DoSurvive: A webtool for investigating the prognostic power of a single or combined cancer biomarker.

We present DoSurvive, a user-friendly survival analysis web tool and a cancer prognostic biomarker centered database. DoSurvive is the first database that allows users to perform multivariant survival analysis for cancers with customized gene/patient list. DoSurvive offers three survival analysis methods, Log rank test, Cox regression and accelerated failure time model (AFT), for users to analyze five types of quantitative features (mRNA, miRNA, lncRNA, protein and methylation of CpG islands) with four survival types, i.e. overall survival, disease-specific survival, disease-free interval, and progression-free interval, in 33 cancer types. Notably, the implemented AFT model provides an alternative method for genes/features which failed the proportional hazard assumption in Cox regression. With the unprecedented number of survival models implemented and high flexibility in analysis, DoSurvive is a unique platform for the identification of clinically relevant targets for cancer researcher and practitioners. DoSurvive is freely available at http://dosurvive.lab.nycu.edu.tw/.

HER3 targeting augments the efficacy of panobinostat in claudin-low triple-negative breast cancer cells.

Patients with triple-negative breast cancer (TNBC) have a poor prognosis and high relapse rate due to limited therapeutic options. This study was conducted to determine the mechanisms of action of panobinostat, a pan-inhibitor of histone deacetylase (HDAC) and FDA-approved medication for multiple myeloma, in TNBC and to provide a rationale for effective drug combinations against this aggressive disease. RNA sequencing analyses of the claudin-low (CL) TNBC (MDA-MB-231) cells untreated or treated with panobinostat were performed to identify the differentially expressed genes. Adaptive alterations in gene expression were analyzed and validated in additional CL TNBC cells. Tumor xenograft models were used to test the in vivo antitumor activity of panobinostat alone or its combinations with gefitinib, an EGFR-tyrosine kinase inhibitor (TKI). Panobinostat potently inhibited proliferation and induced apoptosis in all TNBC cells tested. However, in CL TNBC cells, this HDAC inhibitor markedly enhanced expression of HER3, which interacted with EGFR to activate both receptors and Akt signaling pathways. Combinations of panobinostat and gefitinib synergistically suppressed CL TNBC cell proliferation and promoted apoptosis in vitro and in vivo. Upregulation of HER3 compromises the efficacy of panobinostat in CL TNBC. Inactivation of HER3 combined with panobinostat represents a practical approach to combat CL TNBC.

Repurposing a plant alkaloid homoharringtonine targets insulinoma associated-1 in N-Myc-activated neuroblastoma.

High-risk neuroblastoma (NB) is a heterogeneous and malignant childhood cancer that is frequently characterized by MYCN proto-oncogene amplification or elevated N-Myc protein (N-Myc) expression. An N-Myc downstream target gene, insulinoma associated-1 (INSM1) has emerged as a biomarker that plays a critical role in facilitating NB tumor cell growth and transformation. N-Myc activates endogenous INSM1 gene expression through binding to the E2-box of the INSM1 proximal promoter in NB. We identified a plant alkaloid, homoharringtonine (HHT), from a chemical library screening showing potent inhibition of INSM1 promoter activity. This positive-hit plant alkaloid exemplifies an effective screening approach for repurposed compound targeting INSM1 expression in NB cancer therapy. The elevated N-Myc and INSM1 expression in NB constitutes a positive-loop through INSM1 activation that promotes N-Myc stability. In the present study, the biological effects and anti-tumor properties of HHT against NB were examined. HHT either down regulates and/or interferes with the binding of N-Myc to the E2-box of the INSM1 promoter and the inhibition of PI3K/AKT-mediated N-Myc stability could lead to the NB cell apoptosis. HHT inhibition of NB cell proliferation is consistent with the INSM1 expression as higher level of INSM1 exhibits a more sensitive IC50 value. The combination treatment of HHT and A674563 provides a better option of increasing potency and reducing cellular cytotoxicity than HHT or A674563 treatment alone. Taken together, the suppression of the INSM1-associated signaling pathway axis promotes the inhibition of NB tumor cell growth. This study developed a feasible approach for repurposing an effective anti-NB drug.

CpG Site-Based Signature Predicts Survival of Colorectal Cancer.

