguous involvement of the splenic flexure of the colon and the greater curvature of the stomach was noted. Distal pancreaticosplenectomy, gastric wedge resection with segmental colectomy and primary anastomosis were performed. Histology revealed a SAA with rupture into the colon. This case report shows that en-bloc resection of a ruptured SAA can be performed with success in the emergency setting.

Expression profiling of snoRNAs in normal hematopoiesis and AML.

Small nucleolar RNAs (snoRNAs) are noncoding RNAs that contribute to ribosome biogenesis and RNA splicing by modifying ribosomal RNA and spliceosome RNAs, respectively. We optimized a next-generation sequencing approach and a custom analysis pipeline to identify and quantify expression of snoRNAs in acute myeloid leukemia (AML) and normal hematopoietic cell populations. We show that snoRNAs are expressed in a lineage- and development-specific fashion during hematopoiesis. The most striking examples involve snoRNAs located in 2 imprinted loci, which are highly expressed in hematopoietic progenitors and downregulated during myeloid differentiation. Although most snoRNAs are expressed at similar levels in AML cells compared with CD34+, a subset of snoRNAs showed consistent differential expression, with the great majority of these being decreased in the AML samples. Analysis of host gene expression, splicing patterns, and whole-genome sequence data for mutational events did not identify transcriptional patterns or genetic alterations that account for these expression differences. These data provide a comprehensive analysis of the snoRNA transcriptome in normal and leukemic cells and should be helpful in the design of studies to define the contribution of snoRNAs to normal and malignant hematopoiesis.

A situational analysis of breast cancer early detection services in Trinidad and Tobago.

PURPOSE: A situational analysis of breast cancer (BC) early detection services was carried out to investigate whether Trinidad and Tobago (T&T) has the framework for successful organized national screening. METHODS: An online survey was designed to assess the availability, accessibility, quality control and assurance (QC&A), and monitoring and evaluation (M&E) mechanisms for public and private BC early detection. A focus group with local radiologists (n = 3) was held to identify unaddressed challenges and make recommendations for improvement. RESULTS: Major public hospitals offer free detection services with wait times of 1-6 months for an appointment. Private institutions offer mammograms for TTD$240 (USD$37) at minimum with same day service. Both sectors report a lack of trained staff. Using 1.2 mammograms per 10,000 women ≥40 years as sufficient, the public sector's rate of 0.19 mammograms per 10,000 women ≥40 years for screening and diagnosis is inadequate. Program M&E mechanisms, QC&A guidelines for machinery use, delays in receipt of pathology reports, and unreliable drug access are further unaddressed challenges. CONCLUSION: T&T must first strengthen its human and physical resources, implement M&E and QC&A measures, strengthen cancer care, and address other impediments to BC early detection before investing in nationally organized BC screening.

Clinicopathology and treatment of a giant malignant phyllodes tumor of the breast: A case report and literature review.

INTRODUCTION: Phyllodes tumors (PTs) of the breast are extremely rare accounting for less than 1% of all breast tumors globally. Case records at the Trinidad and Tobago Cancer Registry show that only 0.003% of the reported breast cancer cases between 1995 and 2009 were PTs. PRESENTATION OF THE CASE: We report a 45-year-old woman who presented with swelling of the left breast. Ultrasound, mammogram and computed tomography imaging confirmed the presence of a mass in the right upper inner quadrant of the left breast. A biopsy revealed features supportive of a benign phyllodes tumor. A wide local excision was performed with the removal of a 19×11×10cm mass. Histopathological analysis revealed features consistent with malignant phyllodes tumor. A complete mastectomy of the left breast was subsequently performed. Follow up over a 5-year period did not reveal any evidence of local recurrence or residual disease. To the best of our knowledge, this is the first case report of a malignant PT from the Caribbean and Latin America. DISCUSSION: Phyllodes tumors are classified as benign, borderline, or malignant based on histologic features including presence of a clear margin, cellularity, stromal overgrowth, tumor necrosis and mitotic index. The clinical challenge is to assess the risk of local tumor and metastatic recurrence in the context of fluid classifications. CONCLUSION: Our case management approach shows that for patients with malignant PT, a thorough preoperative workup regimen followed by appropriate surgical intervention can result in a desirable prognosis.

Gynecologic cancer mortality in Trinidad and Tobago and comparisons of mortality-to-incidence rate ratios across global regions.

