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1.
Nature ; 628(8007): 416-423, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38538786

RESUMO

Antibody and chimeric antigen receptor (CAR) T cell-mediated targeted therapies have improved survival in patients with solid and haematologic malignancies1-9. Adults with T cell leukaemias and lymphomas, collectively called T cell cancers, have short survival10,11 and lack such targeted therapies. Thus, T cell cancers particularly warrant the development of CAR T cells and antibodies to improve patient outcomes. Preclinical studies showed that targeting T cell receptor ß-chain constant region 1 (TRBC1) can kill cancerous T cells while preserving sufficient healthy T cells to maintain immunity12, making TRBC1 an attractive target to treat T cell cancers. However, the first-in-human clinical trial of anti-TRBC1 CAR T cells reported a low response rate and unexplained loss of anti-TRBC1 CAR T cells13,14. Here we demonstrate that CAR T cells are lost due to killing by the patient's normal T cells, reducing their efficacy. To circumvent this issue, we developed an antibody-drug conjugate that could kill TRBC1+ cancer cells in vitro and cure human T cell cancers in mouse models. The anti-TRBC1 antibody-drug conjugate may provide an optimal format for TRBC1 targeting and produce superior responses in patients with T cell cancers.


Assuntos
Imunoconjugados , Leucemia de Células T , Linfoma de Células T , Receptores de Antígenos de Linfócitos T alfa-beta , Linfócitos T , Animais , Feminino , Humanos , Camundongos , Imunoconjugados/imunologia , Imunoconjugados/uso terapêutico , Imunoterapia Adotiva , Leucemia de Células T/tratamento farmacológico , Leucemia de Células T/imunologia , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Nature ; 596(7870): 126-132, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34290408

RESUMO

PD-1 blockade unleashes CD8 T cells1, including those specific for mutation-associated neoantigens (MANA), but factors in the tumour microenvironment can inhibit these T cell responses. Single-cell transcriptomics have revealed global T cell dysfunction programs in tumour-infiltrating lymphocytes (TIL). However, the majority of TIL do not recognize tumour antigens2, and little is known about transcriptional programs of MANA-specific TIL. Here, we identify MANA-specific T cell clones using the MANA functional expansion of specific T cells assay3 in neoadjuvant anti-PD-1-treated non-small cell lung cancers (NSCLC). We use their T cell receptors as a 'barcode' to track and analyse their transcriptional programs in the tumour microenvironment using coupled single-cell RNA sequencing and T cell receptor sequencing. We find both MANA- and virus-specific clones in TIL, regardless of response, and MANA-, influenza- and Epstein-Barr virus-specific TIL each have unique transcriptional programs. Despite exposure to cognate antigen, MANA-specific TIL express an incompletely activated cytolytic program. MANA-specific CD8 T cells have hallmark transcriptional programs of tissue-resident memory (TRM) cells, but low levels of interleukin-7 receptor (IL-7R) and are functionally less responsive to interleukin-7 (IL-7) compared with influenza-specific TRM cells. Compared with those from responding tumours, MANA-specific clones from non-responding tumours express T cell receptors with markedly lower ligand-dependent signalling, are largely confined to HOBIThigh TRM subsets, and coordinately upregulate checkpoints, killer inhibitory receptors and inhibitors of T cell activation. These findings provide important insights for overcoming resistance to PD-1 blockade.


Assuntos
Antígenos de Neoplasias/imunologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Regulação da Expressão Gênica , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Antígenos de Neoplasias/genética , Linfócitos T CD8-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Células Cultivadas , Humanos , Memória Imunológica , Neoplasias Pulmonares/genética , Receptor de Morte Celular Programada 1/antagonistas & inibidores , RNA-Seq , Receptores de Interleucina-7/imunologia , Análise de Célula Única , Transcriptoma/genética , Microambiente Tumoral
3.
Proc Natl Acad Sci U S A ; 120(15): e2220704120, 2023 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-37014860

