Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Δευτέρα 30 Μαΐου 2016
Weighted gene co-expression network analysis reveals key genes involved in pancreatic ductal adenocarcinoma development
Abstract
Purpose
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy. Up till now, the patient's prognosis remains poor which, among others, is due to the paucity of reliable early diagnostic biomarkers. In the past, candidate diagnostic biomarkers and therapeutic targets have been delineated from genes that were found to be differentially expressed in normal versus tumour samples. Recently, new systems biology approaches have been developed to analyse gene expression data, which may yield new biomarkers. As of yet, the weighted gene co-expression network analysis (WGCNA) tool has not been applied to PDAC microarray-based gene expression data.
Methods
PDAC microarray-based gene expression datasets, listed in the Gene Expression Omnibus (GEO) database, were analysed. After pre-processing of the data, we built two final datasets, Normal and PDAC, encompassing 104 and 129 patient samples, respectively. Next, we constructed a weighted gene co-expression network and identified modules of co-expressed genes distinguishing normal from disease conditions. Functional annotations of the genes in these modules were carried out to highlight PDAC-associated molecular pathways and common regulatory mechanisms. Finally, overall survival analyses were carried out to assess the suitability of the genes identified as prognostic biomarkers.
Results
Using WGCNA, we identified several key genes that may play important roles in PDAC. These genes are mainly related to either endoplasmic reticulum, mitochondrion or membrane functions, exhibit transferase or hydrolase activities and are involved in biological processes such as lipid metabolism or transmembrane transport. As a validation of the applied method, we found that some of the identified key genes (CEACAM1, MCU, VDAC1, CYCS, C15ORF52, TMEM51, LARP1 and ERLIN2) have previously been reported by others as potential PDAC biomarkers. Using overall survival analyses, we found that several of the newly identified genes may serve as biomarkers to stratify PDAC patients into low- and high-risk groups.
Conclusions
Using this new systems biology approach, we identified several genes that appear to be critical to PDAC development. As such, they may represent potential diagnostic biomarkers as well as therapeutic targets with clinical utility.
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Genomic Characterization of High-Grade Serous Ovarian Cancer: Dissecting Its Molecular Heterogeneity as a Road Towards Effective Therapeutic Strategies
Abstract
High-grade serous ovarian carcinoma (HGSOC) accounts for the majority of the ovarian cancer deaths, but over the last years little improvement in overall survival has been achieved. HGSOC is a molecularly and clinically heterogeneous disease. At genomic level, it represents a C-class malignancy having frequent gene losses (NF1, RB1, PTEN) and gains (CCNE1, MYC). HGSOC shows a simple mutational profile with TP53 nearly always mutated and with other genes mutated at low frequency. Importantly, 50 % of all HGSOCs have genetic features indicating a homologous recombination (HR) deficiency. HR deficient tumors are highly sensitive to PARP inhibitor anticancer agents, which exhibit synthetic lethality with a defective HR pathway. Transcriptionally, HGSOCs can be grouped into different molecular subtypes with distinct biology and prognosis. Molecular stratification of HGSOC based on these genomic features may result in improved therapeutic strategies.
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Anomalous origin of the left coronary artery from the pulmonary artery in children: diagnostic use of multidetector computed tomography
Abstract
Background
Anomalous origin of the left coronary artery from the pulmonary artery is a rare congenital anomaly. It is important to demonstrate the anomalous origin of the left coronary artery and its course before surgery.
Objective
To explore the clinical diagnostic use of multidetector CT coronary angiography in detecting anomalous origin of the left coronary artery from the pulmonary artery in children.
Materials and methods
Nine children (2 boys, 7 girls) ages 2 months to 9 years with surgically confirmed anomalous origin of the left coronary artery from the pulmonary artery were studied. Clinical data, transthoracic echocardiography and CT coronary angiography images were retrospectively analyzed.
Results
Transthoracic echocardiography correctly diagnosed anomalous origin of the left coronary artery from the pulmonary artery in 7 of 9 patients (95% CI: 40–97%). CT coronary angiography revealed the anomalous origin of the left coronary artery in all children (95% CI: 66–100%). In a 4-year-old girl and a 9-year-old girl, CT coronary angiography showed dilation of the right coronary artery and collateral circulation between the right and the left coronary arteries.
Conclusion
CT coronary angiography is a useful method to show the anomalous origin of the coronary artery in children with anomalous origin of the left coronary artery from the pulmonary artery, especially for patients in whom origin of the left coronary artery cannot be detected by transthoracic echocardiography.