PURPOSE: To examine the factors associated with gynecologic cancer mortality risks, to estimate the mortality-to-incidence rate ratios (MIR) in Trinidad and Tobago (TT), and to compare the MIRs to those of select countries. METHODS: Data on 3,915 incident gynecologic cancers reported to the National Cancer Registry of TT from 1 January 1995 to 31 December 2009 were analyzed using proportional hazards models to determine factors associated with mortality. MIRs for cervical, endometrial, and ovarian cancers were calculated using cancer registry data (TT), GLOBOCAN 2012 incidence data, and WHO Mortality Database 2012 data (WHO regions and select countries). RESULTS: Among the 3,915 incident gynecologic cancers diagnosed in TT during the study period, 1,795 (45.8%) were cervical, 1,259 (32.2%) were endometrial, and 861 (22.0%) were ovarian cancers. Older age, African ancestry, geographic residence, tumor stage, and treatment non-receipt were associated with increased gynecologic cancer mortality in TT. Compared to GLOBOCAN 2012 data, TT MIR estimates for cervical (0.49 vs. 0.53), endometrial (0.61 vs. 0.65), and ovarian cancers (0.32 vs. 0.48) were elevated. While the Caribbean region had intermediate gynecologic cancer MIRs, MIRs in TT were among the highest of the countries examined in the Caribbean region. CONCLUSIONS: Given its status as a high-income economy, the relatively high gynecologic cancer MIRs observed in TT are striking. These findings highlight the urgent need for improved cancer surveillance, screening, and treatment for these (and other) cancers in this Caribbean nation.

Giant Cystic Pheochromocytoma with Low Risk of Malignancy: A Case Report and Literature Review.

Giant pheochromocytomas are rare silent entities that do not present with the classical symptoms commonly seen in catecholamine-secreting tumors. In many cases they are accidentally discovered. The algorithm to diagnose a pheochromocytoma consists of biochemical evaluation and imaging of a retroperitoneal mass. The female patient in this case report presented with a palpable abdominal mass and was cured with surgical resection. She suffered no recurrence or complications on follow-up. The left retroperitoneal mass measured 27 × 18 × 12 cm and weighed 3,315 grams. Biochemical, radiological, and pathological examinations confirmed the diagnosis of a pheochromocytoma. In this paper, we report on our experience treating this patient and provide a summary of all giant pheochromocytomas greater than 10 cm reported to date in English language medical journals. Our patient's giant cystic pheochromocytoma was the fourth heaviest and fifth largest maximal diameter identified using our literature search criteria. Additionally, this tumor had the largest maximal diameter of all histologically confirmed benign/low metastatic risk pheochromocytomas. Giant cystic pheochromocytomas are rare entities requiring clinical suspicion coupled with strategic diagnostic evaluation to confirm the diagnosis.

Pelvic exenteration case series: A single surgeon's experience at one institution in Trinidad and Tobago.

INTRODUCTION: Pelvic exenteration (PE) is an ultra-radical surgical procedure characterized by the en bloc resection of the pelvic organs. METHODS: In this case series, we report retrospectively on four patients who underwent PE in Trinidad and Tobago from 2012 to 2016. One male patient had rectal cancer while one each of three women had cervical, colon, or rectal cancer. RESULTS: Early postoperative complications (≤30days) occurred in all patients, while late complications (>30days) occurred in one patient (Grade 1 - Clavien-Dindo classification). Disease recurrence occurred in 50% of patients, and the median overall survival was 8 months (range, 4-15 months). DISCUSSION: There are many inherent challenges to conducting such major procedures in developing countries, including inadequate blood product supplies, intensive care unit beds, and pre- and post-operative support services. With increased surgical capacity and support infrastructure, hospitals in these regions would be equipped to perform PEs with better outcomes. CONCLUSION: This case series adds to existing data on the feasibility of performing PE in developing countries. We demonstrate that PE can be performed without major postoperative complications in a resource-limited hospital. To the best of our knowledge, this is the first case series that describes PE in the Caribbean.

A case report of the clear cell variant of gallbladder carcinoma.

