Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 73
Filtrar
1.
Pathol Res Pract ; 220: 153406, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33740545

RESUMO

Gut-associated lymphoid tissue (GALT) carcinoma is a colorectal neoplasm characterized by cystically dilated neoplastic glands that extend into prominent, well-circumscribed submucosal lymphoid tissue. Although often subtle, lamina propria between and around the neoplastic glands (identified by plasma cells, scattered eosinophils, etc.) is frequent in cases with classic morphology, arguing (at least in such cases) in favor of adenoma extending into lymphoglandular complexes rather than true invasive carcinoma. Some have postulated that the tumor arises from M-cells, specialized epithelial cells overlying GALT, and others have suggested it represents a unique pathway to carcinoma, specific to the environmental conditions of epithelium overlying lymphoid tissue. Although both hypotheses are intriguing, definitive phenotypic and genetic support is currently lacking. To address these possibilities, we undertook whole exome sequencing and immunohistochemical characterization of a GALT neoplasm recently identified on our clinical service. We discovered well-known mutations in both APC and KRAS, as well as mutations in several Wnt pathway components (MED12, BCL9L, RFX4, DACT3). No immunohistochemical expression of GP2, a marker of M-cell differentiation, was identified. Expression of CDX2, SATB2, and the DNA mismatch repair proteins was observed, while expression of both CK7 and CK20 was absent. No PD-L1 expression was present on tumor cells, but PD-L1 expression was noted in a subset of tumor-adjacent mononuclear cells. Overall, the findings suggest that GALT neoplasms, although morphologically distinct, may be a precursor or early form of typical sporadic colon carcinoma.

2.
Nat Commun ; 11(1): 3644, 2020 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-32686686

RESUMO

Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR = 0.42, 95% CI: 0.21-0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR = 1.53, 95% CI: 1.21-1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features.


Assuntos
Neoplasias Colorretais/genética , Proteínas de Neoplasias/genética , Neoplasias do Colo/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação INDEL , Mutação , Prognóstico , Proteína Supressora de Tumor p53/genética
3.
Cancer ; 126(13): 2980-2985, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32315455

RESUMO

BACKGROUND: Emerging evidence has suggested that DNA repair gene alterations may be important in prostate cancer pathogenesis. In the current study, the authors sought to characterize alterations in DNA repair pathway genes in both primary and metastatic prostate tumors with attention to tissue distribution as well as specific genomic alterations. METHODS: The authors studied the distribution and type of alterations in 24 genes that are considered important for DNA repair in 944 prostate cancers harvested from localized and metastatic tumors. Tumor DNA underwent hybrid capture for all coding exons of 287 or 395 cancer-related genes plus select introns from 19 or 31 genes frequently rearranged in cancer. Captured libraries were sequenced to a median exon coverage depth of >×500. Specific genomic alterations were characterized and the frequencies of mutations by tissue site (prostate vs metastases) were compared using logistic regression. RESULTS: A total of 152 patients from the cohort of 944 men (16%) harbored a germline or somatic mutation in ≥1 DNA repair genes. The most frequently mutated genes were BRCA2 (11.4%) and ATM (5.8%), followed by MSH6 (2.5%) and MSH2 (2.1%). Mutations were identified in approximately 20.1% of primary prostate tumors compared with 18.8% of bone metastases. When stratified by tissue site, the highest rates of DNA repair mutations were found in solid organ metastases, including brain and visceral metastases, compared with prostate. CONCLUSIONS: DNA repair gene mutations are more common in metastatic than localized prostate tumors. Visceral and other solid organ metastases appear enriched for these mutations compared with localized tumors or bone and lymph node metastases.

7.
Nat Med ; 25(10): 1615-1626, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31591588

RESUMO

Oncogenesis is driven by germline, environmental and stochastic factors. It is unknown how these interact to produce the molecular phenotypes of tumors. We therefore quantified the influence of germline polymorphisms on the somatic epigenome of 589 localized prostate tumors. Predisposition risk loci influence a tumor's epigenome, uncovering a mechanism for cancer susceptibility. We identified and validated 1,178 loci associated with altered methylation in tumoral but not nonmalignant tissue. These tumor methylation quantitative trait loci influence chromatin structure, as well as RNA and protein abundance. One prominent tumor methylation quantitative trait locus is associated with AKT1 expression and is predictive of relapse after definitive local therapy in both discovery and validation cohorts. These data reveal intricate crosstalk between the germ line and the epigenome of primary tumors, which may help identify germline biomarkers of aggressive disease to aid patient triage and optimize the use of more invasive or expensive diagnostic assays.


