RESUMEN
Ancestrally diverse and admixed populations, including the Hispanic/Latino/a/x/e community, are underrepresented in cancer genetic and genomic studies. Leveraging the Latino Colorectal Cancer Consortium, we analyzed whole exome sequencing data on tumor/normal pairs from 718 individuals with colorectal cancer (128 Latino, 469 non-Latino) to map somatic mutational features by ethnicity and genetic ancestry. Global proportions of African, East Asian, European, and Native American ancestries were estimated using ADMIXTURE. Associations between global genetic ancestry and somatic mutational features across genes were examined using logistic regression. TP53 , APC , and KRAS were the most recurrently mutated genes. Compared to non-Latino individuals, tumors from Latino individuals had fewer KRAS (OR=0.64, 95%CI=0.41-0.97, p=0.037) and PIK3CA mutations (OR=0.55, 95%CI=0.31-0.98, p=0.043). Genetic ancestry was associated with presence of somatic mutations in 39 genes (FDR-adjusted LRT p<0.05). Among these genes, a 10% increase in African ancestry was associated with significantly higher odds of mutation in KNCN (OR=1.34, 95%CI=1.09-1.66, p=5.74×10 -3 ) and TMEM184B (OR=1.53, 95%CI=1.10-2.12, p=0.011). Among RMGs, we found evidence of association between genetic ancestry and mutation status in CDC27 (LRT p=0.0084) and between SMAD2 mutation status and AFR ancestry (OR=1.14, 95%CI=1.00-1.30, p=0.046). Ancestry was not associated with tumor mutational burden. Individuals with above-average Native American ancestry had a lower frequency of microsatellite instable (MSI-H) vs microsatellite stable tumors (OR=0.45, 95%CI=0.21-0.99, p=0.048). Our findings provide new knowledge about the relationship between ancestral haplotypes and somatic mutational profiles that may be useful in developing precision medicine approaches and provide additional insight into genomic contributions to cancer disparities. Significance: Our data in ancestrally diverse populations adds essential information to characterize mutational features in the colorectal cancer genome. These results will help enhance equity in the development of precision medicine strategies.
RESUMEN
[This corrects the article DOI: 10.18632/oncotarget.26574.].
RESUMEN
BACKGROUND: For the advancement of cancer research, the collection of tissue specimens from drug-resistant tumors after targeted therapy is crucial. Although patients with lung cancer are often provided targeted therapy, post-therapy specimens are not routinely collected due to the risks of collection, limiting the study of targeted therapy resistance mechanisms. Posthumous rapid tissue donation (RTD) is an expedient collection process that provides an opportunity to understand treatment-resistant lung cancers. METHODS: Consent to participate in the thoracic RTD protocol was obtained during patient care. When death occurred, tumor and paired non-tumor, cytology, and blood specimens were collected within 48 hours and preserved as formalin-fixed and frozen specimens. Tissue sections were evaluated with hematoxylin and eosin staining and immunohistochemistry (IHC) against multiple biomarkers, including various programmed death ligand 1 (PD-L1) clones. Next-generation sequencing was performed on 13 specimens from 5 patients. RESULTS: Postmortem specimens (N = 180) were well preserved from 9 patients with lung cancer. PD-L1 IHC revealed heterogeneity within and between tumors. An AGK-BRAF fusion was newly identified in tumor from a donor with a known echinoderm microtubule-associated protein-like 4 to anaplastic lymphoma kinase (EML4-ALK) fusion and history of anaplastic lymphoma kinase (ALK) inhibitor therapy. RNA expression analysis revealed a clonal genetic origin of metastatic cancer cells. CONCLUSIONS: Post-therapy specimens demonstrated PD-L1 heterogeneity and an acyl glycerol kinase to B-rapidly accelerated fibrosarcoma (AGK-BRAF) fusion in a patient with an EML4-ALK-positive lung adenocarcinoma as a potential resistance mechanism to ALK inhibitor therapy. Rapid tissue donation collection of postmortem tissue from lung cancer patients is a novel approach to cancer research that enables studies of molecular evolution and drug resistance.