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Weighted gene co-expression network analysis reveals key genes involved in pancreatic ductal adenocarcinoma development
Abstract
Purpose
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy. Up till now, the patient's prognosis remains poor which, among others, is due to the paucity of reliable early diagnostic biomarkers. In the past, candidate diagnostic biomarkers and therapeutic targets have been delineated from genes that were found to be differentially expressed in normal versus tumour samples. Recently, new systems biology approaches have been developed to analyse gene expression data, which may yield new biomarkers. As of yet, the weighted gene co-expression network analysis (WGCNA) tool has not been applied to PDAC microarray-based gene expression data.
Methods
PDAC microarray-based gene expression datasets, listed in the Gene Expression Omnibus (GEO) database, were analysed. After pre-processing of the data, we built two final datasets, Normal and PDAC, encompassing 104 and 129 patient samples, respectively. Next, we constructed a weighted gene co-expression network and identified modules of co-expressed genes distinguishing normal from disease conditions. Functional annotations of the genes in these modules were carried out to highlight PDAC-associated molecular pathways and common regulatory mechanisms. Finally, overall survival analyses were carried out to assess the suitability of the genes identified as prognostic biomarkers.
Results
Using WGCNA, we identified several key genes that may play important roles in PDAC. These genes are mainly related to either endoplasmic reticulum, mitochondrion or membrane functions, exhibit transferase or hydrolase activities and are involved in biological processes such as lipid metabolism or transmembrane transport. As a validation of the applied method, we found that some of the identified key genes (CEACAM1, MCU, VDAC1, CYCS, C15ORF52, TMEM51, LARP1 and ERLIN2) have previously been reported by others as potential PDAC biomarkers. Using overall survival analyses, we found that several of the newly identified genes may serve as biomarkers to stratify PDAC patients into low- and high-risk groups.
Conclusions
Using this new systems biology approach, we identified several genes that appear to be critical to PDAC development. As such, they may represent potential diagnostic biomarkers as well as therapeutic targets with clinical utility.
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Prevalence of Germline Mutations in the Spindle Assembly Checkpoint Gene BUB1B in Individuals with Early-Onset Colorectal Cancer
ABSTRACT
Germline mutations in BUB1B, encoding BUBR1, one of the crucial components of the spindle assembly checkpoint (SAC), have been shown to cause variable phenotypes, including the recessive mosaic variegated aneuploidy (MVA) syndrome, which predisposes to cancer. Reduced levels of the wild-type BUBR1 protein have been linked to the development of gastrointestinal neoplasms. To determine whether mutations in BUB1B are enriched in individuals with colorectal cancer (CRC), we performed amplicon-based targeted next-generation sequencing of BUB1B on germline DNA of 192 individuals with early-onset CRC (≤50 years). None of the individuals was found to be homozygous or compound heterozygous for mutations in BUB1B. However, we did identify two rare heterozygous variants, p.Glu390del and p.Cys945Tyr, in patients who developed CRC at the ages of 41 and 43 years, respectively. Both variants were shown not to affect BUBR1 protein expression levels and protein localization. Since the p.Glu390del variant is located in the BUB3-binding domain, we also performed immunoprecipitation to examine whether this variant affects the binding of BUB1 or BUB3 to BUBR1 but, compared to wild-type BUBR1, no difference was observed. Our data suggest that mutations in BUB1B do not occur frequently in the germline of individuals with CRC and that BUB1B unlikely plays a major role in the predisposition to early-onset CRC. Whether carriers of pathogenic BUB1B mutations, such as the parents of MVA syndrome patients, have an increased risk for cancer remains of interest, as studies in mice have suggested that haploinsufficiency of BUB1B may cause an increase in carcinogen-induced tumours. This article is protected by copyright. All rights reserved.