INTRODUCTION: Clear cell gallbladder carcinoma accounts for less than 1% of all gallbladder malignancies and demonstrates its unique histopathological characteristics in patients with no prior medical illness or familial predisposition. PRESENTATION OF CASE: Here we present a case of a 56-year-old female, with no prior medical conditions presented with a 2-month history of upper abdominal pain. Routine hematological and biochemical tests were unremarkable. An abdominal ultrasound revealed the presence of a gallbladder calculi, and a fundic mass while magnetic resonance cholangiopancreatography revealed a 8.0cm×3.5cm gallbladder mass. Computed tomography imaging excluded any distant haematogenous metastases. An open cholecystectomy with lymphadenectomy was proceeded by staging laparoscopy. Upon pathologic investigation, the morphologic and immunophenotypic features supported a diagnosis of clear cell variant of gallbladder carcinoma. DISCUSSION: Pathological prognostications for primary clear cell gall bladder carcinomas are not well defined due to the rarity of cases and possible misidentification as secondary metastases. Foci of adenocarcinoma within the tumor along with immunohistochemical staining probes can be informative in consideration of differential diagnosis. CONCLUSION: In these cases, clinical case management should be personalized for increased survival with the possible incorporation of next generation sequencing approaches to guide therapeutic algorithms. We discuss this exceedingly rare case of the clear cell variant of gallbladder carcinoma in detail, highlighting some of the diagnostic, and clinical challenges.

Rare nodular malignant melanoma of the heel in the Caribbean: A case report.

INTRODUCTION: Malignant melanoma of the heel is a rare melanoma subtype with incidence rates that reflect the complex relationship between sun exposure at certain geographic locations, individual melanin levels and overall melanoma risk. It is oftentimes characterized by poor prognosis because of delays in presentation resulting in longitudinal tumor invasion, lymph node involvement and metastasis. PRESENTATION OF CASE: A 59-year-old woman was admitted to the Eric Williams Medical Sciences Complex, Trinidad and Tobago with a 5mm pruritic lesion on her left heel. At presentation, the lesion was asymmetric with border irregularities, color heterogeneity, with dynamics in elevation and overall size. She was subsequently diagnosed with malignant melanoma with left inguinal lymphadenopathy. A single stage wide local excision (WLE) of the left heel lesion with a split-thickness skin graft (STSG) and a left inguinal lymphadenectomy were performed. Dacarbazine (Bayer) was administered post operatively. DISCUSSION: Globally, the incidence of malignant melanoma is rapidly increasing, particularly, in countries like Trinidad and Tobago with a significant population of non-fair skinned individuals. There is need for strategic initiatives to increase patient adherence in these populations. CONCLUSION: The rarity of malignant heel melanomas heightens the need for increased patient awareness and greater clinical surveillance to ensure early diagnosis and treatment.

A case of distal extrahepatic cholangiocarcinoma with two positive resection margins.

Cholangiocarcinoma is an uncommon primary malignancy of the biliary tract that is challenging to diagnose and treat effectively due to its relatively silent and late clinical presentation. The present study reports a case of a 60-year-old male with distal extrahepatic cholangiocarcinoma with a 3-week history of painless obstructive jaundice symptoms and subjective weight loss. Imaging revealed an obstructing lesion in the common bile duct, just distal to the entrance of the cystic duct. Pathology revealed moderately differentiated cholangiocarcinoma with two positive proximal resection margins. The two positive resection margins presented a challenge during surgery and points to an urgent need for further studies to better illuminate diagnostic and therapeutic options for patients with similar clinicopathological presentation.

Right sided spleen laying retro-duodenal: A case report and review of the literature.

INTRODUCTION: Unlike left sided accessory spleen that are seen in 10-30% of cases at autopsy, cases of right accessory spleens are extremely rare. This congenital body of healthy splenic tissue simulates tumors from neighboring organs and presents a challenge in formulating a differential diagnosis. PRESENTATION OF CASE: We present the case of a patient whose CT scan of the abdomen showed a large mass, 11×8cm, arising retro-duodenal and lying just anterior to the right kidney. To the best of our knowledge, this is the only case where the accessory spleen was found retro-duodenal, directly anterior to the kidney and completely separate from the supra-renal gland. The chief complaint of the patient was right upper quadrant pain, radiating to the back, and colicky in nature. The patient was diagnosed with duodenal gastro-intestinal stromal tumor and a retro-peritoneal sarcoma. The mass was removed via a Kocher's incision and immunohistological examination showed that it was a right sided accessory spleen. The patient's left sided spleen appeared normal. DISCUSSION: Efforts to distinguish an accessory spleen from a retroperitoneal tumor with available scans, percutaneous biopsy or biochemical tests are inconclusive. Differential diagnosis between a retroperitoneal tumor and an accessory spleen can only be made after surgical exploration. CONCLUSION: This case highlights the fact that surgeons should consider the possibility of an accessory spleen when making a differential diagnosis of retroperitoneal tumors.