Asunto(s)
Adenocarcinoma del Pulmón/tratamiento farmacológico , Biomarcadores de Tumor/genética , Investigación Participativa Basada en la Comunidad/métodos , Resistencia a Antineoplásicos/genética , Neoplasias Pulmonares/tratamiento farmacológico , Obtención de Tejidos y Órganos/métodos , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/mortalidad , Adenocarcinoma del Pulmón/patología , Anciano , Antígeno B7-H1/genética , Biomarcadores de Tumor/análisis , Evolución Molecular , Femenino , Florida , Heterogeneidad Genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica , Pulmón/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Proteínas Proto-Oncogénicas B-raf/genéticaRESUMEN
Lung cancer patients with mutations in epidermal growth factor receptor (EGFR) benefit from treatments targeting tyrosine kinase inhibitors (TKIs). However, both intrinsic and acquired resistance of tumors to TKIs are common, and EGFR variants have been identified that are resistant to multiple TKIs. In the present study, we characterized selected EGFR variants previously observed in lung cancer patients and expressed in a murine bone marrow pro-B Ba/F3 cell model. Among these EGFR variants, we report that an exon 20 deletion/insertion mutation S768insVGH is resistant to erlotinib (a first-generation TKI), but sensitive to osimertinib (a third-generation TKI). We also characterized a rare exon 21 germline variant, EGFR P848L, which transformed Ba/F3 cells and conferred resistance to multiple EGFR-targeting TKIs. Our analysis revealed that P848L (a) does not bind erlotinib; (b) is turned over less rapidly than L858R (a common tumor-derived EGFR mutation); (c) is not autophosphorylated at Tyr 1045 [the major docking site for Cbl proto-oncogene (c-Cbl) binding]; and (d) does not bind c-Cbl. Using viability assays including 300 clinically relevant targeted compounds, we observed that Ba/F3 cells transduced with EGFR P848L, S768insVGH, or L858R have very different drug-sensitivity profiles. In particular, EGFR P848L, but not L858R or S768insVGH, was sensitive to multiple Janus kinase 1/2 inhibitors. In contrast, cells driven by L858R, but not by P848L, were sensitive to multikinase MAPK/extracellular-signal-regulated kinase (ERK) kinase and ERK inhibitors including EGFR-specific TKIs. These observations suggest that continued investigation of rare TKI-resistant EGFR variants is warranted to identify optimal treatments for cancer.
Asunto(s)
Modelos Animales de Enfermedad , Variación Genética/genética , Neoplasias Pulmonares/genética , Animales , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Receptores ErbB/genética , Receptores ErbB/metabolismo , Células HEK293 , Humanos , Neoplasias Pulmonares/metabolismo , Ratones , Ratones Transgénicos , Microscopía Fluorescente , Mutación , Nitrilos , Inhibidores de Proteínas Quinasas/farmacología , Proto-Oncogenes Mas , Pirazoles/farmacología , Pirimidinas/farmacologíaRESUMEN
Transforming growth factor beta (TGFß) plays a key role in regulating epithelial-to-mesenchymal transition (EMT). A gene expression signature (TGFß-EMT) associated with TGFß-induced EMT activities was developed using human Non-Small Cell Lung Carcinoma (NSCLC) cells treated with TGFß-1 and subjected to Affymetrix microarray analysis. The final 105-probeset TGFß-EMT signature covers 77 genes, and a NanoString assay utilized a subset of 60 of these genes (TGFß-EMTN signature). We found that the TGFß-EMT and TGFß-EMTN gene signatures predicted overall survival (OS) and metastasis-free survival (MFS). The TGFß-EMT signature was validated as prognostic of 5-year MFS in 3 cohorts: a 133 NSCLC tumor dataset (P = 0.0002), a NanoString assays of RNA isolated from formalin-fixed paraffin-embedded samples from these same tumors (P = 0.0015), and a previously published NSCLC MFS dataset (P = 0.0015). The separation between high and low metastasis signature scores was higher at 3 years (ΔMFS TGFß-EMT = -28.6%; ΔMFS TGFß-EMTN = -25.2%) than at 5 years (ΔMFS TGFß-EMT = -18.6%; ΔMFS TGFß-EMTN = -11.8%). In addition, the TGFß-EMT signature correlated with whether the cancer had already metastasized or not at time of surgery in a colon cancer cohort. The results show that the TGFß-EMT signature successfully discriminated lung cancer cell lines capable of undergoing EMT in response to TGFß-1 and predicts MFS in lung adenocarcinomas. Thus, the TGFß-EMT signature has the potential to be developed as a clinically relevant predictive biomarker, for example to identify those patients with resected early stage lung cancer who may benefit from adjuvant therapy.
