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PURPOSE: The benefit of using individual risk prediction tools to identify high-risk individuals for breast cancer (BC) screening is uncertain, despite the personalized approach of risk-based screening. METHODS: We studied the overlap of predicted high-risk individuals among 246,142 women enrolled in the UK Biobank. Risk predictors assessed include the Gail model (Gail), BC family history (FH, binary), BC polygenic risk score (PRS), and presence of loss-of-function (LoF) variants in BC predisposition genes. Youden J-index was used to select optimal thresholds for defining high-risk. RESULTS: In total, 147,399 were considered at high risk for developing BC within the next 2 years by at least 1 of the 4 risk prediction tools examined (Gail2-year > 0.5%: 47%, PRS2-yea r > 0.7%: 30%, FH: 6%, and LoF: 1%); 92,851 (38%) were flagged by only 1 risk predictor. The overlap between individuals flagged as high-risk because of genetic (PRS) and Gail model risk factors was 30%. The best-performing combinatorial model comprises a union of high-risk women identified by PRS, FH, and, LoF (AUC2-year [95% CI]: 62.2 [60.8 to 63.6]). Assigning individual weights to each risk prediction tool increased discriminatory ability. CONCLUSION: Risk-based BC screening may require a multipronged approach that includes PRS, predisposition genes, FH, and other recognized risk factors.
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Neoplasias de la Mama , Femenino , Humanos , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Bancos de Muestras Biológicas , Predisposición Genética a la Enfermedad , Factores de Riesgo , Medición de Riesgo , Reino Unido/epidemiologíaRESUMEN
PURPOSE: Precision oncology has transformed the management of advanced cancers through implementation of advanced molecular profiling technologies to identify increasingly defined subsets of patients and match them to appropriate therapy. We report outcomes of a prospective molecular profiling study in a high-volume Asian tertiary cancer center. PATIENTS AND METHODS: Patients with advanced cancer were enrolled onto a prospective protocol for genomic profiling, the Individualized Molecular Profiling for Allocation to Clinical Trials Singapore study, at the National Cancer Center Singapore. Primary objective was to identify molecular biomarkers in patient's tumors for allocation to clinical trials. The study commenced in February 2012 and is ongoing, with the results of all patients who underwent multiplex next-generation sequencing (NGS) testing until December 2018 presented here. The results were discussed at a molecular tumor board where recommendations for allocation to biomarker-directed trials or targeted therapies were made. RESULTS: One thousand fifteen patients were enrolled with a median age of 58 years (range 20-83 years). Most common tumor types were lung adenocarcinoma (26%), colorectal cancer (15%), and breast cancer (12%). A total of 1,064 NGS assays were performed, on fresh tumor tissue for 369 (35%) and archival tumor tissue for 687 (65%) assays. TP53 (39%) alterations were most common, followed by EGFR (21%), KRAS (14%), and PIK3CA (10%). Of 405 NGS assays with potentially actionable alterations, 111 (27%) were allocated to a clinical trial after molecular tumor board and 20 (4.9%) were enrolled on a molecularly matched clinical trial. Gene fusions were detected in 23 of 311 (7%) patients tested, including rare fusions in new tumor types and known fusions in rare tumors. CONCLUSION: Individualized Molecular Profiling for Allocation to Clinical Trials Singapore demonstrates the feasibility of a prospective broad molecular profiling program in an Asian tertiary cancer center, with the ability to develop and adapt to a dynamic landscape of precision oncology.
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Ensayos Clínicos como Asunto , Perfilación de la Expresión Génica , Neoplasias/genética , Neoplasias/terapia , Medicina de Precisión , Adulto , Anciano , Anciano de 80 o más Años , Instituciones Oncológicas , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Singapur , Centros de Atención Terciaria , Adulto JovenRESUMEN
Cancer-related cognitive impairment (CRCI) adversely affects cancer patients. We had previously demonstrated that the BDNF Val66Met genetic polymorphism is associated with lower odds of subjective CRCI in the multitasking and verbal ability domains among breast cancer patients receiving chemotherapy. To further assess our previous findings, we evaluated the association of BDNF Val66Met polymorphism with subjective and objective CRCI in a temporally separate cohort of patients and pooled findings from both the original (n = 145) and current (n = 193) cohorts in a meta-analysis. Subjective CRCI was assessed using FACT-Cog. Objective CRCI was evaluated using computerized neuropsychological tests. Genotyping was carried out using Sanger sequencing. The association of BDNF Val66Met genotypes and CRCI was examined with logistic regression. A fixed-effect meta-analysis was conducted using the inverse variance method. In the meta-analysis (n = 338), significantly lower odds of CRCI were associated with Met allele carriers based on the global FACT-Cog score (OR = 0.52, 95% CI 0.29-0.94). Furthermore, Met allele carriers were at lower odds of developing impairment in the domains of memory (OR = 0.34, 95% CI: 0.17-0.70), multitasking (OR = 0.33, 95% CI: 0.18-0.59), and verbal ability (OR = 0.46, 95% CI: 0.24-0.88). Consistent with the previous study, lower odds of subjective CRCI among patients with the BDNF Met allele was observed after adjusting for potential confounders in the multitasking (OR = 0.30, 95% CI: 0.14-0.67) domain. In conclusion, carriers of the BDNF Met allele were protected against global subjective CRCI, particularly in the domains of memory, multitasking, and verbal ability. Our findings further contribute to the understanding of CRCI pathophysiology.