RESUMO

The analysis of cell-free DNA (cfDNA) from plasma offers great promise for the earlier detection of cancer. At present, changes in DNA sequence, methylation, or copy number are the most sensitive ways to detect the presence of cancer. To further increase the sensitivity of such assays with limited amounts of sample, it would be useful to be able to evaluate the same template molecules for all these changes. Here, we report an approach, called MethylSaferSeqS, that achieves this goal, and can be applied to any standard library preparation method suitable for massively parallel sequencing. The innovative step was to copy both strands of each DNA-barcoded molecule with a primer that allows the subsequent separation of the original strands (retaining their 5-methylcytosine residues) from the copied strands (in which the 5-methylcytosine residues are replaced with unmodified cytosine residues). The epigenetic and genetic alterations present in the DNA molecules can then be obtained from the original and copied strands, respectively. We applied this approach to plasma from 265 individuals, including 198 with cancers of the pancreas, ovary, lung, and colon, and found the expected patterns of mutations, copy number alterations, and methylation. Furthermore, we could determine which original template DNA molecules were methylated and/or mutated. MethylSaferSeqS should be useful for addressing a variety of questions relating genetics and epigenetics.


Assuntos
Variações do Número de Cópias de DNA , Neoplasias , Feminino , Humanos , Metilação , 5-Metilcitosina , DNA/genética , Mutação , Neoplasias/genética , Metilação de DNA
4.
N Engl J Med ; 386(24): 2261-2272, 2022 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-35657320

RESUMO

BACKGROUND: The role of adjuvant chemotherapy in stage II colon cancer continues to be debated. The presence of circulating tumor DNA (ctDNA) after surgery predicts very poor recurrence-free survival, whereas its absence predicts a low risk of recurrence. The benefit of adjuvant chemotherapy for ctDNA-positive patients is not well understood. METHODS: We conducted a trial to assess whether a ctDNA-guided approach could reduce the use of adjuvant chemotherapy without compromising recurrence risk. Patients with stage II colon cancer were randomly assigned in a 2:1 ratio to have treatment decisions guided by either ctDNA results or standard clinicopathological features. For ctDNA-guided management, a ctDNA-positive result at 4 or 7 weeks after surgery prompted oxaliplatin-based or fluoropyrimidine chemotherapy. Patients who were ctDNA-negative were not treated. The primary efficacy end point was recurrence-free survival at 2 years. A key secondary end point was adjuvant chemotherapy use. RESULTS: Of the 455 patients who underwent randomization, 302 were assigned to ctDNA-guided management and 153 to standard management. The median follow-up was 37 months. A lower percentage of patients in the ctDNA-guided group than in the standard-management group received adjuvant chemotherapy (15% vs. 28%; relative risk, 1.82; 95% confidence interval [CI], 1.25 to 2.65). In the evaluation of 2-year recurrence-free survival, ctDNA-guided management was noninferior to standard management (93.5% and 92.4%, respectively; absolute difference, 1.1 percentage points; 95% CI, -4.1 to 6.2 [noninferiority margin, -8.5 percentage points]). Three-year recurrence-free survival was 86.4% among ctDNA-positive patients who received adjuvant chemotherapy and 92.5% among ctDNA-negative patients who did not. CONCLUSIONS: A ctDNA-guided approach to the treatment of stage II colon cancer reduced adjuvant chemotherapy use without compromising recurrence-free survival. (Supported by the Australian National Health and Medical Research Council and others; DYNAMIC Australian New Zealand Clinical Trials Registry number, ACTRN12615000381583.).