RESUMEN
BACKGROUND: Lung cancer biomarker-driven therapies are the gold standard of treatment and recent studies suggest a higher prevalence of specific targetable biomarkers among Hispanic/Latinos (H/L) than Non-Hispanic Whites (NHW). The study aimed (1) to identify Florida (FL) and Puerto Rico (PR) physicians' knowledge and perceived value of newer genomic data regarding race/ethnicity in relation to optimal lung cancer treatment and survival; and (2) to identify modifiable practice barriers both across and within each location regarding biomarker testing in lung cancer. METHODS: A 25-item survey was administered to a stratified random sample of physicians in FL and PR (medical oncologists, radiation oncologists, pulmonologists, and pathologists). Questions targeted domains of biomarker knowledge, attitudes toward testing, barriers, and practice behaviors regarding lung cancer biomarker testing. RESULTS: The response rate was 45%. Participants identified guiding treatment decisions (82%) and personalizing treatments for patients (78%) as key benefits to mutation testing. PR physicians were more likely (p=0.022) to believe H/L had an elevated incidence of targetable epidermal growth factor receptor (EGFR) mutations compared to NHW. They also perceived lack of appropriate testing resources as a primary barrier compared to FL physicians (43.6% vs. 20.6%, p<0.001), whereas FL physicians identified mutation tests not conducted routinely as part of patient diagnosis as a primary barrier (43.1% vs 24.2%, p= 0.008). CONCLUSIONS: Practice behaviors differed by specialty and between locations, and differences were noted concerning physician's preferences for ordering mutation testing, indicating a clear need for education among physicians in both locations. IMPACT: Educating physicians regarding biomarker testing is imperative to improve patient care.
RESUMEN
Prediction of lung cancer metastasis relies on post-resection assessment of tumor histology, which is a severe limitation since only a minority of lung cancer patients are diagnosed with resectable disease. Therefore, characterization of metastasis-predicting biomarkers in pre-resection small biopsy specimens is urgently needed. Here we report a biomarker consisting of the phosphorylation of the retinoblastoma protein (Rb) on serine 249 combined with elevated p39 expression. This biomarker correlates with epithelial-to-mesenchymal transition traits in non-small cell lung carcinoma (NSCLC) cells. Immunohistochemistry staining of NSCLC tumor microarrays showed that strong phospho-Rb S249 staining positively correlated with tumor grade specifically in the squamous cell carcinoma (SCC) subtype. Strong immunoreactivity for p39 positively correlated with tumor stage, lymph node invasion, and distant metastases, also in SCC. Linear regression analyses showed that the combined scoring for phospho-Rb S249, p39 and E-cadherin in SCC is even more accurate at predicting tumor staging, relative to each score individually. We propose that combined immunohistochemistry staining of NSCLC samples for Rb phosphorylation on S249, p39, and E-cadherin protein expression could aid in the assessment of tumor staging and metastatic potential when tested in small primary tumor biopsies. The intense staining for phospho-Rb S249 that we observed in high grade SCC could also aid in the precise sub-classification of poorly differentiated SCCs.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/metabolismo , Proteínas del Citoesqueleto/biosíntesis , Transición Epitelial-Mesenquimal , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/metabolismo , Proteína de Retinoblastoma/metabolismo , Biomarcadores de Tumor/genética , Cadherinas/biosíntesis , Cadherinas/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Adhesión Celular/genética , Línea Celular Tumoral , Proteínas del Citoesqueleto/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Clasificación del Tumor , Metástasis de la Neoplasia , Fosforilación , Proteína de Retinoblastoma/genéticaRESUMEN