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Antineoplásicos/efectos adversos , Factor Neurotrófico Derivado del Encéfalo/genética , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Alelos , Ansiedad/complicaciones , Disfunción Cognitiva/psicología , Fatiga/complicaciones , Femenino , Frecuencia de los Genes/genética , Humanos , Persona de Mediana Edad , Oportunidad Relativa , Prevalencia , Reproducibilidad de los ResultadosRESUMEN
Chromosomal instability (CIN), a high rate of chromosome loss or gain, is often associated with poor prognosis and drug resistance in cancers. Aneuploid, including near-polyploid, cells contain an abnormal number of chromosomes and exhibit CIN. The post-mitotic cell fates following generation of different degrees of chromosome mis-segregation and aneuploidy are unclear. Here we used aneuploidy inducers, nocodazole and reversine, to create different levels of aneuploidy. A higher extent of aneuploid and near-polyploid cells in a given population led to senescence. This was in contrast to cells with relatively lower levels of abnormal ploidy that continued to proliferate. Our findings revealed that senescence was accompanied by DNA damage and robust p53 activation. These senescent cells acquired the senescence-associated secretory phenotype (SASP). Depletion of p53 reduced the number of senescent cells with concomitant increase in cells undergoing DNA replication. Characterisation of these SASP factors demonstrated that they conferred paracrine pro-tumourigenic effects such as invasion, migration and angiogenesis both in vitro and in vivo. Finally, a correlation between increased aneuploidy and senescence was observed at the invasive front in breast carcinomas. Our findings demonstrate functional non-equivalence of discernable aneuploidies on tumourigenesis and suggest a cell non-autonomous mechanism by which aneuploidy-induced senescent cells and SASP can affect the tumour microenvironment to promote tumour progression.
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The most commonly utilized class of chemotherapeutic agents administered as a first-line therapy are antimitotic drugs; however, their clinical success is often impeded by chemoresistance and disease relapse. Hence, a better understanding of the cellular pathways underlying escape from cell death is critical. Mitotic slippage describes the cellular process where cells exit antimitotic drug-enforced mitotic arrest and "slip" into interphase without proper chromosome segregation and cytokinesis. The current report explores the cell fate consequence following mitotic slippage and assesses a major outcome following treatment with many chemotherapies, therapy-induced senescence. It was found that cells postslippage entered senescence and could impart the senescence-associated secretory phenotype (SASP). SASP factor production elicited paracrine protumorigenic effects, such as migration, invasion, and vascularization. Both senescence and SASP factor development were found to be dependent on autophagy. Autophagy induction during mitotic slippage involved the autophagy activator AMPK and endoplasmic reticulum stress response protein PERK. Pharmacologic inhibition of autophagy or silencing of autophagy-related ATG5 led to a bypass of G1 arrest senescence, reduced SASP-associated paracrine tumorigenic effects, and increased DNA damage after S-phase entry with a concomitant increase in apoptosis. Consistent with this, the autophagy inhibitor chloroquine and microtubule-stabilizing drug paclitaxel synergistically inhibited tumor growth in mice. Sensitivity to this combinatorial treatment was dependent on p53 status, an important factor to consider before treatment.Implications: Clinical regimens targeting senescence and SASP could provide a potential effective combinatorial strategy with antimitotic drugs. Mol Cancer Res; 16(11); 1625-40. ©2018 AACR.
