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1.
Sci Rep ; 11(1): 2259, 2021 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-33500440

RESUMO

Axillary lymph node status is an important prognostic factor for breast cancer patients and sentinel lymph node biopsy (SLNB) is a less invasive surgical proxy. We examined if consecutively derived molecular subtypes from primary breast cancers provide additional predictive value for SLNB status. 1556 patients with a breast cancer > 10 mm underwent primary surgical procedure including SLNB and tumor specimens were assigned with a transcriptomics-based molecular subtype. 1020 patients had a negative sentinel node (SN) and 536 a positive. A significant association between tumor size and SN status (p < 0.0001) was found across all samples, but no association between size and SN status (p = 0.14) was found for BasL tumors. A BasL subtype was a predictor of an SN-negative status (p = 0.001, OR 0.58, 95% CI 0.38;0.90) and among the BasL, postmenopausal status was a predictor for SN-negative status (p = 0.01). Overall survival was significantly lower (p = 0.02) in patients with BasL tumors and a positive SN. Interestingly, we identified a significant correlation between hormone receptor activity and SN status within the BasL subtype. Taken together, molecular subtypes and hormone receptor activity of breast cancers add predictive value for SLNB status.

3.
Bioessays ; 42(12): e2000097, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33145808

RESUMO

Cytoplasmic messenger ribonucleoprotein particles (mRNPs) represent the cellular transcriptome, and recent data have challenged our current understanding of their architecture, transport, and complexity before translation. Pre-translational mRNPs are composed of a single transcript, whereas P-bodies and stress granules are condensates. Both pre-translational mRNPs and actively translating mRNPs seem to adopt a linear rather than a closed-loop configuration. Moreover, assembly of pre-translational mRNPs in physical RNA regulons is an unlikely event, and co-regulated translation may occur locally following extracellular cues. We envisage a stochastic mRNP transport mechanism where translational repression of single mRNPs-in combination with microtubule-mediated cytoplasmic streaming and docking events-are prerequisites for local translation, rather than direct transport.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33051725

RESUMO

PURPOSE: The purpose of our study was to compare genomic changes in sinonasal intestinal-type adenocarcinoma (sITAC) and colorectal adenocarcinoma (CRC), as they are histomorphologically indistinguishable. This can cause diagnostic difficulties as sinonasal tumours initially diagnosed as sITAC may represent metastasis from CRC, a frequent cancer. Previous studies have not uncovered the underlying mechanism behind the histomorphological resemblance. METHODS/PATIENTS: Tissue samples from all consecutive patients with sITAC at our facility (20 patients) were compared to samples from 20 patients with CRC as well as samples from 2 patients with both CRC and sinonasal tumours. DNA sequencing was performed using Illumina TruSight Oncology 500 panel consisting of 523 cancer-associated genes. Frequent mutations were inspected manually using the Integrative Genomics Viewer. RESULTS: Several well-known cancer-associated genes were mutated in the CRC group, but also in the sinonasal ITAC group. These genes included APC mutated in 65% of the CRC group and 37% of the sinonasal ITAC group, and TP53 mutated in 65% of CRC samples and 58% of ITAC samples. These shared mutations may explain the histomorphological similarities. Successful DNA sequencing was performed on the colorectal sample from one of the two patients with both CRC and sinonasal tumour. Comparing mutations in these samples from one patient we have shown that the sinonasal tumour in all probability was a CRC metastasis. CONCLUSION: We have identified several genetic similarities between sITAC and CRC. This discovery brings us closer to understanding mechanisms behind the development of sITAC-and hopefully in the future targeted therapy.

5.
Analyst ; 145(17): 5836-5844, 2020 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-32648858

RESUMO

Two types of clinically important nucleic acid biomarkers, microRNA (miRNA) and circulating tumor DNA (ctDNA) were detected and quantified from human serum using an amplification-free fluorescence hybridization assay. Specifically, miRNAs hsa-miR-223-3p and hsa-miR-486-5p with relevance for rheumatoid arthritis and cancer related mutations BRAF and KRAS of ctDNA were directly measured. The required oligonucleotide probes for the assay were rationally designed and synthesized through a novel "clickable" approach which is time and cost-effective. With no need for isolating nucleic acid components from serum, the fluoresence-based assay took only 1 hour. Detection and absolute quantification of targets was successfully achieved despite their notoriously low abundance, with a precision down to individual nucleotides. Obtained miRNA and ctDNA amounts showed overall a good correlation with current techniques. With appropriate probes, our novel assay and signal boosting approach could become a useful tool for point-of-care measuring other low abundance nucleic acid biomarkers.