Assuntos
Antineoplásicos , Quimioterapia Adjuvante , DNA Tumoral Circulante , Neoplasias do Colo , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Austrália , Quimioterapia Adjuvante/métodos , DNA Tumoral Circulante/análise , DNA Tumoral Circulante/sangue , Neoplasias do Colo/sangue , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Neoplasias do Colo/terapia , Intervalo Livre de Doença , Fluoruracila/uso terapêutico , Humanos , Recidiva Local de Neoplasia/prevenção & controle , Estadiamento de Neoplasias , Oxaliplatina/uso terapêutico
5.
Proc Natl Acad Sci U S A ; 119(15): e2123406119, 2022 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-35394875

RESUMO

HIV-1 infection is incurable due to the persistence of the virus in a latent reservoir of resting memory CD4+ T cells. "Shock-and-kill" approaches that seek to induce HIV-1 gene expression, protein production, and subsequent targeting by the host immune system have been unsuccessful due to a lack of effective latency-reversing agents (LRAs) and kill strategies. In an effort to develop reagents that could be used to promote killing of infected cells, we constructed T cell receptor (TCR)-mimic antibodies to HIV-1 peptide-major histocompatibility complexes (pMHC). Using phage display, we panned for phages expressing antibody-like variable sequences that bound HIV-1 pMHC generated using the common HLA-A*02:01 allele. We targeted three epitopes in Gag and reverse transcriptase identified and quantified via Poisson detection mass spectrometry from cells infected in vitro with a pseudotyped HIV-1 reporter virus (NL4.3 dEnv). Sequences isolated from phages that bound these pMHC were cloned into a single-chain diabody backbone (scDb) sequence, such that one fragment is specific for an HIV-1 pMHC and the other fragment binds to CD3ε, an essential signal transduction subunit of the TCR. Thus, these antibodies utilize the sensitivity of T cell signaling as readouts for antigen processing and as agents to promote killing of infected cells. Notably, these scDbs are exquisitely sensitive and specific for the peptide portion of the pMHC. Most importantly, one scDb caused killing of infected cells presenting a naturally processed target pMHC. This work lays the foundation for a novel therapeutic killing strategy toward elimination of the HIV-1 reservoir.


Assuntos
Anticorpos Biespecíficos , Infecções por HIV , Soropositividade para HIV , HIV-1 , Linfócitos T CD4-Positivos , Humanos , Mimetismo Molecular , Receptores de Antígenos de Linfócitos T , Latência Viral
7.
Nature ; 564(7735): 273-277, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30542164

RESUMO

Cytokine release syndrome (CRS) is a life-threatening complication of several new immunotherapies used to treat cancers and autoimmune diseases1-5. Here we report that atrial natriuretic peptide can protect mice from CRS induced by such agents by reducing the levels of circulating catecholamines. Catecholamines were found to orchestrate an immunodysregulation resulting from oncolytic bacteria and lipopolysaccharide through a self-amplifying loop in macrophages. Myeloid-specific deletion of tyrosine hydroxylase inhibited this circuit. Cytokine release induced by T-cell-activating therapeutic agents was also accompanied by a catecholamine surge and inhibition of catecholamine synthesis reduced cytokine release in vitro and in mice. Pharmacologic catecholamine blockade with metyrosine protected mice from lethal complications of CRS resulting from infections and various biotherapeutic agents including oncolytic bacteria, T-cell-targeting antibodies and CAR-T cells. Our study identifies catecholamines as an essential component of the cytokine release that can be modulated by specific blockers without impairing the therapeutic response.


Assuntos
Catecolaminas/antagonistas & inibidores , Catecolaminas/metabolismo , Citocinas/efeitos adversos , Síndrome , Animais , Fator Natriurético Atrial/farmacologia , Complexo CD3/antagonistas & inibidores , Catecolaminas/biossíntese , Citocinas/imunologia , Epinefrina/metabolismo , Feminino , Humanos , Imunoterapia Adotiva , Técnicas In Vitro , Estimativa de Kaplan-Meier , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , Norepinefrina/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/uso terapêutico , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , alfa-Metiltirosina/farmacologia
8.
Nature ; 561(7722): 201-205, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30177826

RESUMO

Most adult carcinomas develop from noninvasive precursor lesions, a progression that is supported by genetic analysis. However, the evolutionary and genetic relationships among co-existing lesions are unclear. Here we analysed the somatic variants of pancreatic cancers and precursor lesions sampled from distinct regions of the same pancreas. After inferring evolutionary relationships, we found that the ancestral cell had initiated and clonally expanded to form one or more lesions, and that subsequent driver gene mutations eventually led to invasive pancreatic cancer. We estimate that this multi-step progression generally spans many years. These new data reframe the step-wise progression model of pancreatic cancer by illustrating that independent, high-grade pancreatic precursor lesions observed in a single pancreas often represent a single neoplasm that has colonized the ductal system, accumulating spatial and genetic divergence over time.


