RESUMO
Importance: Surgery currently offers the only chance for a cure in pancreatic ductal adenocarcinoma (PDAC), but it carries a significant morbidity and mortality risk and results in varying oncologic outcomes. At present, to our knowledge, there are no tests available before surgical resection to identify tumors with an aggressive biological phenotype that could guide personalized treatment strategies. Objective: Identification of noninvasive genetic biomarkers that could direct therapy in patients whose cases are amenable to pancreatic cancer resection. Design, Setting, and Participants: This multicenter study combined a prospective European cohort of patients with PDAC who underwent pancreatic resection (from University Hospital of Zurich, Zurich, Switzerland; Cantonal Hospital of Winterthur, Winterthur, Switzerland; and University Clinic of Ulm, Ulm, Germany) with data from the Cancer Genome Atlas database in the United States, which includes prospectively registered patients with PDAC. A genome-wide screening for functional single-nucleotide polymorphisms (SNPs) that affect PDAC survival was conducted using the European cohort for identification and the Cancer Genome Atlas cohort for validation. We used Cox proportional hazards models to screen for high-frequency polymorphic variants that are associated with allelic differences in tumor-associated survival and either result in an altered protein structure and function or reside in known regulatory noncoding genomic regions. The false-discovery rate method was applied for multiple hypothesis-testing corrections. Data analysis occurred from November 2017 to May 2018. Exposures: Pancreatic resection. Main Outcomes and Measures: Tumor-associated survival. Results: A total of 195 patients in the European cohort were included, as well as 136 patients in the Cancer Genome Atlas cohort (overall median [range] age, 66 [19-87] years; 156 [47.1%] were women, and 175 [52.9%] were men). Two SNPs in noncoding, functional regions of genes that regulate cancer progression, invasion, and metastasis were identified (CHI3L2 SNP rs684559 and CD44 SNP rs353630). These were associated with survival after PDAC resection; patients who carry the risk alleles at 1 of both SNP loci had a 2.63-fold increased risk for tumor-associated death compared with those with protective genotypes (hazard ratio for survival, 0.38 [95% CI, 0.27-0.53]; P = 1.0 × 10-8). Conclusions and Relevance: The identified polymorphisms may serve as a noninvasive biomarker signature of prospective survival after pancreatic resection that is readily available at the time of PDAC diagnosis. This signature can be used to identify a subset of high-risk patients with PDAC with very low survival probability who might be eligible for inclusion in clinical trials of new therapeutic strategies, including neoadjuvant chemotherapy protocols. In addition, the biological knowledge about these SNPs could help guide the development of individualized genomic strategies for PDAC therapies.
Assuntos
Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/diagnóstico , Tomada de Decisões , Estudo de Associação Genômica Ampla/métodos , Pancreatectomia , Neoplasias Pancreáticas/diagnóstico , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/cirurgia , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Detecção Precoce de Câncer , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/cirurgia , Estudos Retrospectivos , Adulto JovemRESUMO
Conventional high-grade osteosarcoma is the most common primary bone malignancy. Although altered expression of the p53 inhibitor HDMX (Mdmx/Mdm4) is associated with cancer risk, progression, and outcome in other tumor types, little is known about its role in osteosarcoma. High expression of the Hdmx splice variant HDMX-S relative to the full-length transcript (the HDMX-S/HDMX-FL ratio) correlates with reduced HDMX protein expression, faster progression, and poorer survival in several cancers. Here, we show that the HDMX-S/HDMX-FL ratio positively correlates with less HDMX protein expression, faster metastatic progression, and a trend to worse overall survival in osteosarcomas. We found that the HDMX-S/HDMX-FL ratio associated with common somatic genetic lesions connected with p53 inhibition, such as p53 mutation and HDM2 overexpression in osteosarcoma cell lines. Interestingly, this finding was not limited to osteosarcomas as we observed similar associations in breast cancer and a variety of other cancer cell lines, as well as in tumors from patients with soft tissue sarcoma. The HDMX-S/HDMX-FL ratio better defined patients with sarcoma with worse survival rates than p53 mutational status. We propose a novel role for alternative splicing of HDMX, whereby it serves as a mechanism by which HDMX protein levels are reduced in cancer cells that have already inhibited p53 activity. Alternative splicing of HDMX could, therefore, serve as a more effective biomarker for p53 pathway attenuation in cancers than p53 gene mutation.