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Modeling the Efficacy of the Extent of Surgical Resection in the Setting of Radiation Therapy for GBM
Summary
Standard therapy for GBM includes maximal surgical resection and radiation therapy. While it is established that radiation therapy provides the greatest survival benefit of standard treatment modalities, the impact of the extent of surgical resection (EOR) on patient outcome remains highly controversial. While some studies describe no correlation between EOR and patient survival even up to total resection, others propose either qualitative (partial vs subtotal vs complete resection) or quantitative EOR thresholds, below which there is no correlation with survival. This work uses a mathematical model in the form of a reaction-diffusion partial differential equation to simulate tumor growth and treatment with radiation therapy and surgical resection based on tumor-specific rates of diffusion and proliferation. Simulation of 36 tumors across a wide spectrum of diffusion and proliferation rates suggests that while partial or subtotal resections generally do not provide a survival advantage, complete resection significantly improves patient outcomes. Furthermore, our model predicts a tumor-specific quantitative threshold below which EOR has no effect on patient survival and demonstrates that this threshold increases with tumor aggressiveness, particularly with the rate of proliferation. Thus, this model may serve as an aid for determining both when surgical resection is indicated as well as the surgical margins necessary to provide clinically significant improvements in patient survival. Additionally, by assigning relative benefits to radiation and surgical resection based on tumor invasiveness and proliferation, this model confirms that (with the exception of the least aggressive tumors) the survival benefit of radiation therapy exceeds that of surgical resection.
This article is protected by copyright. All rights reserved.
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Sensitivities to various EGFR-TKIs of uncommon EGFR mutations L861Q and S768I: what is the optimal EGFR-TKI?
Summary
Most patients with non-small cell lung cancer (NSCLC) harboring common epidermal growth factor receptor (EGFR) mutations, such as deletions in exon 19 or the L858R mutation in exon 21, respond dramatically to EGFR tyrosine kinase inhibitors (EGFR-TKIs), and their sensitivities to various EGFR-TKIs have been well characterized. Our previous article showed the in vitro sensitivities of EGFR exon 18 mutations to EGFR-TKIs, but little information regarding the sensitivities of other uncommon EGFR mutations is available. First, stable transfectant Ba/F3 cell lines harboring EGFR L858R (Ba/F3-L858R), L861Q (Ba/F3-L861Q) or S768I (Ba/F3-S768I) mutations were created and their drug sensitivities to various EGFR-TKIs were examined. Both the Ba/F3-L861Q and Ba/F3-S768I cell lines were less sensitive to erlotinib, compared with the Ba/F3-L858R cell line, but their sensitivities to afatinib were similar to that of the Ba/F3-L858R cell line. The Ba/F3-L861Q cell line was similarly sensitive and the Ba/F3-S768I cell line was less sensitive to osimertinib, compared with the Ba/F3-L858R cell line. The results of western blot analyses were consistent with these sensitivities. Next, similar experiments were also performed using the KYSE270 (L861Q) and KYSE 450 (S768I) cell lines, and their results were compatible with those of the transfectant Ba/F3 cell lines. Our findings suggest that NSCLC harboring the EGFR L861Q mutation might be sensitive to afatinib or osimertinib and that NSCLC harboring the EGFR S768I mutation might be sensitive to afatinib. Overall, afatinib might be the optimal EGFR-TKI against these uncommon EGFR mutations.
This article is protected by copyright. All rights reserved.
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Regulation of H-Ras-driven MAPK signaling, transformation and tumorigenesis, but not PI3K signaling and tumor progression, by plasma membrane microdomains
Regulation of H-Ras-driven MAPK signaling, transformation and tumorigenesis, but not PI3K signaling and tumor progression, by plasma membrane microdomains
Oncogenesis 5, e228 (May 2016). doi:10.1038/oncsis.2016.36
Authors: J V Michael, J G T Wurtzel & L E Goldfinger
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Dietary fat overcomes the protective activity of thrombospondin-1 signaling in the ApcMin/+ model of colon cancer
Dietary fat overcomes the protective activity of thrombospondin-1 signaling in the ApcMin/+ model of colon cancer
Oncogenesis 5, e230 (May 2016). doi:10.1038/oncsis.2016.37
Authors: D R Soto-Pantoja, J M Sipes, G Martin-Manso, B Westwood, N L Morris, A Ghosh, N J Emenaker & D D Roberts
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An ANCCA/PRO2000-miR-520a-E2F2 regulatory loop as a driving force for the development of hepatocellular carcinoma
An ANCCA/PRO2000-miR-520a-E2F2 regulatory loop as a driving force for the development of hepatocellular carcinoma
Oncogenesis 5, e229 (May 2016). doi:10.1038/oncsis.2016.22
Authors: J Huang, J Yang, Y Lei, H Gao, T Wei, L Luo, F Zhang, H Chen, Q Zeng & L Guo
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PTEN negatively regulates mTORC2 formation and signaling in grade IV glioma via Rictor hyperphosphorylation at Thr1135 and direct the mode of action of an mTORC1/2 inhibitor
PTEN negatively regulates mTORC2 formation and signaling in grade IV glioma via Rictor hyperphosphorylation at Thr1135 and direct the mode of action of an mTORC1/2 inhibitor
Oncogenesis 5, e227 (May 2016). doi:10.1038/oncsis.2016.34
Authors: K Bhattacharya, S Maiti & C Mandal
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Migration and invasion is inhibited by silencing ROR1 and ROR2 in chemoresistant ovarian cancer
Migration and invasion is inhibited by silencing ROR1 and ROR2 in chemoresistant ovarian cancer
Oncogenesis 5, e226 (May 2016). doi:10.1038/oncsis.2016.32
Authors: C E Henry, E Llamosas, A Djordjevic, N F Hacker & C E Ford
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Cancer negatively impacts on sexual function in adolescents and young adults: The Aya Hope study
Abstract
Objective
This cohort study examined the impact of cancer on sexual function and intimate relationships in adolescents and young adults (AYAs). We also explored factors predicting an increased likelihood that cancer had negatively affected these outcomes.
