RESUMEN
Background: Based on its mechanism of action, PARP inhibitor therapy is expected to benefit mainly tumor cases with homologous recombination deficiency (HRD). Therefore, identification of tumor types with increased HRD is important for the optimal use of this class of therapeutic agents. HRD levels can be estimated using various mutational signatures from next generation sequencing data and we used this approach to determine whether breast cancer brain metastases show altered levels of HRD scores relative to their corresponding primary tumor. Patients and methods: We used a previously published next generation sequencing dataset of 21 matched primary breast cancer/brain metastasis pairs to derive the various mutational signatures/HRD scores strongly associated with HRD. We also carried out the myChoice HRD analysis on an independent cohort of 17 breast cancer patients with matched primary/brain metastasis pairs. Results: All of the mutational signatures indicative of HRD showed a significant increase in the brain metastases relative to their matched primary tumor in the previously published whole exome sequencing dataset. In the independent validation cohort, the myChoice HRD assay showed an increased level in 87.5% of the brain metastases relative to the primary tumor, with 56% of brain metastases being HRD positive according to the myChoice criteria. Conclusions: The consistent observation that brain metastases of breast cancer tend to have higher HRD measures may raise the possibility that brain metastases may be more sensitive to PARP inhibitor treatment. This observation warrants further investigation to assess whether this increase is common to other metastatic sites as well, and whether clinical trials should adjust their strategy in the application of HRD measures for the prioritization of patients for PARP inhibitor therapy.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Encefálicas/genética , Neoplasias de la Mama/genética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Reparación del ADN por Recombinación , Adulto , Anciano , Encéfalo/patología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/secundario , Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Análisis Mutacional de ADN , Conjuntos de Datos como Asunto , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Persona de Mediana Edad , Mutación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéuticoRESUMEN
BACKGROUND: Glioblastoma (GBM) is the most common malignant brain cancer occurring in adults, and is associated with dismal outcome and few therapeutic options. GBM has been shown to predominantly disrupt three core pathways through somatic aberrations, rendering it ideal for precision medicine approaches. METHODS: We describe a 35-year-old female patient with recurrent GBM following surgical removal of the primary tumour, adjuvant treatment with temozolomide and a 3-year disease-free period. Rapid whole-genome sequencing (WGS) of three separate tumour regions at recurrence was carried out and interpreted relative to WGS of two regions of the primary tumour. RESULTS: We found extensive mutational and copy-number heterogeneity within the primary tumour. We identified a TP53 mutation and two focal amplifications involving PDGFRA, KIT and CDK4, on chromosomes 4 and 12. A clonal IDH1 R132H mutation in the primary, a known GBM driver event, was detectable at only very low frequency in the recurrent tumour. After sub-clonal diversification, evidence was found for a whole-genome doubling event and a translocation between the amplified regions of PDGFRA, KIT and CDK4, encoded within a double-minute chromosome also incorporating miR26a-2. The WGS analysis uncovered progressive evolution of the double-minute chromosome converging on the KIT/PDGFRA/PI3K/mTOR axis, superseding the IDH1 mutation in dominance in a mutually exclusive manner at recurrence, consequently the patient was treated with imatinib. Despite rapid sequencing and cancer genome-guided therapy against amplified oncogenes, the disease progressed, and the patient died shortly after. CONCLUSION: This case sheds light on the dynamic evolution of a GBM tumour, defining the origins of the lethal sub-clone, the macro-evolutionary genomic events dominating the disease at recurrence and the loss of a clonal driver. Even in the era of rapid WGS analysis, cases such as this illustrate the significant hurdles for precision medicine success.