Assuntos
Neoplasias Ósseas/genética , Genes p53 , Mutação , Proteínas Nucleares/genética , Osteossarcoma/genética , Proteínas Proto-Oncogênicas/genética , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Processamento Alternativo , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Neoplasias Ósseas/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/biossíntese , Osteossarcoma/metabolismo , Prognóstico , Isoformas de Proteínas , Proteínas Proto-Oncogênicas/biossíntese , Proteína Supressora de Tumor p53/antagonistas & inibidores , Adulto JovemRESUMO
PURPOSE: Finding markers or gene sets that would further classify patients into different risk categories and thus allow more individually adapted multimodality treatment regimens in soft tissue sarcomas is necessary. In this study, we investigated the prognostic values of hypoxia-inducible factor 1a (HIF1a), heparin-binding epidermal growth factor-like growth factor (HB-EGF), vascular endothelial growth factor (VEGF), and other angiogenesis-related gene expressions, as well as their interrelationships. EXPERIMENTAL DESIGN: Formalin-fixed paraffin-embedded tissue samples were obtained from 45 patients with soft tissue sarcoma (median age 57 years, range 16-85 years). After laser capture microdissection direct quantitative real-time reverse transcription-PCR (TaqMan) assays were done in triplicates to determine HIF1a, HB-EGF, VEGF, and other gene expression levels. RESULTS: Multivariate Cox [corrected] regression analysis revealed significant independent associations of HB-EGF, HIF1a, and VEGF-C gene expression to the overall survival (P < 0.0001). A combined factor of these three genes showed a relative risk for shorter survival of 5.5, more than twice higher as in an increasing International Union against Cancer Stage. Receiver operating characteristic curve analysis showed a significant sensitivity of 73% and specificity of 82% of this factor for the diagnosis of short (<3 years) versus long (3-9 years) survival (P = 0.0002). VEGF-A showed significant gender differences in the association to survival. CONCLUSIONS: Measuring HIF1a, HB-EGF, and VEGF-C expression may contribute to a better understanding of the prognosis of patients with soft tissue sarcoma and may even play a crucial role for the distribution of patients to multimodal therapeutic regimens. Prospective studies investigating the response to different adjuvant or palliative therapies seem to be warranted.
Assuntos
Perfilação da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Sarcoma/genética , Fator C de Crescimento do Endotélio Vascular/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Regulação Neoplásica da Expressão Gênica , Fator de Crescimento Semelhante a EGF de Ligação à Heparina , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Prognóstico , Sarcoma/diagnóstico , Sarcoma/mortalidade , Sensibilidade e Especificidade , Análise de Sobrevida , Adulto JovemRESUMO
Gastrointestinal stromal tumors (GISTs) are characterized by alterations in genes involved in cell cycle regulation. Although p16 (INK4A) have been extensively investigated in GISTs, there are still discrepancies regarding its prognostic value. Therefore, we evaluated the clinical occurrence, diagnostic and prognostic value of p16 staining in GIST. One hundred one patients (54 women and 47 men) with a mean age of 64.1 years (range, 17-94 years) were surgically treated for a GIST within a 10-year period. Of these patients, 28 (28%) were affected by metastases (mean follow-up, 4.5 years). In 36 patients (36%), GIST occurred coincidentally with other malignancies. Expression of c-kit was confirmed in 97 GIST patients (96%). In patients with high-risk GIST, the expression of p16 expression was highly predictive for poor prognosis, i.e., the development of recurrence or metastases (P = .006) and poor survival (P = .004). In addition, the expression of p16 was highly predictive for reduction of the survival in patients who were affected by metastases or recurrence (P = .041). The disease-specific and disease-free 1-, 3-, and 5-year survival rate was 96%, 90%, and 85% and 81%, 77%, and 72%, respectively. Primary tumor state, tumor size, and high-risk classification were confirmed as relevant predictors for unfavorable prognosis in GIST (P < .001). Our results indicate that in high-risk GIST and in patients with recurrence or metastases, the expression of p16 is highly predictive for poor outcome. Thus, in addition to high-risk classification, p16 expression might be an indicator for "very high risk GIST."
Assuntos
Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/genética , Genes p16 , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Diagnóstico Diferencial , Feminino , Tumores do Estroma Gastrointestinal/mortalidade , Tumores do Estroma Gastrointestinal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Metástase Neoplásica , Valor Preditivo dos Testes , Prognóstico , Recidiva , Fatores de Risco , Adulto JovemRESUMO
The coincidence of a gastrointestinal stromal tumor (GIST) and a neuroendocrine tumor (NET) in neurofibromatosis type 1 (NF1) is described only five times within the literature. We report on a 63 year old Caucasian female with the rare condition of neurofibromatosis type 1 coinciding with recurrent gastrointestinal stromal tumor plus bilateral pheochromocytoma (PCC). After a history of palpitations and dizziness that lasted for years, a left adrenal mass was detected by CT. Laparotomy revealed a pheochromocytoma of the left adrenal gland while an ileoterminal GIST was found incidentally intraoperatively. After six months contralateral PCC and multiple recurrent GIST were resected again. After four years the patient is doing well without any signs of further recurrent tumors. Discussion includes review of the literature.