OBJECTIVE: The collection of posthumous tissue from advanced stage lung cancer patients is beneficial to medical science. Recruiting living patients to a Rapid Tissue Donation Program (RTD) poses several psychosocial challenges and little is known about perceptions of joining this type of program. This study qualitatively examined perceptions of advanced stage lung cancer patients (n=14) participating in a lung cancer RTD program, their NoK (n=11), and physicians (n=6) at the Thoracic Oncology Clinic at H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida USA. METHODS: Semi-structured interviews were conducted with participants and interview transcripts were analyzed using the constant comparison method. RESULTS: Majority of patients joined to give back to research, discussed participation with family members, and desired for family to receive information about the use of the tissue after their death. All participating NoK were supportive of their family member's decision. Physicians described the program as running smoothly, but provided suggestions for process improvements. CONCLUSION: Participants joined with intention to give back to research community and families were supportive of loved one's participation in RTD. Physicians agreed with overall process. PRACTICE IMPLICATIONS: Key factors for a successful RTD program is tailoring to institutional and individual needs.
Asunto(s)
Actitud del Personal de Salud , Cuidadores/psicología , Familia/psicología , Neoplasias Pulmonares/psicología , Selección de Paciente , Médicos/psicología , Obtención de Tejidos y Órganos , Anciano , Toma de Decisiones , Femenino , Florida , Humanos , Entrevistas como Asunto , Masculino , Persona de Mediana Edad , Investigación CualitativaRESUMEN
INTRODUCTION: To address the lack of genomic data from Hispanic/Latino (H/L) patients with lung cancer, the Latino Lung Cancer Registry was established to collect patient data and biospecimens from H/L patients. METHODS: This retrospective observational study examined lung cancer tumor samples from 163 H/L patients, and tumor-derived DNA was subjected to targeted-exome sequencing (>1000 genes, including EGFR, KRAS, serine/threonine kinase 11 gene [STK11], and tumor protein p53 gene [TP53]) and ancestry analysis. Mutation frequencies in this H/L cohort were compared with those in a similar cohort of non-Hispanic white (NHW) patients and correlated with ancestry, sex, smoking status, and tumor histologic type. RESULTS: Of the adenocarcinomas in the H/L cohort (n = 120), 31% had EGFR mutations, versus 17% in the NHW control group (p < 0.001). KRAS (20% versus 38% [p = 0.002]) and STK11 (8% versus 16% [p = 0.065]) mutations occurred at lower frequency, and mutations in TP53 occurred at similar frequency (46% versus 40% [p = 0.355]) in H/L and NHW patients, respectively. Within the Hispanic cohort, ancestry influenced the rate of TP53 mutations (p = 0.009) and may have influenced the rate of EGFR, KRAS, and STK11 mutations. CONCLUSIONS: Driver mutations in H/L patients with lung adenocarcinoma differ in frequency from those in NHW patients associated with their indigenous American ancestry. The spectrum of driver mutations needs to be further assessed in the H/L population.
Asunto(s)
Neoplasias Pulmonares/genética , Mutación/genética , Femenino , Hispánicos o Latinos , Humanos , Neoplasias Pulmonares/patología , Masculino , Estudios RetrospectivosRESUMEN
BACKGROUND: Lung cancer is the most common cancer in the world. In addition to the geographical and sex-specific differences in the incidence, mortality, and survival rates of lung cancer, growing evidence suggests that racial and ethnic differences exist. METHODS: We reviewed published data related to racial and ethnic differences in lung cancer. RESULTS: Current knowledge and substantive findings related to racial and ethnic differences in lung cancer were summarized, focusing on incidence, mortality, survival, cigarette smoking, prevention and early detection, and genomics. Systems-level and health care professional-related issues likely to contribute to specific racial and ethnic health disparities were also reviewed to provide possible suggestions for future strategies to reduce the disproportionate burden of lung cancer. CONCLUSIONS: Although lung carcinogenesis is a multifactorial process driven by exogenous exposures, genetic variations, and an accumulation of somatic genetic events, it appears to have racial and ethnic differences that in turn impact the observed epidemiological differences in rates of incidence, mortality, and survival.