Assuntos
Ductos Pancreáticos/patologia , Lesões Pré-Cancerosas/patologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem da Célula/genética , Progressão da Doença , Evolução Molecular , Humanos , Mutação INDEL/genética , Modelos Biológicos , Mutagênese , Invasividade Neoplásica , Ductos Pancreáticos/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Polimorfismo de Nucleotídeo Único/genética , Lesões Pré-Cancerosas/genética , Fatores de Tempo , Sequenciamento do Exoma
9.
Proc Natl Acad Sci U S A ; 118(12)2021 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-33731480

RESUMO

Developing therapeutic agents with potent antitumor activity that spare normal tissues remains a significant challenge. Clonal loss of heterozygosity (LOH) is a widespread and irreversible genetic alteration that is exquisitely specific to cancer cells. We hypothesized that LOH events can be therapeutically targeted by "inverting" the loss of an allele in cancer cells into an activating signal. Here we describe a proof-of-concept approach utilizing engineered T cells approximating NOT-gate Boolean logic to target counterexpressed antigens resulting from LOH events in cancer. The NOT gate comprises a chimeric antigen receptor (CAR) targeting the allele of human leukocyte antigen (HLA) that is retained in the cancer cells and an inhibitory CAR (iCAR) targeting the HLA allele that is lost in the cancer cells. We demonstrate that engineered T cells incorporating such NOT-gate logic can be activated in a genetically predictable manner in vitro and in mice to kill relevant cancer cells. This therapeutic approach, termed NASCAR (Neoplasm-targeting Allele-Sensing CAR), could, in theory, be extended to LOH of other polymorphic genes that result in altered cell surface antigens in cancers.


Assuntos
Biomarcadores Tumorais , Imunoterapia , Perda de Heterozigosidade , Terapia de Alvo Molecular , Neoplasias/etiologia , Neoplasias/terapia , Alelos , Antígenos de Neoplasias/imunologia , Terapia Baseada em Transplante de Células e Tecidos , Antígenos HLA/genética , Antígenos HLA/imunologia , Humanos , Imunoterapia/métodos , Imunoterapia Adotiva , Terapia de Alvo Molecular/efeitos adversos , Terapia de Alvo Molecular/métodos , Anticorpos de Cadeia Única/farmacologia , Anticorpos de Cadeia Única/uso terapêutico
10.
J Comput Assist Tomogr ; 47(6): 845-849, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37948357

RESUMO

BACKGROUND: Existing (artificial intelligence [AI]) tools in radiology are modeled without necessarily considering the expectations and experience of the end user-the radiologist. The literature is scarce on the tangible parameters that AI capabilities need to meet for radiologists to consider them useful tools. OBJECTIVE: The purpose of this study is to explore radiologists' attitudes toward AI tools in pancreatic cancer imaging and to quantitatively assess their expectations of these tools. METHODS: A link to the survey was posted on the www.ctisus.com website, advertised in the www.ctisus.com email newsletter, and publicized on LinkedIn, Facebook, and Twitter accounts. This survey asked participants about their demographics, practice, and current attitudes toward AI. They were also asked about their expectations of what constitutes a clinically useful AI tool. The survey consisted of 17 questions, which included 9 multiple choice questions, 2 Likert scale questions, 4 binary (yes/no) questions, 1 rank order question, and 1 free text question. RESULTS: A total of 161 respondents completed the survey, yielding a response rate of 46.3% of the total 348 clicks on the survey link. The minimum acceptable sensitivity of an AI program for the detection of pancreatic cancer chosen by most respondents was either 90% or 95% at a specificity of 95%. The minimum size of pancreatic cancer that most respondents would find an AI useful at detecting was 5 mm. Respondents preferred AI tools that demonstrated greater sensitivity over those with greater specificity. Over half of respondents anticipated incorporating AI tools into their clinical practice within the next 5 years. CONCLUSION: Radiologists are open to the idea of integrating AI-based tools and have high expectations regarding the performance of these tools. Consideration of radiologists' input is important to contextualize expectations and optimize clinical adoption of existing and future AI tools.