Clinicopathological and Targeted Exome Gene Features of a Patient with Metastatic Acinic Cell Carcinoma of the Parotid Gland Harboring an ARID2 Nonsense Mutation and CDKN2A/B Deletion.

We describe the presentation, treatment, clinical outcome, and targeted genome analysis of a metastatic salivary acinic cell carcinoma (AciCC). A 71-year-old male presented with a 3 cm right tail of a parotid lesion, first detected as a nodule by the patient seven months earlier. He had a right total parotidectomy with cranial nerve VII resection, right facial nerve resection and grafting, resection of the right conchal cartilage, and right modified radical neck dissection. The primary tumor revealed AciCC with two distinct areas: a well-differentiated component with glandular architecture and a dedifferentiated component with infiltrative growth pattern associated with prominent stromal response, necrosis, perineural invasion, and cellular pleomorphism. Tumor staging was pT4 N0 MX. Immunohistochemistry staining showed pankeratin (+), CD56 (-), and a Ki67 proliferation index of 15%. Upon microscopic inspection, 49 local lymph nodes resected during parotidectomy were negative for cancer cells. Targeted sequencing of the primary tumor revealed deletions of CDKN2A and CDKN2B, a nonsense mutation in ARID2, and single missense mutations of unknown significance in nine other genes. Despite postoperative localized radiation treatment, follow-up whole body PET/CT scan showed lung, soft tissue, bone, and liver metastases. The patient expired 9 months after resection of the primary tumor.

Building capacity for human genetics and genomics research in Trinidad and Tobago / Aumento de la capacidad de investigación en genética y genómica humanas en Trinidad y Tabago

Advances in human genetics and genomic sciences and the corresponding explosion of biomedical technologies have deepened current understanding of human health and revolutionized medicine. In developed nations, this has led to marked improvements in disease risk stratification and diagnosis. These advances have also led to targeted intervention strategies aimed at promoting disease prevention, prolonging disease onset, and mitigating symptoms, as in the well-known case of breast cancer and the BRCA1 gene. In contrast, in the developing nation of Trinidad and Tobago, this scientific revolution has not translated into the development and application of effective genomics-based interventions for improving public health. While the reasons for this are multifactorial, the underlying basis may be rooted in the lack of pertinence of internationally driven genomics research to the local public health needs in the country, as well as a lack of relevance of internationally conducted genetics research to the genetic and environmental contexts of the population. Indeed, if Trinidad and Tobago is able to harness substantial public health benefit from genetics/genomics research, then there is a dire need, in the near future, to build local capacity for the conduct and translation of such research. Specifically, it is essential to establish a national human genetics/genomics research agenda in order to build sustainable human capacity through education and knowledge transfer and to generate public policies that will provide the basis for the creation of a mutually beneficial framework (including partnerships with more developed nations) that is informed by public health needs and contextual realities of the nation.

Los avances en materia de ciencias genéticas y genómicas humanas y la correspondiente expansión de las tecnologías biomédicas han ampliado la comprensión actual de la salud humana y han revolucionado la medicina. En las naciones desarrolladas, ello ha conducido a intensas mejoras en la estratificación del riesgo y el diagnóstico de las enfermedades. Estos avances también han conducido a estrategias de intervención dirigidas a promover la prevención de las enfermedades, retardar su aparición, y atenuar sus síntomas, como en el caso del cáncer de mama y el gen BRCA1. Por el contrario, en Trinidad y Tabago, nación en desarrollo, esta revolución científica no se ha traducido en la elaboración y aplicación de intervenciones eficaces basadas en la genómica para mejorar la salud pública. Aunque las razones de ello son multifactoriales, el motivo subyacente puede radicar en la falta de adecuación de la investigación genómica a escala internacional a las necesidades locales de salud pública del país, así como a la escasa relevancia de la investigación en genética realizada internacionalmente para los contextos genéticos y ambientales de la población. En efecto, para que Trinidad y Tabago pueda aprovechar los sustanciales beneficios en materia de salud pública de la investigación en genética y genómica, es extremadamente necesario, en un futuro próximo, desarrollar la capacidad local para la realización y traducción de ese tipo de investigación. En concreto, es esencial establecer un programa nacional de investigación en genética y genómica humanas con objeto de desarrollar una capacidad humana sostenible mediante la educación y la transferencia de conocimientos, y generar políticas públicas que proporcionen la base para la creación de un marco mutuamente beneficioso (incluidas las alianzas con naciones más desarrolladas) fundamentado en las necesidades de salud pública y en las realidades contextuales del país.