Methods
Participants (n = 465, ages 15-39) in the Adolescent and Young Adult Health Outcomes and Patient Experience (AYA HOPE) study completed two surveys approximately 1 and 2 years post cancer diagnosis. We used multivariable logistic regression to determine factors negatively affected by perceptions of sexual function at 2 years post-diagnosis.
Results
Forty-nine percent of AYAs reported negative effects on sexual function at one year post cancer diagnosis and 70% of those persisted in their negative perceptions two years after diagnosis. Those reporting a negative impact at two years were more likely to be 25 years or older (OR, 2.53; 95% CI, 1.44-4.42), currently not raising children (OR, 1.81; 95% CI, 1.06-3.08), experiencing fatigue (OR, .99; 95% CI, .975-.998) and more likely to report that their diagnosis has had a negative effect on physical appearance (OR, 3.08; 95% CI, 1.97-4.81). Clinical factors and mental health were not significant predictors of negative effects on sexual function.
Conclusions
Many AYAs diagnosed with cancer experience a persistent negative impact on sexual life up to two years following diagnosis. The findings underscore the need to develop routine protocols to assess sexual function in AYAs with cancer and to provide comprehensive management in the clinical setting. This article is protected by copyright. All rights reserved.
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Initial Testing (Stage 1) of MK-8242—A Novel MDM2 Inhibitor—by the Pediatric Preclinical Testing Program
Background
MK-8242 is an inhibitor of MDM2 that stabilizes the tumor suppressor TP53 and induces growth arrest or apoptosis downstream of TP53 induction.
Procedures
MK-8242 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro cell line panel at concentrations from 1.0 nM to 10.0 μM and against the PPTP in vivo xenograft panels using oral gavage on Days 1–5 and Day 15–19 at a dose of 125 mg/kg (solid tumors) or 75 mg/kg (acute lymphoblastic leukemia [ALL] models).
Results
The median IC50 for MK-8242 was 0.07 μM for TP53 wild-type cell lines versus >10 μM for TP53 mutant cell lines. MK-8242 induced a twofold or greater delay in time to event in 10 of 17 (59%) of TP53 wild-type solid tumor xenografts, excluding osteosarcoma xenografts that have very low TP53 expression. Objective responses were observed in seven solid tumor xenografts representing multiple histotypes. For the systemic-disease ALL panel, among eight xenografts there were two complete responses (CRs) and six partial responses (PRs). Two additional MLL-rearranged xenografts (MV4;11 and RS4;11) grown subcutaneously showed maintained CR and PR, respectively. The expected pharmacodynamic responses to TP53 activation were observed in TP53 wild-type models treated with MK-8242. Pharmacokinetic analysis showed that MK-8242 drug exposure in SCID mice appears to exceed that was observed in adult phase 1 trials.
Conclusions
MK-8242-induced tumor regressions across multiple solid tumor histotypes and induced CRs or PRs for most ALL xenografts. This activity was observed at MK-8242 drug exposures that appear to exceed those observed in human phase 1 trials.
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Prevalence of Helicobacter pylori Infection in Patients with Squamous Cell Carcinoma of the Oesophagus. A Descriptive Case Series Study
Abstract
Introduction
Helicobacter pylori is an important causative factor in gastric carcinogenesis; its role in extra-gastric gastrointestinal malignancies such as oesophageal cancer is controversial. H. pylori is thought to cause extensive gastric atrophy associated with squamous cell carcinoma of the oesophagus. We conducted a study to determine the prevalence of H. pylori infection in patients with squamous cell carcinoma of the oesophagus.