Asunto(s)
Neoplasias Encefálicas/genética , Cromosomas Humanos , Glioblastoma/genética , Isocitrato Deshidrogenasa/genética , Mutación , Adulto , Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/enzimología , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Quimioterapia Adyuvante , Quinasa 4 Dependiente de la Ciclina/genética , Dacarbazina/análogos & derivados , Dacarbazina/uso terapéutico , Progresión de la Enfermedad , Resultado Fatal , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Glioblastoma/enzimología , Glioblastoma/patología , Glioblastoma/terapia , Humanos , Mesilato de Imatinib/uso terapéutico , Clasificación del Tumor , Recurrencia Local de Neoplasia , Procedimientos Neuroquirúrgicos , Fenotipo , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-kit/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Temozolomida , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Exome or whole-genome deep sequencing of tumor DNA along with paired normal DNA can potentially provide a detailed picture of the somatic mutations that characterize the tumor. However, analysis of such sequence data can be complicated by the presence of normal cells in the tumor specimen, by intratumor heterogeneity, and by the sheer size of the raw data. In particular, determination of copy number variations from exome sequencing data alone has proven difficult; thus, single nucleotide polymorphism (SNP) arrays have often been used for this task. Recently, algorithms to estimate absolute, but not allele-specific, copy number profiles from tumor sequencing data have been described. MATERIALS AND METHODS: We developed Sequenza, a software package that uses paired tumor-normal DNA sequencing data to estimate tumor cellularity and ploidy, and to calculate allele-specific copy number profiles and mutation profiles. We applied Sequenza, as well as two previously published algorithms, to exome sequence data from 30 tumors from The Cancer Genome Atlas. We assessed the performance of these algorithms by comparing their results with those generated using matched SNP arrays and processed by the allele-specific copy number analysis of tumors (ASCAT) algorithm. RESULTS: Comparison between Sequenza/exome and SNP/ASCAT revealed strong correlation in cellularity (Pearson's r = 0.90) and ploidy estimates (r = 0.42, or r = 0.94 after manual inspecting alternative solutions). This performance was noticeably superior to previously published algorithms. In addition, in artificial data simulating normal-tumor admixtures, Sequenza detected the correct ploidy in samples with tumor content as low as 30%. CONCLUSIONS: The agreement between Sequenza and SNP array-based copy number profiles suggests that exome sequencing alone is sufficient not only for identifying small scale mutations but also for estimating cellularity and inferring DNA copy number aberrations.
Asunto(s)
Variaciones en el Número de Copia de ADN/genética , Dosificación de Gen/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Neoplasias/genética , Algoritmos , Alelos , Secuencia de Bases , Exoma/genética , Humanos , Mutación , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN , Programas InformáticosRESUMEN
The aim of the present study was to analyse the preoperative platelet count and the platelet-lymphocyte ratio (PLR) in patients with colorectal cancer (CRC) of different stages and with hepatic metastasis of CRC (mCRC) and to compare these factors as potential prognostic markers. Clinicopathological data of 10 years were collected retrospectively from 336 patients with CRC and 118 patients with mCRC. Both in the CRC and the mCRC group overall survival (OS) was significantly worse in patients who had elevated platelet count (hazard ratio [HR] = 2.2, p < 0.001 and HR = 2.9, p = 0.018, respectively). Multivariate analysis indicated that elevated platelet count was an independent prognostic factor of CRC (HR = 1.7, p = 0.035) and mCRC (HR = 3.1, p = 0.017). Disease-free survival (DFS) was significantly worse in patients with elevated platelet count in the CRC group (HR = 2.0, p = 0.011). In the multivariate analysis the PLR was not a prognostic factor in either of the two cohorts (HR = 0.92, p < 0.001 and HR = 0.89, p = 0.789, respectively). The platelet count is a valuable prognostic marker for the survival in patients both with CRC and mCRC while the PLR is not prognostic in either group.
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Plaquetas/fisiología , Carcinoma/diagnóstico , Neoplasias Colorrectales/diagnóstico , Neoplasias Hepáticas/diagnóstico , Trombocitosis/diagnóstico , Anciano , Biomarcadores de Tumor/metabolismo , Carcinoma/mortalidad , Carcinoma/secundario , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Femenino , Humanos , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/secundario , Linfocitos/fisiología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Activación Plaquetaria , Recuento de Plaquetas , Pronóstico , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
We examined the microRNA (miRNA) expression profile of 40 prostatectomy specimens from stage T2a/b, early relapse and non-relapse cancer patients, to better understand the relationship between miRNA dysregulation and prostate oncogenesis. Paired analysis was carried out with microdissected, malignant and non-involved areas of each specimen, using high-throughput liquid-phase hybridization (mirMASA) reactions and 114 miRNA probes. Five miRNAs (miR-23b, -100, -145, -221 and -222) were significantly downregulated in malignant tissues, according to significance analysis of microarrays and paired t-test with Bonferroni correction. Lowered expression of miR-23b, -145, -221 and -222 in malignant tissues was validated by quantitative reverse transcription (qRT)-PCR analyses. Ectopic expression of these miRNAs significantly reduced LNCaP cancer cell growth, suggesting growth modulatory roles for these miRNAs. Patient subset analysis showed that those with post-surgery elevation of prostate-specific antigen (chemical relapse) displayed a distinct expression profile of 16 miRNAs, as compared with patients with non-relapse disease. A trend of increased expression (>40%) of miR-135b and miR-194 was observed by qRT-PCR confirmatory analysis of 11 patients from each clinical subset. These findings indicate that an altered miRNA expression signature accompanied the prostate oncogenic process. Additional, aberrant miRNA expression features may reflect a tendency for early disease relapse. Growth inhibition through the reconstitution of miRNAs is potentially applicable for experimental therapy of prostate cancer, pending molecular validation of targeted genes.