Asunto(s)
Etnicidad , Neoplasias Pulmonares/epidemiología , Anciano , Femenino , Genómica , Humanos , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
BACKGROUND: The scarcity of tissues from racial and ethnic minorities at biobanks poses a scientific constraint to research addressing health disparities in minority populations. METHODS: To address this gap, the Minority Biospecimen/Biobanking Geographic Management Program for region 3 (BMaP-3) established a working infrastructure for a "biobanking" hub in the southeastern United States and Puerto Rico. Herein we describe the steps taken to build this infrastructure, evaluate the feasibility of collecting formalin-fixed, paraffin-embedded tissue blocks and associated data from a single cancer type (breast), and create a web-based database and tissue microarrays (TMAs). RESULTS: Cancer registry data from 6 partner institutions were collected, representing 12,408 entries from 8,279 unique patients with breast cancer (years 2001-2011). Data were harmonized and merged, and deidentified information was made available online. A TMA was constructed from formalin-fixed, paraffin-embedded samples of invasive ductal carcinoma (IDC) representing 427 patients with breast cancer (147 African Americans, 168 Hispanics, and 112 non-Hispanic whites) and was annotated according to biomarker status and race/ethnicity. Biomarker analysis of the TMA was consistent with the literature. CONCLUSIONS: Contributions from participating institutions have facilitated a robust research tool. TMAs of IDC have now been released for 5 projects at 5 different institutions.
Asunto(s)
Carcinoma Ductal de Mama/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Etnicidad , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Análisis de Matrices TisularesRESUMEN
Clinicians routinely prescribe adjuvant chemotherapy (ACT) for resected non-small cell lung cancer patients. However, ACT only improves five-year disease-free survival in stage I-III non-small cell lung cancer by 5-15%, with most patients deriving no benefit. Herein, deregulation of the E2F pathway was explored as a biomarker in lung adenocarcinoma patients. An E2F pathway scoring system, based on 74 E2F-regulated genes, was trained for RNA from two platforms: fresh-frozen (FF) or formalin-fixed paraffin-embedded (FFPE) tissues. The E2F score was tested as a prognostic biomarker in five FF-based cohorts and two FFPE-based cohorts. The E2F score was tested as a predictive biomarker in two randomized clinical trials; JBR10 and the NATCH (Neo-Adjuvant Taxol-Carboplatin Hope) trial. The E2F score was prognostic in untreated patients in all seven datasets examined (p < 0.05). Stage-specific analysis of combined cohorts demonstrated that the E2F score was prognostic in stage I patients (p = 0.0495 to <0.001; hazard ratio, HR, =2.04- 2.22) with a similar trend in other stages. The E2F score was strongly predictive in stage II patients from the two combined randomized clinical trials with a significant differential treatment effect (p = 0.015). Specifically, ACT improved survival in stage II patients with high E2F (p = 0.01; HR= 0.21). The 5-year survival increased from 18% to 81%. In contrast, in patients with low E2F, 5-year survival was 57% in untreated patients and 41% in ACT-treated patients with a HR of 1.55 (p = 0.47). In summary, the E2F score provides valuable prognostic information for Stage I and predictive information for Stage II lung adenocarcinoma patients and should be further explored as a decision support tool for their treatment.