Assuntos
Metilação de DNA/genética , Epigenoma/genética , Mutação em Linhagem Germinativa/genética , Neoplasias da Próstata/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Genoma Humano/genética , Humanos , Masculino , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/genética , Locos de Características Quantitativas/genética
8.
Arch Toxicol ; 93(10): 2961-2978, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31511937

RESUMO

The aryl hydrocarbon receptor (AHR) mediates many toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, the AHR alone does not explain the widely different outcomes among organisms. To identify the other factors involved, we evaluated three transgenic mouse lines, each expressing a different rat AHR isoform (rWT, DEL, and INS) providing widely different resistance to TCDD toxicity, as well as C57BL/6 and DBA/2 mice which exhibit a ~ tenfold divergence in TCDD sensitivity (exposures of 5-1000 µg/kg TCDD). We supplement these with whole-genome sequencing, together with transcriptomic and proteomic analyses of the corresponding rat models, Long-Evans (L-E) and Han/Wistar (H/W) rats (having a ~ 1000-fold difference in their TCDD sensitivities; 100 µg/kg TCDD), to identify genes associated with TCDD-response phenotypes. Overall, we identified up to 50% of genes with altered mRNA abundance following TCDD exposure are associated with a single AHR isoform (33.8%, 11.7%, 5.2% and 0.3% of 3076 genes altered unique to rWT, DEL, C57BL/6 and INS respectively following 1000 µg/kg TCDD). Hepatic Pxdc1 was significantly repressed in all three TCDD-sensitive animal models (C57BL/6 and rWT mice, and L-E rat) after TCDD exposure. Three genes, including Cxxc5, Sugp1 and Hgfac, demonstrated different AHRE-1 (full) motif occurrences within their promoter regions between rat strains, as well as different patterns of mRNA abundance. Several hepatic proteins showed parallel up- or downward alterations with their RNAs, with three genes (SNRK, IGTP and IMPA2) showing consistent, strain-dependent changes. These data show the value of integrating genomic, transcriptomic and proteomic evidence across multi-species models in toxicologic studies.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Poluentes Ambientais/toxicidade , Fígado/metabolismo , Dibenzodioxinas Policloradas/toxicidade , Receptores de Hidrocarboneto Arílico/genética , Animais , Relação Dose-Resposta a Droga , Poluentes Ambientais/administração & dosagem , Genômica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Transgênicos , Dibenzodioxinas Policloradas/administração & dosagem , Proteômica , RNA Mensageiro/genética , Ratos , Ratos Long-Evans , Ratos Wistar , Especificidade da Espécie , Transcriptoma
9.
Sci Rep ; 9(1): 3590, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30837567

RESUMO

Genomic rearrangements are a hallmark of cancer biology and progression, allowing cells to rapidly transform through alterations in regulatory structures, changes in expression patterns, reprogramming of signaling pathways, and creation of novel transcripts via gene fusion events. Though functional gene fusions encoding oncogenic proteins are the most dramatic outcomes of genomic rearrangements, we investigated the relationship between rearrangements evidenced by fusion transcripts and local expression changes in cancer using transcriptome data alone. 9,953 gene fusion predictions from 418 primary serious ovarian cancer tumors were analyzed, identifying depletions of gene fusion breakpoints within coding regions of fused genes as well as an N-terminal enrichment of breakpoints within fused genes. We identified 48 genes with significant fusion-associated upregulation and furthermore demonstrate that significant regional overexpression of intact genes in patient transcriptomes occurs within 1 megabase of 78 novel gene fusions that function as central markers of these regions. We reveal that cancer transcriptomes select for gene fusions that preserve protein and protein domain coding potential. The association of gene fusion transcripts with neighboring gene overexpression supports rearrangements as mechanism through which cancer cells remodel their transcriptomes and identifies a new way to utilize gene fusions as indicators of regional expression changes in diseased cells with only transcriptomic data.