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Adenocarcinoma/genética , Perfilación de la Expresión Génica , MicroARNs/análisis , Neoplasias de la Próstata/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/cirugía , Línea Celular Tumoral/química , Progresión de la Enfermedad , Humanos , Masculino , MicroARNs/biosíntesis , Metástasis de la Neoplasia , Estadificación de Neoplasias/métodos , Periodo Posoperatorio , Prostatectomía , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/cirugía , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Genes in the MHC have been associated with mate choice and odor preferences in a variety of animals. Although the role of HLA genes in human mate choice has been controversial, studies in the Hutterites have demonstrated fewer than expected numbers of couples who match for an HLA haplotype, suggesting that in this population there is avoidance of mates with HLA haplotypes similar to one's own haplotype. Recently, 18 olfactory receptor (OR) genes have been mapped to the HLA region, telomeric to the HLA-F locus, providing a potential mechanism for HLA-based odor recognition and perhaps mate preferences in humans. We screened a sample of Hutterites with diverse HLA haplotypes for polymorphisms in the HLA-linked olfactory receptor gene, FAT11, by sequencing, denaturing high performance liquid chromatography, and allele-specific oligo dot-blotting. Three single nucleotide polymorphisms were detected in the single translated exon of this gene, all of which resulted in amino acid substitutions (Phe587Leu, Ala642Val, and Thr1157Ala). The FAT11 Phe587- Val642-Ala1157 allele occurred on 17 different HLA haplotypes, the Leu587-Ala642-Ala1157 allele on 15 haplotypes, the Phe587-Ala642-Ala1157 allele on 16 haplotypes, and the Phe587-Ala642-Thr1157 allele on a single haplotype. Thus, four alleles of the FAT11 gene are present in the Hutterites. This level of variation in the FAT11 gene alone may not be sufficient to contribute to the observed patterns of mate choice in the Hutterites and to individual variation in odor preferences.
Asunto(s)
Antígenos HLA-A/inmunología , Complejo Mayor de Histocompatibilidad , Proteínas de la Membrana , Polimorfismo Genético , Receptores de Superficie Celular/genética , Receptores Odorantes/genética , Alelos , Cristianismo , Cromatografía Líquida de Alta Presión/métodos , Etnicidad/genética , Humanos , Análisis de Secuencia de ADNRESUMEN
The mechanisms maintaining natural diversity at the major histocompatibility complex (MHC) are not well understood. To increase knowledge of one potential mechanism, I examined the use of MHC genes for mate choice by wild house mice in a controlled laboratory setting. Three rearing groups of wild test mice were produced: non-fostered control mice, mice fostered into families of an inbred laboratory mouse strain, and mice fostered into families of a second, MHC-congenic mouse strain. Mature test mice were given a choice of two opposite-sex stimulus mice from the two MHC-congenic strains used for fostering, and were scored for several measures of preference. The results were non-significant in general, but females of two rearing groups spent significantly more time with mice of one MHC-type, and in most rearing groups, mice tended to spend more time with this same MHC-type. Other results showed that male test mice ejaculated indiscriminantly and that female wild mice mated to ejaculation more often in longer length trials, but showed no significant preferences. In this study, fostering seemed to have little or no effect on MHC-based mate preferences of wild house mice, and wild mice did not appear to be using the MHC to avoid inbreeding. However, some wild female mice used the MHC to choose potential mates.