Method
We collected biopsies from the antrum and corpus of 59 patients with confirmed squamous cell carcinoma of the oesophagus, two from each area. These were then examined by an experienced histopathologist using methylene blue staining for the presence of H. pylori.
Results
H. pylori was found in 30 (51 %) of the patients, a prevalence similar to that of the general population in South Africa. Five patients were found to have associated intestinal metaplasia, and all but two had chronic inflammation.
Conclusion
The prevalence of H. pylori in our patients with squamous cell carcinoma of the oesophagus is 51 %, similar to that previously reported in the general population.
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Defining the optimal timing of adjuvant therapy for resected pancreatic adenocarcinoma: A statewide cancer registry analysis
Background
Long-term results of the ESPAC-3 trial suggest that while completing adjuvant therapy (AT) is necessary after resection of pancreatic ductal adenocarcinoma (PDAC), early initiation (within 8 weeks) may not be associated with improved overall survival (OS). The primary aim of this study was to evaluate the OS impact of early versus late AT in a statewide analysis.
Methods
Patients with stages I–III PDAC in the Kentucky Cancer Registry (KCR) from 2004 to 2013, were evaluated. Those undergoing pancreatectomy were stratified into two groups ("early," <8 weeks, vs. "late," 8–16 weeks).
Results
Of 2,221 diagnosed patients with stages I–III, 831 (37.4%) underwent pancreatectomy upfront. Of these, only 420 (50.5%) received AT. Initiation date of AT was not associated with OS (median OS: early, 20.2 vs. late, 19.0 months, P = 0.97). On multivariate analysis, factors that affected OS included stage (II, HR-1.82, P = 0.017; III, HR-3.77, P < 0.001), node positivity (HR-1.51, P = 0.004), poorly/undifferentiated grade (HR-1.34; P = 0.011), but not AT initiation date.
Conclusions
In this statewide analysis, there was no difference in OS between early and late AT initiation for resected PDAC. The ideal window for AT initiation remains unknown as tumor biology continues to trump regimens from the past decade. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.
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Intralesional PV-10 for in-transit melanoma—A single-center experience
Background and Objectives
Patients with in-transit melanoma metastasis have longer median survival than patients with distant metastatic disease. Furthermore, local disease control is an important endpoint for symptom management. The treatment of unresectable loco-regional recurrence or in-transit disease has been historically managed with a combination of treatments including surgery, radiotherapy, isolated limb infusion or perfusion as well as systemic therapies. Intralesional PV-10 has been used at Peter MacCallum Cancer Centre since 2010, and the current report presents a retrospective analysis of patient outcomes, reporting the response rates, durability of responses, and observed toxicities.
Methods
Records were analyzed retrieving details of 19 patients treated with PV-10 over a 4-year period from 2010 to 2014. Medical records were reviewed for these patients and data extracted.
Results
Nineteen patients with in-transit melanoma were treated with intralesional PV-10 between 2010 and 2014. Disease control (complete or partial response or disease stability) was achieved in 68% of patients with 26% having a complete response. This was achieved with minimal associated toxicity.
Conclusions
PV-10 is an effective, durable, well-tolerated treatment tool with an acceptable side effect profile for the management of unresectable in-transit melanoma. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.
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Patterns of major wound complications following multidisciplinary therapy for lower extremity soft tissue sarcoma
Background and Objectives
The purpose of this study was to determine the pattern and timing of major wound complications (MWCs) in patients at our institution who received multimodality treatment for lower extremity soft tissue sarcoma (LE-STS) and to evaluate the impact of MWCs on tumor control and patient outcomes.
Methods
The medical records of 102 LE-STS patients treated with limb-sparing surgery and radiation therapy were reviewed. MWCs were defined as secondary operations with anesthesia, seroma/hematoma aspiration, admission for IV antibiotics, or persistent deep packing.
Results
MWCs occurred in 22% of patients, with 45% of events occurring >120 days after resection. On multivariate analysis, preoperative external beam radiation therapy (EBRT) (OR 4.29, 95% CI 1.06–17.40, P = 0.042) and skin graft placement (OR 6.39, 95% CI 1.37–29.84, P = 0.018) were found to be independent predictors of MWCs. MWC occurrence did not predict for chronic toxicity and did not impact tumor control or survival.
Conclusions
A considerable proportion of MWCs occur >120 days from surgical resection with preoperative EBRT and skin graft placement independent predictors for MWCs. While an additional source of morbidity, MWC occurrence did not impact tumor control, nor did it predict for chronic toxicity. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.
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