Assuntos
Pontos de Quebra do Cromossomo , Regulação Neoplásica da Expressão Gênica , Fusão Gênica , Proteínas de Fusão Oncogênica , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Transcriptoma , Biomarcadores Tumorais/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Gradação de Tumores
10.
Blood ; 133(25): 2651-2663, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-30923040

RESUMO

Targeted sequencing of 103 leukemia-associated genes in leukemia cells from 841 treatment-naive patients with chronic lymphocytic leukemia (CLL) identified 89 (11%) patients as having CLL cells with mutations in genes encoding proteins that putatively are involved in hedgehog (Hh) signaling. Consistent with this finding, there was a significant association between the presence of these mutations and the expression of GLI1 (χ2 test, P < .0001), reflecting activation of the Hh pathway. However, we discovered that 38% of cases without identified mutations also were GLI1+ Patients with GLI1+ CLL cells had a shorter median treatment-free survival than patients with CLL cells lacking expression of GLI1 independent of IGHV mutation status. We found that GANT61, a small molecule that can inhibit GLI1, was highly cytotoxic for GLI1+ CLL cells relative to that of CLL cells without GLI1. Collectively, this study shows that a large proportion of patients have CLL cells with activated Hh signaling, which is associated with early disease progression and enhanced sensitivity to inhibition of GLI1.


Assuntos
Proteínas Hedgehog/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Proteína GLI1 em Dedos de Zinco/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Regulação Leucêmica da Expressão Gênica/genética , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Masculino , Pessoa de Meia-Idade , Piridinas/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
11.
Artigo em Inglês | MEDLINE | ID: mdl-30478095

RESUMO

Since the first draft of the human genome was completed, next-generation DNA sequencing technology has dramatically reduced the cost of sequencing a genome. Computational analysis has not advanced as fast as the instruments that generate the data, and storing all the data remains a challenge. Nevertheless, personal genomics has arrived and is already being used in the clinic. Significant privacy issues remain, however, and these are not widely understood. The Genetic Information Non-Discrimination Act (GINA) needs to be extended and the probabilistic nature of genetic predisposition must be better explained to both the public and physicians. We must also be wary that this promising new technology and its applications do not amplify existing healthcare disparities.


Assuntos
Genoma Humano , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/tendências , Análise de Sequência de DNA/tendências , Biologia Computacional , Predisposição Genética para Doença , Testes Genéticos/legislação & jurisprudência , Genômica/tendências , Humanos
12.
Artigo em Inglês | MEDLINE | ID: mdl-30478097

RESUMO

Although DNA and RNA sequencing has a history spanning five decades, large-scale massively parallel sequencing, or next-generation sequencing (NGS), has only been commercially available for about 10 years. Nonetheless, the meteoric increase in sequencing throughput with NGS has dramatically changed our understanding of our genome and ourselves. Sequencing the first human genome as a haploid reference took nearly 10 years but now a full diploid human genome sequence can be accomplished in just a few days. NGS has also reduced the cost of generating sequence data and a plethora of sequence-based methods for probing a genome have emerged using NGS as the readout and have been applied to many species. NGS methods have also entered the medical realm and will see an increasing use in diagnosis and treatment. NGS has largely been driven by short-read generation (150 bp) but new platforms have emerged and are now capable of generating long multikilobase reads. These latter platforms enable reference-independent genome assemblies and long-range haplotype generation. Rapid DNA and RNA sequencing is now mainstream and will continue to have an increasing impact on biology and medicine.


Assuntos
Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Biologia Computacional , Genoma Humano , Humanos , Análise de Sequência de DNA , Análise de Sequência de RNA
13.
Nature ; 563(7732): 579-583, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30429608

RESUMO

The use of liquid biopsies for cancer detection and management is rapidly gaining prominence1. Current methods for the detection of circulating tumour DNA involve sequencing somatic mutations using cell-free DNA, but the sensitivity of these methods may be low among patients with early-stage cancer given the limited number of recurrent mutations2-5. By contrast, large-scale epigenetic alterations-which are tissue- and cancer-type specific-are not similarly constrained6 and therefore potentially have greater ability to detect and classify cancers in patients with early-stage disease. Here we develop a sensitive, immunoprecipitation-based protocol to analyse the methylome of small quantities of circulating cell-free DNA, and demonstrate the ability to detect large-scale DNA methylation changes that are enriched for tumour-specific patterns. We also demonstrate robust performance in cancer detection and classification across an extensive collection of plasma samples from several tumour types. This work sets the stage to establish biomarkers for the minimally invasive detection, interception and classification of early-stage cancers based on plasma cell-free DNA methylation patterns.