Asunto(s)
Adenocarcinoma/genética , Biomarcadores de Tumor/genética , Factores de Transcripción E2F/genética , Neoplasias Pulmonares/genética , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adenocarcinoma del Pulmón , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/administración & dosificación , Línea Celular Tumoral , Quimioterapia Adyuvante , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Terapia Neoadyuvante , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Medicina de Precisión , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Factores de Tiempo , Transcriptoma , Resultado del TratamientoRESUMEN
Epithelial-mesenchymal transition (EMT) is one mechanism of acquired resistance to inhibitors of the epidermal growth factor receptor-tyrosine kinases (EGFR-TKIs) in non-small cell lung cancer (NSCLC). The precise mechanisms of EMT-related acquired resistance to EGFR-TKIs in NSCLC remain unclear. We generated erlotinib-resistant HCC4006 cells (HCC4006ER) by chronic exposure of EGFR-mutant HCC4006 cells to increasing concentrations of erlotinib. HCC4006ER cells acquired an EMT phenotype and activation of the TGF-ß/SMAD pathway, while lacking both T790M secondary EGFR mutation and MET gene amplification. We employed gene expression microarrays in HCC4006 and HCC4006ER cells to better understand the mechanism of acquired EGFR-TKI resistance with EMT. At the mRNA level, ZEB1 (TCF8), a known regulator of EMT, was >20-fold higher in HCC4006ER cells than in HCC4006 cells, and increased ZEB1 protein level was also detected. Furthermore, numerous ZEB1 responsive genes, such as CDH1 (E-cadherin), ST14, and vimentin, were coordinately regulated along with increased ZEB1 in HCC4006ER cells. We also identified ZEB1 overexpression and an EMT phenotype in several NSCLC cells and human NSCLC samples with acquired EGFR-TKI resistance. Short-interfering RNA against ZEB1 reversed the EMT phenotype and, importantly, restored erlotinib sensitivity in HCC4006ER cells. The level of micro-RNA-200c, which can negatively regulate ZEB1, was significantly reduced in HCC4006ER cells. Our results suggest that increased ZEB1 can drive EMT-related acquired resistance to EGFR-TKIs in NSCLC. Attempts should be made to explore targeting ZEB1 to resensitize TKI-resistant tumors.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Resistencia a Antineoplásicos , Receptores ErbB/antagonistas & inhibidores , Proteínas de Homeodominio/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Factores de Transcripción/antagonistas & inhibidores , Antineoplásicos/farmacología , Western Blotting , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal , Receptores ErbB/genética , Receptores ErbB/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Técnicas para Inmunoenzimas , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Mutación , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Células Tumorales Cultivadas , Homeobox 1 de Unión a la E-Box con Dedos de ZincRESUMEN
Few studies have reported on African American and Hispanic (AA and H) populations' informational needs when seeking cancer care at an institution that offers clinical trials. Moffitt Cancer Center (MCC) sought to identify and examine the decision making process, the perceptions, and the preferred channels of communication about cancer care services for AA and H communities in order to develop a list of marketing recommendations. Five focus groups (N = 45) consisting of two AA and three H were conducted in four counties of the MCC catchment area in Tampa, FL. Participants were asked about their perceptions, knowledge, attitudes, and beliefs about cancer care and MCC. Focus groups were audio-recorded and verbatim transcripts were analyzed using content analysis. Similarities in responses were found between AA and H participants. Participants received general health and cancer information from media sources and word of mouth and preferred to hear patient testimonials. There were concerns about costs, insurance coverage, and the actual geographic location of the cancer center. In general, H participants were not opposed to participating in cancer clinical trials/research, whereas, AA participants were more hesitant. A majority of participants highly favored an institution that offered standard care and clinical trials. AA and H participants shared similar concerns and preferences in communication channels, but each group had specific informational needs. The perceptions and preferences of AA and H must be explored in order to successfully and efficiently increase cancer clinical trial participation.