Assuntos
Neoplasias Pancreáticas , Radiologia , Humanos , Inteligência Artificial , Motivação , Radiologistas , Radiologia/métodos , Neoplasias Pancreáticas/diagnóstico por imagem
11.
Proc Natl Acad Sci U S A ; 117(2): 857-864, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31882448

RESUMO

Cancer is driven by the sequential accumulation of genetic and epigenetic changes in oncogenes and tumor suppressor genes. The timing of these events is not well understood. Moreover, it is currently unknown why the same driver gene change appears as an early event in some cancer types and as a later event, or not at all, in others. These questions have become even more topical with the recent progress brought by genome-wide sequencing studies of cancer. Focusing on mutational events, we provide a mathematical model of the full process of tumor evolution that includes different types of fitness advantages for driver genes and carrying-capacity considerations. The model is able to recapitulate a substantial proportion of the observed cancer incidence in several cancer types (colorectal, pancreatic, and leukemia) and inherited conditions (Lynch and familial adenomatous polyposis), by changing only 2 tissue-specific parameters: the number of stem cells in a tissue and its cell division frequency. The model sheds light on the evolutionary dynamics of cancer by suggesting a generalized early onset of tumorigenesis followed by slow mutational waves, in contrast to previous conclusions. Formulas and estimates are provided for the fitness increases induced by driver mutations, often much larger than previously described, and highly tissue dependent. Our results suggest a mechanistic explanation for why the selective fitness advantage introduced by specific driver genes is tissue dependent.


Assuntos
Carcinogênese/genética , Modelos Genéticos , Neoplasias/classificação , Polipose Adenomatosa do Colo/genética , Idoso , Divisão Celular , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose , Humanos , Pessoa de Meia-Idade , Mutação , Neoplasias/genética , Oncogenes/genética
12.
Proc Natl Acad Sci U S A ; 117(9): 4858-4863, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32075918

RESUMO

We report a sensitive PCR-based assay called Repetitive Element AneupLoidy Sequencing System (RealSeqS) that can detect aneuploidy in samples containing as little as 3 pg of DNA. Using a single primer pair, we amplified ∼350,000 amplicons distributed throughout the genome. Aneuploidy was detected in 49% of liquid biopsies from a total of 883 nonmetastatic, clinically detected cancers of the colorectum, esophagus, liver, lung, ovary, pancreas, breast, or stomach. Combining aneuploidy with somatic mutation detection and eight standard protein biomarkers yielded a median sensitivity of 80% in these eight cancer types, while only 1% of 812 healthy controls scored positive.


Assuntos
Aneuploidia , Neoplasias , Sequências Repetitivas de Ácido Nucleico , Biomarcadores Tumorais , DNA Tumoral Circulante , DNA/genética , Esôfago , Humanos , Biópsia Líquida , Mutação , Neoplasias/diagnóstico , Neoplasias/genética , Sequências Repetitivas de Ácido Nucleico/genética , Sequenciamento Completo do Genoma
13.
Genes Dev ; 29(21): 2219-24, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-26515115

RESUMO

Somatic mutations in the promoter of the gene for telomerase reverse transcriptase (TERT) are the most common noncoding mutations in cancer. They are thought to activate telomerase, contributing to proliferative immortality, but the molecular events driving TERT activation are largely unknown. We observed in multiple cancer cell lines that mutant TERT promoters exhibit the H3K4me2/3 mark of active chromatin and recruit the GABPA/B1 transcription factor, while the wild-type allele retains the H3K27me3 mark of epigenetic silencing; only the mutant promoters are transcriptionally active. These results suggest how a single-base-pair mutation can cause a dramatic epigenetic switch and monoallelic expression.