6.
J Clin Invest ; 130(8): 4069-4080, 2020 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-32379725

RESUMO

Haploinsufficiency of factors governing genome stability underlies hereditary breast and ovarian cancer. One significant pathway that is disabled as a result is homologous recombination repair (HRR). With the aim of identifying new candidate genes, we examined early-onset breast cancer patients negative for BRCA1 and BRCA2 pathogenic variants. Here, we focused on CtIP (RBBP8 gene), which mediates HRR through the end resection of DNA double-strand breaks (DSBs). Notably, these patients exhibited a number of rare germline RBBP8 variants. Functional analysis revealed that these variants did not affect DNA DSB end resection efficiency. However, expression of a subset of variants led to deleterious nucleolytic degradation of stalled DNA replication forks in a manner similar to that of cells lacking BRCA1 or BRCA2. In contrast to BRCA1 and BRCA2, CtIP deficiency promoted the helicase-driven destabilization of RAD51 nucleofilaments at damaged DNA replication forks. Taken together, our work identifies CtIP as a critical regulator of DNA replication fork integrity, which, when compromised, may predispose to the development of early-onset breast cancer.

7.
Transl Stroke Res ; 11(6): 1243-1252, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32248435

RESUMO

This study evaluated microRNA (miRNA) changes in cerebrospinal fluid (CSF) and their association with the occurrence of delayed cerebral ischemia (DCI) and poor functional outcome after SAH. Forty-three selected miRNAs were measured in daily CSF samples from a discovery cohort of SAH patients admitted to Rigshospitalet, Copenhagen, Denmark, and compared with neurologically healthy patients. Findings were validated in CSF from a replication cohort of SAH patients admitted to Massachusetts General Hospital, Boston, Massachusetts. The CSF levels of miRNA over time were compared with the occurrence of DCI, and functional outcome after 3 months. miRNAs were quantified in 427 CSF samples from 63 SAH patients in the discovery cohort, in 104 CSF samples from 63 SAH patients in the replication cohort, and in 11 CSF samples from 11 neurologically healthy patients. The miRNA profile changed remarkably immediately after SAH. Elevated miR-9-3p was associated with a poor functional outcome in the discovery cohort (p < 0.0001) after correction for multiple testing (q < 0.01) and in the replication cohort (p < 0.01). Furthermore, elevated miR-9-5p was associated with a poor functional outcome in the discovery cohort (p < 0.01) after correction for multiple testing (q < 0.05). No miRNA was associated with DCI in both cohorts. miR-9-3p and miR-9-5p are elevated in the CSF following SAH and this elevation is associated with a poor functional outcome. These elevations have potential roles in the progression of cerebral injury and could add to early prognostication.

8.
Acta Neurochir (Wien) ; 162(5): 1187-1195, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32016588

RESUMO

OBJECTIVE: Our objective was to investigate if the tumor microRNA (miRNA) expression profile was related to tumor growth rate. Growth-related miRNAs might be potential targets for future therapeutic intervention. MATERIAL AND METHODS: Tumor tissue was sampled during surgery of patients with a sporadic vestibular schwannoma. Tumor growth rate was determined by tumor measurement on the two latest pre-operative MRI scans. Tumor miRNA expression was analyzed using the Affymetrix Gene Chip® protocol, and CEL files were generated using GeneChip® Command Console® Software and normalized using Partek Genomics Suite 6.5. The CEL files were analyzed using the statistical software program R. Principal component analysis, affected gene ontology analysis, and analysis of miRNA expression fold changes were used for analysis of potential relations between miRNA expression profile and tumor growth rate. RESULTS AND CONCLUSION: Tumor miRNA expression is related to the growth rate of sporadic vestibular schwannomas. Rapid tumor growth is associated with deregulation of several miRNAs, including upregulation of miR-29abc, miR-19, miR-340-5p, miR-21, and miR-221 and downregulation of miR-744 and let-7b. Gene ontologies affected by the deregulated miRNAs included neuron development and differentiation, gene silencing, and negative regulation of various biological processes, including cellular and intracellular signaling and metabolism.