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Autofagia/fisiología , Senescencia Celular/fisiología , Mitosis/fisiología , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Quinasas de la Proteína-Quinasa Activada por el AMP , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Autofagia/efectos de los fármacos , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Citocinas/metabolismo , Femenino , Células HCT116 , Células HEK293 , Xenoinjertos , Humanos , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Mitosis/efectos de los fármacos , Neoplasias/metabolismo , Osteosarcoma/metabolismo , Osteosarcoma/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Proteínas Quinasas/metabolismo , Transfección , Pez CebraRESUMEN
PURPOSE: Diagnosis of cervical neoplasia hinges upon microscopic inspection of cervical samples. This has inherent operator-dependent variability. Testing for high-risk human papilloma virus (HPV) may help to triage patients with pre-invasive disease in determining clinical intervention and follow-up. However, HPV presence/absence does not reflect the cervical epithelial cell's molecular status. Epigenetic modifications, e.g. DNA methylation, have been observed in the early stages of neoplastic change, preceding gene mutations. Here, we assess the correlation between cytologic/histologic results and combined DNA methylation data of 5 genes in different grades of cervical dysplasia. EXPERIMENTAL DESIGN: Cervical specimens collected via the liquid-based cytology system were each microscopically examined. Residual cells were subjected to DNA methylation analysis (Methylight) of gene loci CCNA1, PAX1, HS3ST2, DAPK1 and TFPI2. Methylation data were compared with cytologic/histologic reports. Statistical methods were applied to assess the ability of DNA methylation status to subtype the cervical neoplastic lesions according to their corresponding cytologic/histologic reports. RESULTS: A total of 165 subjects provided cytologically proven 63 HSIL, 49 LSIL and 53 normal samples. All patients with HSIL and LSIL underwent colposcopic examination. Patients with LSIL were all found to be CIN1; patients with HSIL were subsequently subdivided into 10 squamous cell carcinoma (SCC), 31 CIN3, 10 CIN2 and 12 CIN1. For each gene, there was increasing frequency of methylation from normal and LSIL (CIN1), through HSIL (CIN2 and CIN3), to SCC. Methylation of ≥1 of genes investigated was observed in 88% of combined HSIL (CIN2 and CIN3) and SCC cases. All genes showed significant increase in methylation level (PMR value) with increasing disease grade (p<0.005). CCNA1 was the only gene that was able to distinguish CIN2 from CIN3 specimens (p=0.016). Based on receiver operating characteristic (ROC) analysis, HS3ST2 was the most significant candidate in segregating HSIL/SCC from normal/LSIL cases (p<0.0001); at an optimal cutoff value, sensitivity and specificity between 70% and 80% were obtained. CONCLUSIONS: Development of DNA methylation status of a gene panel to improve diagnostic accuracy in cervical neoplasia is warranted.
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Metilación de ADN , Displasia del Cuello del Útero/genética , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Quinasas Dependientes de Calcio-Calmodulina/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Ciclina A1/genética , Proteínas Quinasas Asociadas a Muerte Celular , Femenino , Glicoproteínas/genética , Humanos , Modelos Logísticos , Factores de Transcripción Paired Box/genética , Factores de Riesgo , Sulfotransferasas/genética , Displasia del Cuello del Útero/patología , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patologíaRESUMEN
BACKGROUND: Progression of non-small cell lung cancer (NSCLC) from early- to late-stage may signify the accumulation of gene mutations. An advanced-stage tumor's mutation profile may also have prognostic value, guiding treatment decisions. Mutation detection of multiple genes is limited by the low amount of deoxyribonucleic acid extracted from low-volume diagnostic lung biopsies. We explored whole genome amplification (WGA) to enable multiple molecular analyses. METHODS: Eighty-eight advanced-stage NSCLC patients were enrolled. Their low-volume lung biopsies underwent WGA before direct sequencing for epidermal growth factor receptor (EGFR), KRAS (rat sarcoma virus), p53, and CMET (mesenchymal-epithelial transition factor) mutations. Overall survival impact was examined. Surgically-resected tumors from 133 early-stage NSCLC patients were sequenced for EGFR, KRAS and p53 mutations. We compared the mutation frequencies of both groups. RESULTS: It is feasible for low-volume lung biopsies to undergo WGA for mutational analysis. KRAS and CMET mutations have a deleterious effect on overall survival, hazard ratios 5.05 (p = 0.009) and 23.65 (p = 0.005), respectively. EGFR and p53 mutations, however, do not have a survival impact. There also does not seem to be significant differences in the frequency of mutations in EGFR, KRAS, and p53 between early- and advanced-stage disease: 20% versus 24% (p = 0.48), 29% versus 27% (p = 0.75), 10% versus 6% (p = 0.27), respectively. CONCLUSIONS: In advanced-stage NSCLC, KRAS, and CMET mutations suggest poor prognosis, whereas EGFR and p53 mutations do not seem to have survival impact. Mutations in EGFR, KRAS