Assuntos
Cromatina/metabolismo , Regulação Neoplásica da Expressão Gênica , Mutação/genética , Neoplasias/genética , Regiões Promotoras Genéticas/genética , Telomerase/genética , Linhagem Celular Tumoral , Cromatina/genética , Epigênese Genética/genética , Fator de Transcrição de Proteínas de Ligação GA/genética , Fator de Transcrição de Proteínas de Ligação GA/metabolismo , Inativação Gênica , Humanos , Ligação Proteica
14.
Gastroenterology ; 160(6): 2043-2054.e2, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33493502

RESUMO

BACKGROUND & AIMS: Aneuploidy has been proposed as a tool to assess progression in patients with Barrett's esophagus (BE), but has heretofore required multiple biopsies. We assessed whether a single esophageal brushing that widely sampled the esophagus could be combined with massively parallel sequencing to characterize aneuploidy and identify patients with disease progression to dysplasia or cancer. METHODS: Esophageal brushings were obtained from patients without BE, with non-dysplastic BE (NDBE), low-grade dysplasia (LGD), high-grade dysplasia (HGD), or adenocarcinoma (EAC). To assess aneuploidy, we used RealSeqS, a technique that uses a single primer pair to interrogate ∼350,000 genome-spanning regions and identify specific chromosome arm alterations. A classifier to distinguish NDBE from EAC was trained on results from 79 patients. An independent validation cohort of 268 subjects was used to test the classifier at distinguishing patients at successive phases of BE progression. RESULTS: Aneuploidy progression was associated with gains of 1q, 12p, and 20q and losses on 9p and 17p. The entire chromosome 8q was often gained in NDBE, whereas focal gain of 8q24 was identified only when there was dysplasia. Among validation subjects, a classifier incorporating these features with a global measure of aneuploidy scored positive in 96% of EAC, 68% of HGD, but only 7% of NDBE. CONCLUSIONS: RealSeqS analysis of esophageal brushings provides a practical and sensitive method to determine aneuploidy in BE patients. It identifies specific chromosome changes that occur early in NDBE and others that occur late and mark progression to dysplasia. The clinical implications of this approach can now be tested in prospective trials.


Assuntos
Adenocarcinoma/patologia , Aneuploidia , Esôfago de Barrett/genética , Esôfago de Barrett/patologia , Neoplasias Esofágicas/patologia , Adenocarcinoma/genética , Esôfago de Barrett/classificação , Estudos Transversais , Técnicas Citológicas , Progressão da Doença , Neoplasias Esofágicas/genética , Esôfago/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos
16.
Proc Natl Acad Sci U S A ; 116(41): 20482-20488, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31548407

RESUMO

A new evaluation of previously published data suggested to us that the accumulation of mutations might slow, rather than increase, as individuals age. To explain this unexpected finding, we hypothesized that normal stem cell division rates might decrease as we age. To test this hypothesis, we evaluated cell division rates in the epithelium of human colonic, duodenal, esophageal, and posterior ethmoid sinonasal tissues. In all 4 tissues, there was a significant decrease in cell division rates with age. In contrast, cell division rates did not decrease in the colon of aged mice, and only small decreases were observed in their small intestine or esophagus. These results have important implications for understanding the relationship between normal stem cells, aging, and cancer. Moreover, they provide a plausible explanation for the enigmatic age-dependent deceleration in cancer incidence in very old humans but not in mice.


Assuntos
Envelhecimento , Divisão Celular , Desaceleração , Mutação , Neoplasias/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Colo/citologia , Colo/metabolismo , Duodeno/citologia , Duodeno/metabolismo , Esôfago/citologia , Esôfago/metabolismo , Humanos , Incidência , Antígeno Ki-67/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/patologia , Seios Paranasais/citologia , Seios Paranasais/metabolismo , Adulto Jovem
17.
Int J Cancer ; 148(4): 1014-1026, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-32984952