Assuntos
Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neuroma Acústico/metabolismo , Adulto , Biomarcadores Tumorais/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Neuroma Acústico/genética , Neuroma Acústico/patologia
9.
J Clin Med ; 9(3)2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-32106411

RESUMO

Chromothripsis is a mutational mechanism leading to complex and relatively clustered chromosomal rearrangements, resulting in diverse phenotypic outcomes depending on the involved genomic landscapes. It may occur both in the germ and the somatic cells, resulting in congenital and developmental disorders and cancer, respectively. Asymptomatic individuals may be carriers of chromotriptic rearrangements and experience recurrent reproductive failures when two or more chromosomes are involved. Several mechanisms are postulated to underlie chromothripsis. The most attractive hypothesis involves chromosome pulverization in micronuclei, followed by the incorrect reassembly of fragments through DNA repair to explain the clustered nature of the observed complex rearrangements. Moreover, exogenous or endogenous DNA damage induction and dicentric bridge formation may be involved. Chromosome instability is commonly observed in the cells of patients with DNA repair disorders, such as ataxia telangiectasia, Nijmegen breakage syndrome, and Bloom syndrome. In addition, germline variations of TP53 have been associated with chromothripsis in sonic hedgehog medulloblastoma and acute myeloid leukemia. In the present review, we focus on the underlying mechanisms of chromothripsis and the involvement of defective DNA repair genes, resulting in chromosome instability and chromothripsis-like rearrangements.

10.
Clin Cancer Res ; 26(6): 1507-1515, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31919133

RESUMO

PURPOSE: Investigation of signaling pathways altered by recurrent gene mutations and their clinical impact in a consecutive cohort of patients with newly diagnosed chronic lymphocytic leukemia (CLL). The heterogeneous clinical course and genetic complexity of CLL warrant improved molecular prognostication. However, the prognostic value of recurrent mutations at the time of diagnosis remains unclear. EXPERIMENTAL DESIGN: We sequenced samples from 314 consecutive, newly diagnosed patients with CLL to investigate the clinical impact of 56 recurrently mutated genes assessed by next-generation sequencing. RESULTS: Mutations were identified in 70% of patients with enrichment among IGHV unmutated cases. With 6.5 years of follow-up, 15 mutated genes investigated at the time of diagnosis demonstrated significant impact on time to first treatment (TTFT). Carrying driver mutations was associated with shorter TTFT and poor overall survival. For outcome from CLL diagnosis, the number of signaling pathways altered by driver mutations stratified patients better than the number of driver mutations. Moreover, we demonstrated gradual impact on TTFT with increasing number of altered pathways independent of CLL-IPI risk. Thus, a 25-gene, pathway-based biomarker assessing recurrent mutations refines prognostication in CLL, in particular for CLL-IPI low- and intermediate-risk patients. External validation emphasized that a broad gene panel including low burden mutations was key for the biomarker based on altered pathways. CONCLUSIONS: We propose to include the number of pathways altered by driver mutations as a biomarker together with CLL-IPI in prospective studies of CLL from time of diagnosis for incorporation into clinical care and personalized follow-up and treatment.

11.
Cancers (Basel) ; 12(2)2020 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-31991861

RESUMO

Germline protein truncating variants (PTVs) in the FANCM gene have been associated with a 2-4-fold increased breast cancer risk in case-control studies conducted in different European populations. However, the distribution and the frequency of FANCM PTVs in Europe have never been investigated. In the present study, we collected the data of 114 European female breast cancer cases with FANCM PTVs ascertained in 20 centers from 13 European countries. We identified 27 different FANCM PTVs. The p.Gln1701* PTV is the most common PTV in Northern Europe with a maximum frequency in Finland and a lower relative frequency in Southern Europe. On the contrary, p.Arg1931* seems to be the most common PTV in Southern Europe. We also showed that p.Arg658*, the third most common PTV, is more frequent in Central Europe, and p.Gln498Thrfs*7 is probably a founder variant from Lithuania. Of the 23 rare or unique FANCM PTVs, 15 have not been previously reported. We provide here the initial spectrum of FANCM PTVs in European breast cancer cases.

12.
Cell Rep ; 29(3): 736-748.e4, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31618640

RESUMO

Small cytoplasmic mRNP granules are implicated in mRNA transport, translational control, and decay. Using super-resolution microscopy and fluorescence correlation spectroscopy, we analyzed the molecular composition and dynamics of single cytoplasmic YBX1_IMP1 mRNP granules in live cells. Granules appeared elongated and branched, with patches of IMP1 and YBX1 distributed along mRNA, reflecting the attachment of the two RNA-binding proteins in cis. Particles form at the nuclear pore and do not associate with translating ribosomes, so the mRNP is a repository for mRNAs awaiting translation. In agreement with the average number of mRNA-binding sites derived from crosslinked immunoprecipitation (CLIP) analyses, individual mRNPs contain 5-15 molecules of YBX1 and IMP1 and a single poly(A) tail identified by PABPC1. Taken together, we conclude that small cytoplasmic mRNP granules are mRNA singletons, thus depicting the cellular transcriptome. Consequently, expression of functionally related mRNAs in RNA regulons is unlikely to result from coordinated assembly.