Asunto(s)
Acceso a la Información , Negro o Afroamericano/estadística & datos numéricos , Necesidades y Demandas de Servicios de Salud , Hispánicos o Latinos/estadística & datos numéricos , Neoplasias/etnología , Neoplasias/prevención & control , Adulto , Comunicación , Femenino , Grupos Focales , Estudios de Seguimiento , Conocimientos, Actitudes y Práctica en Salud , Humanos , Masculino , Persona de Mediana Edad , PercepciónRESUMEN
Lung cancer is the second most common cancer and the leading cause of cancer-related deaths. Despite recent advances in the development of targeted therapies, patients with advanced disease remain incurable, mostly because metastatic non-small cell lung carcinomas (NSCLC) eventually become resistant to tyrosine kinase inhibitors (TKIs). Kinase inhibitors have the potential for target promiscuity because the kinase super family is the largest family of druggable genes that binds to a common substrate (ATP). As a result, TKIs often developed for a specific purpose have been found to act on other targets. Drug affinity chromatography has been used to show that dasatinib interacts with the TGFß type I receptor (TßR-I), a serine-threonine kinase. To determine the potential biological relevance of this association, we studied the combined effects of dasatinib and TGFß on lung cancer cell lines. We found that dasatinib treatment alone had very little effect; however, when NSCLC cell lines were treated with a combination of TGFß and dasatinib, apoptosis was induced. Combined TGFß-1 + dasatinib treatment had no effect on the activity of Smad2 or other non-canonical TGFß intracellular mediators. Interestingly, combined TGFß and dasatinib treatment resulted in a transient increase in p-Smad3 (seen after 3 hours). In addition, when NSCLC cells were treated with this combination, the pro-apoptotic protein BIM was up-regulated. Knockdown of the expression of Smad3 using Smad3 siRNA also resulted in a decrease in BIM protein, suggesting that TGFß-1 + dasatinib-induced apoptosis is mediated by Smad3 regulation of BIM. Dasatinib is only effective in killing EGFR mutant cells, which is shown in only 10% of NSCLCs. Therefore, the observation that wild-type EGFR lung cancers can be manipulated to render them sensitive to killing by dasatinib could have important implications for devising innovative and potentially more efficacious treatment strategies for this disease.
Asunto(s)
Antineoplásicos/farmacología , Resistencia a Antineoplásicos , Neoplasias Pulmonares/patología , Pirimidinas/farmacología , Transducción de Señal/efectos de los fármacos , Tiazoles/farmacología , Factor de Crecimiento Transformador beta/metabolismo , Compuestos de Anilina/metabolismo , Compuestos de Anilina/farmacología , Antineoplásicos/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Dasatinib , Humanos , Espacio Intracelular/efectos de los fármacos , Espacio Intracelular/metabolismo , Simulación del Acoplamiento Molecular , Nitrilos/metabolismo , Nitrilos/farmacología , Conformación Proteica , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Pirimidinas/metabolismo , Quinolinas/metabolismo , Quinolinas/farmacología , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/química , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Proteína smad3/metabolismo , Tiazoles/metabolismoRESUMEN
In previous work, we demonstrated that transcription factor Trim28 (Tripartite motif containing 28) plays a tumor-suppressor role in early-staged adenocarcinoma of the lung due to its ability to restrain transcription of cell cycle-regulating genes. Herein we examine Trim28's role in the epithelial-to-mesenchymal transition (EMT) which is strongly implicated in cancer metastasis. We found that Trim28 plays a role in TGF-ß-induced EMT in non-small cell lung cancer cells. Silencing Trim28 with inhibitory RNAs alters the expression of numerous EMT markers, such as E-cadherin and N-cadherin, whereas overexpression of Trim28 has an opposite effect. Trim28 expression is induced following TGF-ß treatment at both protein and mRNA levels. Trim28 deficiency impairs TGF-ß-induced EMT and decreases cell migration and invasion. Finally, we demonstrate that the expression of Trim28 affects the acetylation and methylation of histones on E-cadherin and N-cadherin promoters. These results suggest that Trim28 contributes to EMT and might be important for tumor metastasis in lung cancer. Taken together with our previous work these results suggest a model in which Trim28 is a tumor suppressor early in the transformation process in lung cancer, but in later stages it functions as an oncogene.