RESUMO

Studies in multiple solid tumor types have demonstrated the prognostic significance of ctDNA analysis after curative intent surgery. A combined analysis of data across completed studies could further our understanding of circulating tumor DNA (ctDNA) as a prognostic marker and inform future trial design. We combined individual patient data from three independent cohort studies of nonmetastatic colorectal cancer (CRC). Plasma samples were collected 4 to 10 weeks after surgery. Mutations in ctDNA were assayed using a massively parallel sequencing technique called SafeSeqS. We analyzed 485 CRC patients (230 Stage II colon, 96 Stage III colon, and 159 locally advanced rectum). ctDNA was detected after surgery in 59 (12%) patients overall (11.0%, 12.5% and 13.8% for samples taken at 4-6, 6-8 and 8-10 weeks; P = .740). ctDNA detection was associated with poorer 5-year recurrence-free (38.6% vs 85.5%; P < .001) and overall survival (64.6% vs 89.4%; P < .001). The predictive accuracy of postsurgery ctDNA for recurrence was higher than that of individual clinicopathologic risk features. Recurrence risk increased exponentially with increasing ctDNA mutant allele frequency (MAF) (hazard ratio, 1.2, 2.5 and 5.8 for MAF of 0.1%, 0.5% and 1%). Postsurgery ctDNA was detected in 3 of 20 (15%) patients with locoregional and 27 of 60 (45%) with distant recurrence (P = .018). This analysis demonstrates a consistent long-term impact of ctDNA as a prognostic marker across nonmetastatic CRC, where ctDNA outperforms other clinicopathologic risk factors and MAF further stratifies recurrence risk. ctDNA is a better predictor of distant vs locoregional recurrence.


Assuntos
Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Neoplasias Colorretais/genética , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , DNA Tumoral Circulante/sangue , Estudos de Coortes , Neoplasias Colorretais/sangue , Neoplasias Colorretais/cirurgia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/estatística & dados numéricos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Modelos de Riscos Proporcionais , Adulto Jovem
18.
PLoS Med ; 18(5): e1003620, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33939694

RESUMO

BACKGROUND: In patients with resectable colorectal liver metastases (CRLM), the role of pre- and postoperative systemic therapy continues to be debated. Previous studies have shown that circulating tumor DNA (ctDNA) analysis, as a marker of minimal residual disease, is a powerful prognostic factor in patients with nonmetastatic colorectal cancer (CRC). Serial analysis of ctDNA in patients with resectable CRLM could inform the optimal use of perioperative chemotherapy. Here, we performed a validation study to confirm the prognostic impact of postoperative ctDNA in resectable CRLM observed in a previous discovery study. METHODS AND FINDINGS: We prospectively collected plasma samples from patients with resectable CRLM, including presurgical and postsurgical samples, serial samples during any pre- or postoperative chemotherapy, and serial samples in follow-up. Via targeted sequencing of 15 genes commonly mutated in CRC, we identified at least 1 somatic mutation in each patient's tumor. We then designed a personalized assay to assess 1 mutation in plasma samples using the Safe-SeqS assay. A total of 380 plasma samples from 54 patients recruited from July 2011 to Dec 2014 were included in our analysis. Twenty-three (43%) patients received neoadjuvant chemotherapy, and 42 patients (78%) received adjuvant chemotherapy after surgery. Median follow-up was 51 months (interquartile range, 31 to 60 months). At least 1 somatic mutation was identified in all patients' tumor tissue. ctDNA was detectable in 46/54 (85%) patients prior to any treatment and 12/49 (24%) patients after surgery. There was a median 40.93-fold (19.10 to 87.73, P < 0.001) decrease in ctDNA mutant allele fraction with neoadjuvant chemotherapy, but ctDNA clearance during neoadjuvant chemotherapy was not associated with a better recurrence-free survival (RFS). Patients with detectable postoperative ctDNA experienced a significantly lower RFS (HR 6.3; 95% CI 2.58 to 15.2; P < 0.001) and overall survival (HR 4.2; 95% CI 1.5 to 11.8; P < 0.001) compared to patients with undetectable ctDNA. For the 11 patients with detectable postoperative ctDNA who had serial ctDNA sampling during adjuvant chemotherapy, ctDNA clearance was observed in 3 patients, 2 of whom remained disease-free. All 8 patients with persistently detectable ctDNA after adjuvant chemotherapy have recurred. End-of-treatment (surgery +/- adjuvant chemotherapy) ctDNA detection was associated with a 5-year RFS of 0% compared to 75.6% for patients with an undetectable end-of-treatment ctDNA (HR 14.9; 95% CI 4.94 to 44.7; P < 0.001). Key limitations of the study include the small sample size and the potential for false-positive findings with multiple hypothesis testing. CONCLUSIONS: We confirmed the prognostic impact of postsurgery and posttreatment ctDNA in patients with resected CRLM. The potential utility of serial ctDNA analysis during adjuvant chemotherapy as an early marker of treatment efficacy was also demonstrated. Further studies are required to define how to optimally integrate ctDNA analyses into decision-making regarding the use and timing of adjuvant therapy for resectable CRLM. TRIAL REGISTRATION: ACTRN12612000345886.