Assuntos
Grânulos Citoplasmáticos/metabolismo , RNA Mensageiro/metabolismo , Ribonucleoproteínas/metabolismo , Sítios de Ligação , Grânulos Citoplasmáticos/química , Células HeLa , Humanos , Microscopia de Fluorescência , Poro Nuclear/metabolismo , Poli A/genética , Poli A/metabolismo , Proteína I de Ligação a Poli(A)/metabolismo , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Proteína 1 de Ligação a Y-Box/química , Proteína 1 de Ligação a Y-Box/genética , Proteína 1 de Ligação a Y-Box/metabolismo
13.
NPJ Genom Med ; 4: 13, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31263571

RESUMO

Genomic screening of cancer patients for predisposing variants is traditionally based on age at onset, family history and type of cancer. Whereas the clinical guidelines have proven efficient in identifying families exhibiting classical attributes of hereditary cancer, the frequency of patients with alternative presentations is unclear. We identified and characterized germline variants in 636 patients with advanced solid cancer using whole exome sequencing. Pathogenic and likely pathogenic germline variants among 168 genes associated with hereditary cancer were considered. These variants were identified in 17.8% of the patients and within a wide range of cancer types. In particular, patients with mesothelioma, ovarian cancer, cervical cancer, urothelial cancer, and cancer of unknown primary origin displayed high frequencies of pathogenic variants. Variants were predominantly found in DNA-repair pathways and about half were within genes involved in homologous recombination repair. Twenty-two BRCA1 and BRCA2 germline variants were identified in 12 different cancer types, of which 10 (45%) were not previously identified in these patients based on the current clinical guidelines. Loss of heterozygosity and somatic second hits were identified in several of the affected genes, supporting possible causality for cancer development. A potential treatment target based on the pathogenic germline variant could be suggested in 25 patients (4%). The study demonstrates a high frequency of pathogenic germline variants in the homologous recombination pathway in patients with advanced solid cancers. We infer that genetic screening in this group of patients may reveal high-risk families and identify patients with potential PARP inhibitor sensitive tumors.

14.
Oncotarget ; 10(43): 4397-4406, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31320993

RESUMO

Background: Glioblastoma (GB) is an incurable brain cancer with limited treatment options. The aim was to test the feasibility of using cell-free DNA (cfDNA) to support evaluation of treatment response, pseudo-progression and whether progression could be found before clinical and/or radiologic progression. Results: CfDNA fluctuated during treatment with the highest levels before diagnostic surgery and at progression. An increase was seen in 3 out of 4 patients at the time of progression while no increase was seen in 3 out of 4 patients without progression. CfDNA levels could aid in 3 out of 3 questionable cases of pseudo-progression. Methods: Eight newly diagnosed GB patients were included. Blood samples were collected prior to diagnosis, before start and during oncologic treatment until progression. Seven patients received concurrent radiotherapy/Temozolomide with adjuvant Temozolomide with one of the patients included in a clinical trial with either immunotherapy or placebo as add-on. One patient received radiation alone. CfDNA concentration was determined for each blood sample. Conclusions: It was feasible to measure cfDNA concentration. Despite the limited cohort size, there was a good tendency between cfDNA and treatment course and -response, respectively with the highest levels at progression.