BACKGROUND: A critical unmet medical need in clinical management of colorectal cancer (CRC) pivots around lack of noninvasive and or minimally invasive techniques for early diagnosis and prognostic prediction of clinical outcomes. Because DNA methylation can capture the regulatory landscape of tumors and can be measured in body fluids, it provides unparalleled opportunities for the discovery of early diagnostic and prognostics markers predictive of clinical outcomes. Here we investigated use of DNA methylation for the discovery of potential clinically actionable diagnostic and prognostic markers for predicting survival in CRC. METHODS: We analyzed DNA methylation patterns between tumor and control samples to discover signatures of CpG sites and genes associated with CRC and predictive of survival. We conducted functional analysis to identify molecular networks and signaling pathways driving clinical outcomes. RESULTS: We discovered a signature of aberrantly methylated genes associated with CRC and a signature of thirteen (13) CpG sites predictive of survival. We discovered molecular networks and signaling pathways enriched for CpG sites likely to drive clinical outcomes. CONCLUSIONS: The investigation revealed that CpG sites can predict survival in CRC and that DNA methylation can capture the regulatory state of tumors through aberrantly methylated molecular networks and signaling pathways.

Integrating Genomic Information with Tumor-Immune Microenvironment in Triple-Negative Breast Cancer.

BACKGROUND: the development and progression of triple-negative breast cancer (TNBC) is driven by somatic driver mutations and the tumor-immune microenvironment. To date, data on somatic mutations has not been leveraged and integrated with information on the immune microenvironment to elucidate the possible oncogenic interactions and their potential effects on clinical outcomes. Here, we investigated possible oncogenic interactions between somatic mutations and the tumor-immune microenvironment, and their correlation with patient survival in TNBC. METHODS: We performed analysis combining data on 7,875 somatic mutated genes with information on 1,751 immune-modulated genes, using gene-expression data as the intermediate phenotype, and correlated the resulting information with survival. We conducted functional analysis to identify immune-modulated molecular networks and signaling pathways enriched for somatic mutations likely to drive clinical outcomes. RESULTS: We discovered differences in somatic mutation profiles between patients who died and those who survived, and a signature of somatic mutated immune-modulated genes transcriptionally associated with TNBC, predictive of survival. In addition, we discovered immune-modulated molecular networks and signaling pathways enriched for somatic mutations. CONCLUSIONS: The investigation revealed possible oncogenic interactions between somatic mutations and the tumor-immune microenvironment in TNBC, likely to affect clinical outcomes.

Landscape of Molecular Crosstalk Perturbation between Lung Cancer and COVID-19.

BACKGROUND: Lung cancer patients have the worst outcomes when affected by coronavirus disease 2019 (COVID-19). The molecular mechanisms underlying the association between lung cancer and COVID-19 remain unknown. The objective of this investigation was to determine whether there is crosstalk in molecular perturbation between COVID-19 and lung cancer, and to identify a molecular signature, molecular networks and signaling pathways shared by the two diseases. METHODS: We analyzed publicly available gene expression data from 52 severely affected COVID-19 human lung samples, 594 lung tumor samples and 54 normal disease-free lung samples. We performed network and pathways analysis to identify molecular networks and signaling pathways shared by the two diseases. RESULTS: The investigation revealed a signature of genes associated with both diseases and signatures of genes uniquely associated with each disease, confirming crosstalk in molecular perturbation between COVID-19 and lung cancer. In addition, the analysis revealed molecular networks and signaling pathways associated with both diseases. CONCLUSIONS: The investigation revealed crosstalk in molecular perturbation between COVID-19 and lung cancer, and molecular networks and signaling pathways associated with the two diseases. Further research on a population impacted by both diseases is recommended to elucidate molecular drivers of the association between the two diseases.

Diagnosis-to-surgery interval and survival for different histologies of stage I-IIA lung cancer.

BACKGROUND: Guidelines on timeliness of lung cancer surgery are inconsistent. Lung cancer histologic subtypes have different prognosis and treatment. It is important to understand the consequences of delayed surgery for each lung cancer histologic subtype. This study aimed to examine the association between diagnosis-to-surgery time interval and survival for early stage lung cancer and selected histologic subtypes. METHODS: Patients diagnosed with stage I-IIA lung cancer between 2004 and 2015 receiving definitive surgery and being followed up until Dec. 31, 2018, were identified from Surveillance, Epidemiology, and End Results database. Histologic subtypes included adenocarcinoma, squamous or epidermoid carcinoma, bronchioloalveolar carcinoma, large cell carcinoma, adenosquamous carcinoma, carcinoid carcinoma, and small cell carcinoma. Diagnosis-to-surgery interval was treated as multi-categorical variables (<1, 1-2, 2-3, and ