RESUMO
The five discussions of our paper provide several modeling alternatives, extensions, and generalizations that can potentially guide future research in meta-analysis. In this rejoinder, we briefly summarize and comment on some of those points.
Assuntos
Metanálise como Assunto , Neoplasias , Penetrância , Humanos , Neoplasias/epidemiologia , Modelos Estatísticos , Medição de Risco/estatística & dados numéricos , Predisposição Genética para DoençaRESUMO
Strategies for early detection and interception of cancer are based on 2 synergistic elements: proactive search for asymptomatic cancer, precancer, or cancer predisposition and proactive disruption of cancer evolution. Benefits and harms of both these elements will vary widely depending on the screened populations, the types of cancers targeted, the detection modalities, and the health care delivery approaches following diagnosis. This article attempts to identify common elements that can inform the evaluation of alternative strategies across many of these scenarios.
Assuntos
Detecção Precoce de Câncer , Neoplasias , Humanos , Neoplasias/diagnóstico , Neoplasias/terapia , Programas de Rastreamento/métodosRESUMO
The natural history of multiple myeloma is characterized by its localization to the bone marrow and its interaction with bone marrow stromal cells. The bone marrow stromal cells provide growth and survival signals, thereby promoting the development of drug resistance. Here, we show that the interaction between bone marrow stromal cells and myeloma cells (using human cell lines) induces chromatin remodeling of cis-regulatory elements and is associated with changes in the expression of genes involved in the cell migration and cytokine signaling. The expression of genes involved in these stromal interactions are observed in extramedullary disease in patients with myeloma and provides the rationale for survival of myeloma cells outside of the bone marrow microenvironment. Expression of these stromal interaction genes is also observed in a subset of patients with newly diagnosed myeloma and are akin to the transcriptional program of extramedullary disease. The presence of such adverse stromal interactions in newly diagnosed myeloma is associated with accelerated disease dissemination, predicts the early development of therapeutic resistance, and is of independent prognostic significance. These stromal cell induced transcriptomic and epigenomic changes both predict long-term outcomes and identify therapeutic targets in the tumor microenvironment for the development of novel therapeutic approaches.
Assuntos
Montagem e Desmontagem da Cromatina , Regulação Neoplásica da Expressão Gênica , Células-Tronco Mesenquimais , Mieloma Múltiplo , Microambiente Tumoral , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Mieloma Múltiplo/metabolismo , Humanos , Microambiente Tumoral/genética , Linhagem Celular Tumoral , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Transcrição Gênica , Células da Medula Óssea/metabolismo , Movimento Celular/genética , Células Estromais/metabolismo , Células Estromais/patologia , Feminino , MasculinoRESUMO
Multi-gene panel testing allows many cancer susceptibility genes to be tested quickly at a lower cost making such testing accessible to a broader population. Thus, more patients carrying pathogenic germline mutations in various cancer-susceptibility genes are being identified. This creates a great opportunity, as well as an urgent need, to counsel these patients about appropriate risk-reducing management strategies. Counseling hinges on accurate estimates of age-specific risks of developing various cancers associated with mutations in a specific gene, ie, penetrance estimation. We propose a meta-analysis approach based on a Bayesian hierarchical random-effects model to obtain penetrance estimates by integrating studies reporting different types of risk measures (eg, penetrance, relative risk, odds ratio) while accounting for the associated uncertainties. After estimating posterior distributions of the parameters via a Markov chain Monte Carlo algorithm, we estimate penetrance and credible intervals. We investigate the proposed method and compare with an existing approach via simulations based on studies reporting risks for two moderate-risk breast cancer susceptibility genes, ATM and PALB2. Our proposed method is far superior in terms of coverage probability of credible intervals and mean square error of estimates. Finally, we apply our method to estimate the penetrance of breast cancer among carriers of pathogenic mutations in the ATM gene.
Assuntos
Teorema de Bayes , Predisposição Genética para Doença , Penetrância , Humanos , Predisposição Genética para Doença/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Neoplasias da Mama/genética , Feminino , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Simulação por Computador , Cadeias de Markov , Neoplasias/genética , Neoplasias/epidemiologia , Proteínas Supressoras de Tumor/genética , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Método de Monte Carlo , Metanálise como Assunto , Mutação em Linhagem Germinativa , Modelos EstatísticosRESUMO
BACKGROUND: Pancreatic adenocarcinoma (PC) is a highly lethal malignancy with a survival rate of only 12%. Surveillance is recommended for high-risk individuals (HRIs), but it is not widely adopted. To address this unmet clinical need and drive early diagnosis research, we established the Pancreatic Cancer Early Detection (PRECEDE) Consortium. METHODS: PRECEDE is a multi-institutional international collaboration that has undertaken an observational prospective cohort study. Individuals (aged 18-90 years) are enrolled into 1 of 7 cohorts based on family history and pathogenic germline variant (PGV) status. From April 1, 2020, to November 21, 2022, a total of 3,402 participants were enrolled in 1 of 7 study cohorts, with 1,759 (51.7%) meeting criteria for the highest-risk cohort (Cohort 1). Cohort 1 HRIs underwent germline testing and pancreas imaging by MRI/MR-cholangiopancreatography or endoscopic ultrasound. RESULTS: A total of 1,400 participants in Cohort 1 (79.6%) had completed baseline imaging and were subclassified into 3 groups based on familial PC (FPC; n=670), a PGV and FPC (PGV+/FPC+; n=115), and a PGV with a pedigree that does not meet FPC criteria (PGV+/FPC-; n=615). One HRI was diagnosed with stage IIB PC on study entry, and 35.1% of HRIs harbored pancreatic cysts. Increasing age (odds ratio, 1.05; P<.001) and FPC group assignment (odds ratio, 1.57; P<.001; relative to PGV+/FPC-) were independent predictors of harboring a pancreatic cyst. CONCLUSIONS: PRECEDE provides infrastructure support to increase access to clinical surveillance for HRIs worldwide, while aiming to drive early PC detection advancements through longitudinal standardized clinical data, imaging, and biospecimen captures. Increased cyst prevalence in HRIs with FPC suggests that FPC may infer distinct biological processes. To enable the development of PC surveillance approaches better tailored to risk category, we recommend adoption of subclassification of HRIs into FPC, PGV+/FPC+, and PGV+/FPC- risk groups by surveillance protocols.
Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/epidemiologia , Detecção Precoce de Câncer/métodos , Estudos Prospectivos , Predisposição Genética para Doença , Imageamento por Ressonância MagnéticaRESUMO
Multigene panel testing now allows efficient testing of many cancer susceptibility genes leading to a larger number of mutation carriers being identified. They need to be counseled about their cancer risk conferred by the specific gene mutation. An important cancer susceptibility gene is PALB2. Multiple studies reported risk estimates for breast cancer (BC) conferred by pathogenic variants in PALB2. Due to the diverse modalities of reported risk estimates (age-specific risk, odds ratio, relative risk, and standardized incidence ratio) and effect sizes, a meta-analysis combining these estimates is necessary to accurately counsel patients with this mutation. However, this is not trivial due to heterogeneity of studies in terms of study design and risk measure. We utilized a recently proposed Bayesian random-effects meta-analysis method that can synthesize estimates from such heterogeneous studies. We applied this method to combine estimates from 12 studies on BC risk for carriers of pathogenic PALB2 mutations. The estimated overall (meta-analysis-based) risk of BC is 12.80% (6.11%-22.59%) by age 50 and 48.47% (36.05%-61.74%) by age 80. Pathogenic mutations in PALB2 makes women more susceptible to BC. Our risk estimates can help clinically manage patients carrying pathogenic variants in PALB2.