15.
BMC Bioinformatics ; 20(1): 379, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31286861

RESUMO

BACKGROUND: Unsupervised machine learning methods (deep learning) have shown their usefulness with noisy single cell mRNA-sequencing data (scRNA-seq), where the models generalize well, despite the zero-inflation of the data. A class of neural networks, namely autoencoders, has been useful for denoising of single cell data, imputation of missing values and dimensionality reduction. RESULTS: Here, we present a striking feature with the potential to greatly increase the usability of autoencoders: With specialized training, the autoencoder is not only able to generalize over the data, but also to tease apart biologically meaningful modules, which we found encoded in the representation layer of the network. Our model can, from scRNA-seq data, delineate biological meaningful modules that govern a dataset, as well as give information as to which modules are active in each single cell. Importantly, most of these modules can be explained by known biological functions, as provided by the Hallmark gene sets. CONCLUSIONS: We discover that tailored training of an autoencoder makes it possible to deconvolute biological modules inherent in the data, without any assumptions. By comparisons with gene signatures of canonical pathways we see that the modules are directly interpretable. The scope of this discovery has important implications, as it makes it possible to outline the drivers behind a given effect of a cell. In comparison with other dimensionality reduction methods, or supervised models for classification, our approach has the benefit of both handling well the zero-inflated nature of scRNA-seq, and validating that the model captures relevant information, by establishing a link between input and decoded data. In perspective, our model in combination with clustering methods is able to provide information about which subtype a given single cell belongs to, as well as which biological functions determine that membership.


Assuntos
Perfilação da Expressão Gênica/métodos , Redes Neurais de Computação , RNA Mensageiro/química , Análise de Sequência de RNA/métodos , Aprendizado de Máquina não Supervisionado , Análise por Conglomerados , RNA Mensageiro/metabolismo , Análise de Célula Única
16.
Ugeskr Laeger ; 181(7A)2019 Apr 01.
Artigo em Dinamarquês | MEDLINE | ID: mdl-30950375

RESUMO

Genomic medicine refers to genomics and bioinformatics in the context of clinical care and diagnostics. Due to the generic and technology-based nature of the field, genomic medicine relates to a broad variety of medical specialities. Genomic medicine is fuelled by the rapid development of next generation sequencing technologies, which allow rapid sequencing of a complete human genome. In this way genomic data have become part of the early stages of the diagnostic workup. This review provides a brief description of the current status and perspectives of genomic medicine.


Assuntos
Genômica , Medicina de Precisão , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Humanos
17.
Thyroid ; 29(3): 368-377, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30618340

RESUMO

BACKGROUND: Survival of medullary thyroid carcinoma (MTC) subgroups in relation to the general population is poorly described. Data on the factors predicting long-term biochemical cure in MTC patients are nonexistent at a population level. A nationwide retrospective cohort study of MTC in Denmark from 1997 to 2014 was conducted, aiming to detect subgroups with survival similar to that of the general population and to identify prognostic factors for disease-specific survival and long-term biochemical cure. METHODS: The study included 220 patients identified from the nationwide Danish MTC cohort between 1997 and 2014. As a representative sample of the general population, a reference population matched 50:1 to the MTC cohort was used. RESULTS: Patients diagnosed with hereditary MTC by screening (hazard ratio [HR] = 1.5 [confidence interval (CI) 0.5-4.3]), patients without regional metastases (HR = 1.4 [CI 0.9-2.3]), and patients with stage I (HR = 1.3 [CI 0.6-3.1]), stage II (HR = 1.1 [CI 0.6-2.3]), and III (HR = 1.3 [CI 0.4-4.2]) disease had an overall survival similar to the reference population. On multivariate analysis, the presence of distant metastases (HR = 12.3 [CI 6.0-25.0]) predicted worse disease-specific survival, while the absence of regional lymph node metastases (odds ratio = 40.1 [CI 12.0-133.7]) was the only independent prognostic factor for long-term biochemical cure. CONCLUSIONS: Patients with hereditary MTC diagnosed by screening, patients without regional metastases, and patients with stages I, II, and III disease may have similar survival as the general population. The presence of distant metastases predicted worse disease-specific survival, while the absence of regional metastases predicted long-term biochemical cure.


Assuntos
Carcinoma Medular/congênito , Neoplasia Endócrina Múltipla Tipo 2a/epidemiologia , Neoplasia Endócrina Múltipla Tipo 2a/mortalidade , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/mortalidade , Adulto , Idoso , Carcinoma Medular/epidemiologia , Carcinoma Medular/mortalidade , Carcinoma Medular/terapia , Bases de Dados Factuais , Dinamarca/epidemiologia , Intervalo Livre de Doença , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 2a/terapia , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/terapia , Resultado do Tratamento , Adulto Jovem
18.
APMIS ; 127(5): 303-315, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30689231

RESUMO

Breast cancer was the first to take advantage of targeted therapy using endocrine therapy, and for up to 20% of all breast cancer patients a further significant improvement has been obtained by HER2-targeted therapy. Greater insight in precision medicine is to some extent driven by technical and computational progress, with the first wave of a true technical advancement being the application of transcriptomic analysis. Molecular subtyping further improved our understanding of breast cancer biology and has through a new tumor classification enabled allocation of personalized treatment regimens. The next wave in technical progression must be next-generation-sequencing which is currently providing new and exciting results. Large-scale sequencing data unravel novel somatic and potential targetable mutations as well as allowing the identification of new candidate genes predisposing for familial breast cancer. So far, around 15% of all breast cancer patients are genetically predisposed with most genes being factors in pathways implicated in genome maintenance. This review focuses on whole-genome sequencing and the new possibilities that this technique, together with other high-throughput analytic approaches, provides for a more individualized treatment course of breast cancer patients.