Asunto(s)
Cadherinas/fisiología , Transición Epitelial-Mesenquimal/fisiología , Neoplasias Pulmonares/patología , Proteínas Represoras/fisiología , Biomarcadores de Tumor , Línea Celular Tumoral , Humanos , Neoplasias Pulmonares/fisiopatología , Proteínas Represoras/genética , Factor de Crecimiento Transformador beta/fisiología , Proteína 28 que Contiene Motivos TripartitoRESUMEN
The growing Hispanic population in the United States mandates the need for oncology providers to become more familiar with disease patterns and cultural belief systems that can impact cancer care. "Culturally competent care" should be the mandate of all providers. This comprises awareness of cultural differences, communication in a manner that the patient understands, and respect.
Asunto(s)
Diversidad Cultural , Atención a la Salud , Oncología Médica , Cultura , Etnicidad/genética , Marcadores Genéticos , HumanosRESUMEN
Significant cancer health disparities exist in the United States and Puerto Rico. While numerous initiatives have been implemented to reduce cancer disparities, regional coordination of these efforts between institutions is often limited. To address cancer health disparities nation-wide, a series of regional transdisciplinary networks through the Geographic Management Program (GMaP) and the Minority Biospecimen/Biobanking Geographic Management Program (BMaP) were established in six regions across the country. This paper describes the development of the Region 3 GMaP/BMaP network composed of over 100 investigators from nine institutions in five Southeastern states and Puerto Rico to develop a state-of-the-art network for cancer health disparities research and training. We describe a series of partnership activities that led to the formation of the infrastructure for this network, recount the participatory processes utilized to develop and implement a needs and assets assessment and implementation plan, and describe our approach to data collection. Completion, by all nine institutions, of the needs and assets assessment resulted in several beneficial outcomes for Region 3 GMaP/BMaP. This network entails ongoing commitment from the institutions and institutional leaders, continuous participatory and engagement activities, and effective coordination and communication centered on team science goals.
Asunto(s)
Accesibilidad a los Servicios de Salud/normas , Disparidades en el Estado de Salud , Disparidades en Atención de Salud/normas , Salud de las Minorías/normas , Neoplasias/prevención & control , Regionalización/normas , Negro o Afroamericano/estadística & datos numéricos , Redes Comunitarias/organización & administración , Accesibilidad a los Servicios de Salud/organización & administración , Disparidades en Atención de Salud/organización & administración , Hispánicos o Latinos/estadística & datos numéricos , Humanos , Relaciones Interinstitucionales , Salud de las Minorías/estadística & datos numéricos , Evaluación de Necesidades/organización & administración , Evaluación de Necesidades/normas , Neoplasias/diagnóstico , Neoplasias/etnología , Puerto Rico/epidemiología , Regionalización/métodos , Regionalización/organización & administración , Sudeste de Estados Unidos/epidemiologíaRESUMEN
In preparation for the development of a rapid tissue donation (RTD) programme, we surveyed healthcare providers (HCPs) in our institution about knowledge and attitudes related to RTD with lung cancer patients. A 31-item web based survey was developed collecting data on demographics, knowledge and attitudes about RTD. The survey contained three items measuring participants' knowledge about RTD, five items assessing attitudes towards RTD recruitment and six items assessing HCPs' level of agreement with factors influencing decisions to discuss RTD. Response options were presented on a 5-point Likert scale. Ninety-one HCPs participated in the study. 66% indicated they had never heard of RTD prior to the survey, 78% rated knowledge of RTD as none or limited and 95.6% reported not having ethical or religious concerns about discussing RTD with patients. The majority were either not comfortable (17.8%) or not sure if they felt comfortable discussing RTD with cancer patients (42.2%). 56.1% indicated their knowledge of RTD would play an integral role in their decision to discuss RTD with patients. 71.4% reported concerns with RTD discussion and the emotional state of the patient. Physicians and nurses play an important role in initiating conversations about recruitment and donation to research that can ultimately influence uptake. Increasing HCP knowledge about RTD is a necessary step towards building an RTD programme. Our study provides important information about characteristics associated with low levels of knowledge and practice related to RTD where additional education and training may be warranted.