Assuntos
DNA Tumoral Circulante/sangue , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante/estatística & dados numéricos , Neoplasias Colorretais/diagnóstico , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Estudos Prospectivos , Risco , Resultado do Tratamento
19.
Nature ; 525(7568): 261-4, 2015 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-26308893

RESUMO

Most cancers in humans are large, measuring centimetres in diameter, and composed of many billions of cells. An equivalent mass of normal cells would be highly heterogeneous as a result of the mutations that occur during each cell division. What is remarkable about cancers is that virtually every neoplastic cell within a large tumour often contains the same core set of genetic alterations, with heterogeneity confined to mutations that emerge late during tumour growth. How such alterations expand within the spatially constrained three-dimensional architecture of a tumour, and come to dominate a large, pre-existing lesion, has been unclear. Here we describe a model for tumour evolution that shows how short-range dispersal and cell turnover can account for rapid cell mixing inside the tumour. We show that even a small selective advantage of a single cell within a large tumour allows the descendants of that cell to replace the precursor mass in a clinically relevant time frame. We also demonstrate that the same mechanisms can be responsible for the rapid onset of resistance to chemotherapy. Our model not only provides insights into spatial and temporal aspects of tumour growth, but also suggests that targeting short-range cellular migratory activity could have marked effects on tumour growth rates.


Assuntos
Movimento Celular , Variação Genética/genética , Modelos Biológicos , Neoplasias/genética , Neoplasias/patologia , Seleção Genética , Divisão Celular , Resistencia a Medicamentos Antineoplásicos/genética , Evolução Molecular , Humanos , Mutação/genética , Neoplasias/metabolismo , Fatores de Tempo
20.
Proc Natl Acad Sci U S A ; 115(8): 1871-1876, 2018 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-29432176

RESUMO

Aneuploidy is a feature of most cancer cells, and a myriad of approaches have been developed to detect it in clinical samples. We previously described primers that could be used to amplify ∼38,000 unique long interspersed nucleotide elements (LINEs) from throughout the genome. Here we have developed an approach to evaluate the sequencing data obtained from these amplicons. This approach, called Within-Sample AneupLoidy DetectiOn (WALDO), employs supervised machine learning to detect the small changes in multiple chromosome arms that are often present in cancers. We used WALDO to search for chromosome arm gains and losses in 1,677 tumors and in 1,522 liquid biopsies of blood from cancer patients or normal individuals. Aneuploidy was detected in 95% of cancer biopsies and in 22% of liquid biopsies. Using single-nucleotide polymorphisms within the amplified LINEs, WALDO concomitantly assesses allelic imbalances, microsatellite instability, and sample identification. WALDO can be used on samples containing only a few nanograms of DNA and as little as 1% neoplastic content and has a variety of applications in cancer diagnostics and forensic science.


Assuntos
Aneuploidia , Elementos Nucleotídeos Longos e Dispersos/genética , Neoplasias/genética , Aberrações Cromossômicas , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Técnicas de Amplificação de Ácido Nucleico/métodos
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