Assuntos
Neoplasias das Glândulas Suprarrenais/patologia , Tumores do Estroma Gastrointestinal/patologia , Neoplasias Primárias Múltiplas/patologia , Neurofibromatose 1/patologia , Feocromocitoma/patologia , Feminino , Tumores do Estroma Gastrointestinal/etiologia , Humanos , Pessoa de Meia-Idade , Neurofibromatose 1/complicaçõesRESUMO
The importance of the p53 stress response pathway in the suppression of tumor formation is well documented. In a previous report, a single nucleotide polymorphism (SNP309 T/G) was found in the promoter of the MDM2 gene resulting in higher levels of MDM2 RNA and protein and, consequently, in the attenuation of the p53 pathway both in vitro and in vivo. As the SNP309 locus is found in a region of the MDM2 promoter, which is regulated by hormonal signaling pathways, and the G-allele of SNP309 increases the affinity of a well-described cotranscriptional activator of nuclear hormone receptors (i.e., Sp1), the hypothesis that the SNP309 locus could alter the effects of hormones on tumorigenesis was tested in vivo in humans. Data obtained from patients with three different sporadic cancers, from four independent case studies, support this hypothesis, providing an example for the genetic basis of gender differences in cancer and showing that the genotype at a specific locus can affect how hormones, like estrogen, affect tumorigenesis in humans.
Assuntos
Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Linfoma de Células B/genética , Linfoma Difuso de Grandes Células B/genética , Neoplasias Hormônio-Dependentes/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , Sarcoma/genética , Adolescente , Adulto , Fatores Etários , Idoso , Alelos , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Estudos de Casos e Controles , Feminino , Humanos , Linfoma de Células B/patologia , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Hormônio-Dependentes/patologia , Polimorfismo de Nucleotídeo Único , Sarcoma/patologiaRESUMO
PURPOSE: Esophageal perforation (EP) is still associated with a high mortality rate, even after surgical repair. We reviewed 17 cases of EP to evaluate the management of this major surgical problem. METHODS: We reviewed the medical records of all patients treated for EP in our department between November 2001 and November 2004. Therapy was based on various patient-related factors. RESULTS: Seventeen patients, with a mean age of 63 years, presented with EP mostly caused by iatrogenic incidents (11/17). In nine patients, the perforation was located in the thoracic segment, with a mean size of 2.5 +/- 0.6 cm. Thoracic computed tomography (CT) was performed in all patients to assess the periesophageal inflammation precisely. More than 50% showed signs of systemic inflammation indicative of sepsis, reflected by a dramatic increase in serum C-reactive protein and leukocytosis. Treatment consisted of debridement and drainage (n = 3), primary repair (n = 3), reinforced repair (n = 4), esophageal resection (n = 5), and conservative measures (n = 2). All patients, except for three with pre-existing liver dysfunction and other comorbidities, survived, representing a mortality rate of 17.6% (14/17). An analysis of the literature (2000-2005) revealed an overall mortality rate of 19.7% (101/521), ranging from 3% to 67%. CONCLUSION: Our data support the individualized surgical management of EP, based on careful evaluation of various patient-related factors, including CT findings.
Assuntos
Perfuração Esofágica/diagnóstico , Esôfago/cirurgia , Doença Iatrogênica , Adulto , Idoso , Perfuração Esofágica/cirurgia , Esôfago/lesões , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de RiscoRESUMO
The tumor suppressor p53 gene is mutated in minimally half of all cancers. It is therefore reasonable to assume that naturally occurring polymorphic genetic variants in the p53 stress response pathway might determine an individual's susceptibility to cancer. A central node in the p53 pathway is the MDM2 protein, a direct negative regulator of p53. In this report, a single nucleotide polymorphism (SNP309) is found in the MDM2 promoter and is shown to increase the affinity of the transcriptional activator Sp1, resulting in higher levels of MDM2 RNA and protein and the subsequent attenuation of the p53 pathway. In humans, SNP309 is shown to associate with accelerated tumor formation in both hereditary and sporadic cancers. A model is proposed whereby SNP309 serves as a rate-limiting event in carcinogenesis.