and p53 are unlikely to be responsible for the progression of NSCLC from early- to late-stage disease. WGA may be used to expand starting deoxyribonucleic acid from low-volume lung biopsies for further analysis of advanced-stage NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Mutación/genética , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas/genética , Proteína p53 Supresora de Tumor/genética , Proteínas ras/genética , Adenocarcinoma/genética , Adenocarcinoma/secundario , Adenocarcinoma/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Bases , Biopsia , Carcinoma Adenoescamoso/genética , Carcinoma Adenoescamoso/secundario , Carcinoma Adenoescamoso/cirugía , Carcinoma de Células Grandes/genética , Carcinoma de Células Grandes/secundario , Carcinoma de Células Grandes/cirugía , Carcinoma de Pulmón de Células no Pequeñas/secundario , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/secundario , Carcinoma de Células Escamosas/cirugía , ADN de Neoplasias/genética , Estudios de Factibilidad , Femenino , Amplificación de Genes , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Estadificación de Neoplasias , Reacción en Cadena de la Polimerasa , Pronóstico , Proteínas Proto-Oncogénicas p21(ras) , Sensibilidad y Especificidad , Tasa de Supervivencia , Proteína p53 Supresora de Tumor/metabolismoAsunto(s)
Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Análisis Mutacional de ADN , Neoplasias Pulmonares/diagnóstico , Biopsia , Carcinoma de Pulmón de Células no Pequeñas/genética , Diagnóstico Diferencial , Humanos , Neoplasias Pulmonares/genética , PronósticoAsunto(s)
Neoplasias de la Mama/patología , Complicaciones Neoplásicas del Embarazo/patología , Adulto , Anticarcinógenos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Progresión de la Enfermedad , Femenino , Humanos , Comunicación Interdisciplinaria , Estadificación de Neoplasias , Embarazo , Complicaciones Neoplásicas del Embarazo/tratamiento farmacológico , Resultado del TratamientoRESUMEN
BACKGROUND: Accurate mutational analysis, especially epidermal growth factor receptor (EGFR) mutations, of diagnostic biopsies from all Asian NSCLC patients is crucial to their clinical management, but faces problems. Here, we explore, within usual hospital constraints, the practicalities of incorporating mutational analysis in every newly diagnosed case of NSCLC, namely, maximizing tissue acquisition during the diagnostic procedure and determining the maximum quantity and quality of DNA sequence data available from these biopsies. METHODS: Sixty-eight Chinese patients were enrolled. Thirty-five underwent surgical resections for early-stage tumors. Thirty-three underwent diagnostic procedures, i.e., needle aspirates under bronchoscopic or computed tomographic/fluoroscopic guidance, or forceps biopsies via bronchoscopy. Separate samples for research purposes were obtained from these 33 patients during the diagnostic procedure. All samples were analyzed for mutations in EGFR exons 18 to 21, p53 exons 4 to 9, and Kras exon 2. RESULTS: No deaths occurred in this study. Success rates in obtaining sequence data from surgical samples versus low-volume samples for EGFR, p53, and Kras were 100% versus 85%, 100% versus 82%, and 100% versus 85%, respectively. Sequencing nine polymerase chain reaction products from each low-volume sample resulted in the exhaustion of all extracted DNA from three samples. CONCLUSIONS: Acquiring a separate low-volume lung biopsy sample for mutational analysis in lung cancer patients during the diagnostic procedure is feasible and may be a valuable complement to the usual diagnostic workflow in future.
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Biopsia/métodos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Análisis Mutacional de ADN , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Biomarcadores de Tumor/análisis , Distribución de Chi-Cuadrado , Técnicas de Laboratorio Clínico , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Reacción en Cadena de la Polimerasa , Pronóstico , SingapurRESUMEN
PURPOSE: The majority of patients with non-small cell lung cancer (NSCLC) present at an advanced clinical stage, when surgery is not a recommended therapeutic option. In such cases, tissues for molecular research are usually limited to the low-volume samples obtained at the time of diagnosis, usually via fine-needle aspiration (FNA). We tested the feasibility of performing gene expression profiling of advanced NSCLCs using amplified RNA from lung FNAs. EXPERIMENTAL DESIGN AND RESULTS: A total of 46 FNAs was tested, of which 18 yielded RNA of sufficient quality for microarray analysis. Expression profiles of these 18 samples were compared with profiles of 17 pairs of tumor and normal lung tissues that had been surgically obtained. Using a variety of unsupervised and supervised analytical approaches, we found that the FNA profiles were highly distinct from the normal samples and similar to the tumor profiles. CONCLUSIONS: We conclude that when RNA amplification is successful, gene expression profiles from NSCLC FNAs can determine malignancy and suggest that with additional refinement and standardization of sample collection and RNA amplification protocols, it will be possible to conduct additional and more detailed molecular analysis of advanced NSCLC using lung FNAs.