Associations among ancestry, geography and breast cancer incidence, mortality, and survival in Trinidad and Tobago.

UNLABELLED: Breast cancer (BC) is the most common newly diagnosed cancer among women in Trinidad and Tobago (TT) and BC mortality rates are among the highest in the world. Globally, racial/ethnic trends in BC incidence, mortality and survival have been reported. However, such investigations have not been conducted in TT, which has been noted for its rich diversity. In this study, we investigated associations among ancestry, geography and BC incidence, mortality and survival in TT. Data on 3767 incident BC cases, reported to the National Cancer Registry of TT, from 1995 to 2007, were analyzed in this study. Women of African ancestry had significantly higher BC incidence and mortality rates ( INCIDENCE: 66.96; MORTALITY: 30.82 per 100,000) compared to women of East Indian ( INCIDENCE: 41.04, MORTALITY: 14.19 per 100,000) or mixed ancestry ( INCIDENCE: 36.72, MORTALITY: 13.80 per 100,000). Geographically, women residing in the North West Regional Health Authority (RHA) catchment area followed by the North Central RHA exhibited the highest incidence and mortality rates. Notable ancestral differences in survival were also observed. Women of East Indian and mixed ancestry experienced significantly longer survival than those of African ancestry. Differences in survival by geography were not observed. In TT, ancestry and geographical residence seem to be strong predictors of BC incidence and mortality rates. Additionally, disparities in survival by ancestry were found. These data should be considered in the design and implementation of strategies to reduce BC incidence and mortality rates in TT.

Building capacity for human genetics and genomics research in Trinidad and Tobago.

Advances in human genetics and genomic sciences and the corresponding explosion of biomedical technologies have deepened current understanding of human health and revolutionized medicine. In developed nations, this has led to marked improvements in disease risk stratification and diagnosis. These advances have also led to targeted intervention strategies aimed at promoting disease prevention, prolonging disease onset, and mitigating symptoms, as in the well-known case of breast cancer and the BRCA1 gene. In contrast, in the developing nation of Trinidad and Tobago, this scientific revolution has not translated into the development and application of effective genomics-based interventions for improving public health. While the reasons for this are multifactorial, the underlying basis may be rooted in the lack of pertinence of internationally driven genomics research to the local public health needs in the country, as well as a lack of relevance of internationally conducted genetics research to the genetic and environmental contexts of the population. Indeed, if Trinidad and Tobago is able to harness substantial public health benefit from genetics/genomics research, then there is a dire need, in the near future, to build local capacity for the conduct and translation of such research. Specifically, it is essential to establish a national human genetics/genomics research agenda in order to build sustainable human capacity through education and knowledge transfer and to generate public policies that will provide the basis for the creation of a mutually beneficial framework (including partnerships with more developed nations) that is informed by public health needs and contextual realities of the nation.

New concepts in breast cancer genomics and genetics.

Massively parallel DNA and RNA sequencing approaches have generated data on thousands of breast cancer genomes. In this review, we consider progress largely from the perspective of new concepts and hypotheses raised so far. These include challenges to the multistep model of breast carcinogenesis and the discovery of new defects in DNA repair through sequence analysis. Issues for functional genomics include the development of strategies to differentiate between mutations that are likely to drive carcinogenesis and bystander background mutations, as well as the importance of mechanistic studies that examine the role of mutations in genes with roles in splicing, histone methylation, and long non-coding RNA function. The application of genome-annotated patient-derived breast cancer xenografts as a potentially more reliable preclinical model is also discussed. Finally, we address the challenge of extracting medical value from genomic data. A weakness of many datasets is inadequate clinical annotation, which hampers the establishment of links between the mutation spectra and the efficacy of drugs or disease phenotypes. Tools such as dGene and the DGIdb are being developed to identify possible druggable mutations, but these programs are a work in progress since extensive molecular pharmacology is required to develop successful 'genome-forward' clinical trials. Examples are emerging, however, including targeting HER2 in HER2 mutant breast cancer and mutant ESR1 in ESR1 endocrine refractory luminal-type breast cancer. Finally, the integration of DNA- and RNA-based sequencing studies with mass spectrometry-based peptide sequencing and an unbiased determination of post-translational modifications promises a more complete view of the biochemistry of breast cancer cells and points toward a new discovery horizon in our understanding of the pathophysiology of this complex disease.