Assuntos
Neoplasias da Mama/genética , Sequenciamento Completo do Genoma/métodos , Reparo de Erro de Pareamento de DNA , Feminino , Genes BRCA1 , Genes BRCA2 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Medicina de Precisão
19.
Clin Epidemiol ; 11: 93-99, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30666164

RESUMO

Background: The completeness of REarranged during Transfection (RET) testing in patients with medullary thyroid carcinoma (MTC) was recently reported as 60%. However, the completeness on a population level is unknown. Similarly, it is unknown if the first Danish guidelines from 2002, recommending RET testing in all MTC patients, improved completeness in Denmark. We conducted a nationwide retrospective cohort study aiming to evaluate the completeness of RET testing in the Danish MTC cohort. Additionally, we aimed to assess the completeness before and after publication of the first Danish guidelines and characterize MTC patients who had not been tested. Methods: The study included 200 patients identified from the nationwide Danish MTC cohort 1997-2013. To identify RET tested MTC patients before December 31, 2014, the MTC cohort was cross-checked with the nationwide Danish RET cohort 1994-2014. To characterize MTC patients who had not been RET tested, we reviewed their medical records and compared them with MTC patients who had been tested. Results: Completeness of RET testing in the overall MTC cohort was 87% (95% CI: 0.81-0.91; 173/200). In the adjusted MTC cohort, after excluding patients diagnosed with hereditary MTC by screening, completeness was 83% (95% CI: 0.76-0.88; 131/158). Completeness was 88% (95% CI: 0.75-0.95; 42/48) and 81% (95% CI: 0.72-0.88) (89/110) before and after publication of the first Danish guidelines, respectively. Patients not RET tested had a higher median age at diagnosis compared to those RET tested. Median time to death was shorter in those not tested relative to those tested. Conclusion: The completeness of RET testing in MTC patients in Denmark seems to be higher than reported in other cohorts. No improvement in completeness was detected after publication of the first Danish guidelines. In addition, data indicate that advanced age and low life expectancy at MTC diagnosis may serve as prognostic indicators to identify patients having a higher likelihood of missing the compulsory RET test.

20.
Clin Cancer Res ; 25(4): 1239-1247, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30274980

RESUMO

PURPOSE: We evaluated the clinical benefit of tumor molecular profiling to select treatment in the phase I setting. EXPERIMENTAL DESIGN: Patients with advanced solid cancers and exhausted treatment options referred to a phase I unit were included in a prospective, single-center, single-arm open-label study (NCT02290522). Tumor biopsies were obtained for comprehensive genomic analysis including whole-exome sequencing and RNA sequencing. When possible, patients were treated with regimen matched to the genomic profile. Primary endpoint was progression-free survival (PFS). RESULTS: From May 2013 to January 2017, a total of 591 patients were enrolled, with 500 patients undergoing biopsy. Genomic profiles were obtained in 460 patients and a potential actionable target was identified in 352 (70%) of 500 biopsied patients. A total of 101 patients (20%) received matched treatment based on either gene mutations or RNA expression levels of targets available in early clinical trials or off-label treatment. Objective response according to RECIST1.1 was observed in 15 of 101 patients (0% complete response, 15% partial response), with a median PFS of 12 weeks (95% confidence interval, 9.9-14.4). CONCLUSIONS: Our study supports the feasibility of genomic profiling to select patients in the phase I setting and suggests that genomic matching can be beneficial for a minor subset of patients with no other treatment options. Randomized studies may validate this assumption.See related commentary by Ratain, p. 1136.


Assuntos
Genoma Humano/genética , Neoplasias/genética , Medicina de Precisão , Transcriptoma/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Intervalo Livre de Progressão , Análise de Sequência de RNA/métodos , Sequenciamento Completo do Exoma/métodos , Adulto Jovem
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