Assuntos
Ácidos Nucleicos Livres/sangue , Ácidos Nucleicos Livres/metabolismo , Metilação de DNA , DNA de Neoplasias/sangue , DNA de Neoplasias/metabolismo , Detecção Precoce de Câncer/métodos , Neoplasias/classificação , Neoplasias/genética , Adenocarcinoma/sangue , Adenocarcinoma/genética , Animais , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Análise Mutacional de DNA , Epigênese Genética , Feminino , Xenoenxertos , Humanos , Biópsia Líquida , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transplante de Neoplasias , Neoplasias/sangue , Especificidade de Órgãos , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/genética
14.
J Thorac Oncol ; 13(10): 1560-1568, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29981927

RESUMO

INTRODUCTION: EGFR exon 20 insertions (EGFRex20ins) comprise an uncommon subset of EGFR-activating alterations relatively insensitive to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs). However, recent early clinical data suggests these patients may benefit from newer-generation EGFR-TKIs. Comprehensive genomic profiling (CGP) identifies a broad spectrum of EGFRex20ins and associated co-occurring genomic alterations (GAs) present in NSCLC. METHODS: Hybrid capture-based CGP was performed prospectively on 14,483 clinically annotated consecutive NSCLC specimens to a mean coverage depth of greater than 650X for 236 or 315 cancer-related genes. RESULTS: Of 14,483 NSCLC cases, CGP identified 263 (1.8%) cases with EGFRex20ins, representing 12% (263 of 2251) of cases with EGFR mutations. Sixty-four unique EGFRex20ins were identified, most commonly D770_N771>ASVDN (21%) and N771_P772>SVDNP (20%). EGFR amplification occurred in 22% (57 of 263). The most common co-occurring GAs effected tumor protein p53 (TP53) (56%), cyclin dependent kinase inhibitor 2A (CDKN2A) (22%), cyclin dependent kinase inhibitor 2B (CDKN2B) (16%), NK2 homeobox 1 (NKX2-1) (14%) and RB transcriptional corepressor 1 (RB1) (11%); co-occurring GAs in other known lung cancer drivers were rare (5%). Average tumor mutational burden was low (mean 4.3, range 0 to 40.3 mutations/Mb). Clinical outcomes to first- and second-generation EGFR TKIs were obtained for five patients and none responded. CONCLUSIONS: In the largest series of EGFRex20ins NSCLC, diverse EGFRex20ins were detected in 12% of EGFR-mutant NSCLC, a higher frequency than previously reported in smaller single-institution studies. Clinical outcomes showed lack of response to EGFR TKIs. Tumor mutational burden was low, consistent with non-smoking associated NSCLC. Comprehensive sequencing revealed increased proportion and wide variety of EGFRex20ins, representing a population of patients significant enough for focused efforts on effective interventions.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Perfilação da Expressão Gênica/métodos , Genômica/métodos , Neoplasias Pulmonares/genética , Carga Tumoral/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Éxons , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
15.
Nature ; 559(7714): 400-404, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29988082

RESUMO

The incidence of acute myeloid leukaemia (AML) increases with age and mortality exceeds 90% when diagnosed after age 65. Most cases arise without any detectable early symptoms and patients usually present with the acute complications of bone marrow failure1. The onset of such de novo AML cases is typically preceded by the accumulation of somatic mutations in preleukaemic haematopoietic stem and progenitor cells (HSPCs) that undergo clonal expansion2,3. However, recurrent AML mutations also accumulate in HSPCs during ageing of healthy individuals who do not develop AML, a phenomenon referred to as age-related clonal haematopoiesis (ARCH)4-8. Here we use deep sequencing to analyse genes that are recurrently mutated in AML to distinguish between individuals who have a high risk of developing AML and those with benign ARCH. We analysed peripheral blood cells from 95 individuals that were obtained on average 6.3 years before AML diagnosis (pre-AML group), together with 414 unselected age- and gender-matched individuals (control group). Pre-AML cases were distinct from controls and had more mutations per sample, higher variant allele frequencies, indicating greater clonal expansion, and showed enrichment of mutations in specific genes. Genetic parameters were used to derive a model that accurately predicted AML-free survival; this model was validated in an independent cohort of 29 pre-AML cases and 262 controls. Because AML is rare, we also developed an AML predictive model using a large electronic health record database that identified individuals at greater risk. Collectively our findings provide proof-of-concept that it is possible to discriminate ARCH from pre-AML many years before malignant transformation. This could in future enable earlier detection and monitoring, and may help to inform intervention.


Assuntos
Predisposição Genética para Doença , Saúde , Leucemia Mieloide Aguda/genética , Mutação , Adulto , Fatores Etários , Idoso , Progressão da Doença , Registros Eletrônicos de Saúde , Feminino , Humanos , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Mutagênese , Prevalência , Medição de Risco
16.
Genome Res ; 28(8): 1126-1135, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29954844

RESUMO

The SK-BR-3 cell line is one of the most important models for HER2+ breast cancers, which affect one in five breast cancer patients. SK-BR-3 is known to be highly rearranged, although much of the variation is in complex and repetitive regions that may be underreported. Addressing this, we sequenced SK-BR-3 using long-read single molecule sequencing from Pacific Biosciences and develop one of the most detailed maps of structural variations (SVs) in a cancer genome available, with nearly 20,000 variants present, most of which were missed by short-read sequencing. Surrounding the important ERBB2 oncogene (also known as HER2), we discover a complex sequence of nested duplications and translocations, suggesting a punctuated progression. Full-length transcriptome sequencing further revealed several novel gene fusions within the nested genomic variants. Combining long-read genome and transcriptome sequencing enables an in-depth analysis of how SVs disrupt the genome and sheds new light on the complex mechanisms involved in cancer genome evolution.


Assuntos
Neoplasias da Mama/genética , Amplificação de Genes/genética , Rearranjo Gênico/genética , Oncogenes/genética , Neoplasias da Mama/patologia , Feminino , Genoma Humano , Variação Estrutural do Genoma , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Células MCF-7 , Receptor ErbB-2/genética , Sequências Repetitivas de Ácido Nucleico/genética , Transcriptoma/genética
17.
J Am Acad Dermatol ; 79(2): 221-229, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29653212

RESUMO

BACKGROUND: A subset of melanomas carrying a B-Raf proto-oncogene, serine/threonine kinase gene (BRAF) V600E mutation, which is the most common targetable mutation in melanoma, arise in association with a melanocytic nevus that is also harboring a BRAF V600E mutation. The detailed histomorphologic characteristics of nevi positive for BRAF V600E have not been systematically documented. OBJECTIVE: To identify histomorphologic features correlating with BRAF V600E status in nevi. METHODS: We retrospectively identified melanocytic nevi from our laboratory reporting system. We performed a histomorphologic analysis and analysis of BRAF V600E expression by immunohistochemistry. RESULTS: Thirteen nevi (14.8%) were negative and 76 (86.4%) were positive for BRAF V600E. The nevi positive for BRAF V600E were predominantly dermal (predominantly dermal growth in 55.3% of nevi positive for BRAF V600E and 15.4% of nevi negative for BRAF V600E [P = .01]) and showed a congenital growth pattern (congenital growth pattern in 51.3% of nevi positive for BRAF V600E and 15.4% of nevi negative for BRAF V600E [P = .02]). Compared with nevi negative for BRAF V600E, those that were positive for BRAF V600E often exhibited predominantly nested intraepidermal melanocytes, larger junctional nests, abrupt lateral circumscription, and larger cell size. Architectural disorder and inflammatory infiltrates were seen more often in nevi negative for BRAF V600E. BRAF sequencing of a subset of nevi confirmed the immunohistochemical results. LIMITATIONS: Limitations include the study's retrospective design and the small sample size of nevi negative for BRAF V600E. CONCLUSIONS: BRAF V600E is associated with distinct histomorphologic features in nevi. These features may contribute to improving the accuracy of classification and diagnosis of melanocytic neoplasms.


Assuntos
Nevo Pigmentado/classificação , Nevo Pigmentado/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/classificação , Neoplasias Cutâneas/patologia , Adulto , Tamanho Celular , Diagnóstico Diferencial , Epiderme/patologia , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Melanócitos/patologia , Pessoa de Meia-Idade , Mutação , Nevo/diagnóstico , Nevo Pigmentado/genética , Estudos Retrospectivos , Neoplasias Cutâneas/genética
18.
Nat Commun ; 8(1): 656, 2017 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-28939825

RESUMO

Nuclear mutations are well known to drive tumor incidence, aggression and response to therapy. By contrast, the frequency and roles of mutations in the maternally inherited mitochondrial genome are poorly understood. Here we sequence the mitochondrial genomes of 384 localized prostate cancer patients, and identify a median of one mitochondrial single-nucleotide variant (mtSNV) per patient. Some of these mtSNVs occur in recurrent mutational hotspots and associate with aggressive disease. Younger patients have fewer mtSNVs than those who diagnosed at an older age. We demonstrate strong links between mitochondrial and nuclear mutational profiles, with co-occurrence between specific mutations. For example, certain control region mtSNVs co-occur with gain of the MYC oncogene, and these mutations are jointly associated with patient survival. These data demonstrate frequent mitochondrial mutation in prostate cancer, and suggest interplay between nuclear and mitochondrial mutational profiles in prostate cancer.In prostate cancer, the role of mutations in the maternally-inherited mitochondrial genome are not well known. Here, the authors demonstrate frequent, age-dependent mitochondrial mutation in prostate cancer. Strong links between mitochondrial and nuclear mutational profiles are associated with clinical aggressivity.


Assuntos
Adenocarcinoma/genética , DNA Mitocondrial/genética , Mutação Puntual , Neoplasias da Próstata/genética , Adenocarcinoma/patologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Genes myc , Estudos de Associação Genética , Genoma Mitocondrial , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Neoplasias da Próstata/patologia , Análise de Sobrevida
19.
Nature ; 547(7661): 104-108, 2017 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-28658204

RESUMO

In acute myeloid leukaemia, long-term survival is poor as most patients relapse despite achieving remission. Historically, the failure of therapy has been thought to be due to mutations that produce drug resistance, possibly arising as a consequence of the mutagenic properties of chemotherapy drugs. However, other lines of evidence have pointed to the pre-existence of drug-resistant cells. For example, deep sequencing of paired diagnosis and relapse acute myeloid leukaemia samples has provided direct evidence that relapse in some cases is generated from minor genetic subclones present at diagnosis that survive chemotherapy, suggesting that resistant cells are generated by evolutionary processes before treatment and are selected by therapy. Nevertheless, the mechanisms of therapy failure and capacity for leukaemic regeneration remain obscure, as sequence analysis alone does not provide insight into the cell types that are fated to drive relapse. Although leukaemia stem cells have been linked to relapse owing to their dormancy and self-renewal properties, and leukaemia stem cell gene expression signatures are highly predictive of therapy failure, experimental studies have been primarily correlative and a role for leukaemia stem cells in acute myeloid leukaemia relapse has not been directly proved. Here, through combined genetic and functional analysis of purified subpopulations and xenografts from paired diagnosis/relapse samples, we identify therapy-resistant cells already present at diagnosis and two major patterns of relapse. In some cases, relapse originated from rare leukaemia stem cells with a haematopoietic stem/progenitor cell phenotype, while in other instances relapse developed from larger subclones of immunophenotypically committed leukaemia cells that retained strong stemness transcriptional signatures. The identification of distinct patterns of relapse should lead to improved methods for disease management and monitoring in acute myeloid leukaemia. Moreover, the shared functional and transcriptional stemness properties that underlie both cellular origins of relapse emphasize the importance of developing new therapeutic approaches that target stemness to prevent relapse.


Assuntos
Linhagem da Célula , Leucemia Mieloide Aguda/patologia , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/patologia , Animais , Células Clonais/metabolismo , Células Clonais/patologia , Feminino , Humanos , Imunofenotipagem , Leucemia Mieloide Aguda/genética , Camundongos , Mutação , Células Progenitoras Mieloides/metabolismo , Células Progenitoras Mieloides/patologia , Recidiva Local de Neoplasia/genética , Células-Tronco Neoplásicas/metabolismo
20.
Genome Med ; 9(1): 59, 2017 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-28659176

RESUMO

BACKGROUND: A key step in cancer genome analysis is the identification of somatic mutations in the tumor. This is typically done by comparing the genome of the tumor to the reference genome sequence derived from a normal tissue taken from the same donor. However, there are a variety of common scenarios in which matched normal tissue is not available for comparison. RESULTS: In this work, we describe an algorithm to distinguish somatic single nucleotide variants (SNVs) in next-generation sequencing data from germline polymorphisms in the absence of normal samples using a machine learning approach. Our algorithm was evaluated using a family of supervised learning classifications across six different cancer types and ~1600 samples, including cell lines, fresh frozen tissues, and formalin-fixed paraffin-embedded tissues; we tested our algorithm with both deep targeted and whole-exome sequencing data. Our algorithm correctly classified between 95 and 98% of somatic mutations with F1-measure ranges from 75.9 to 98.6% depending on the tumor type. We have released the algorithm as a software package called ISOWN (Identification of SOmatic mutations Without matching Normal tissues). CONCLUSIONS: In this work, we describe the development, implementation, and validation of ISOWN, an accurate algorithm for predicting somatic mutations in cancer tissues in the absence of matching normal tissues. ISOWN is available as Open Source under Apache License 2.0 from https://github.com/ikalatskaya/ISOWN .


Assuntos
Análise Mutacional de DNA/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação , Neoplasias/genética , Aprendizado de Máquina Supervisionado , Humanos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...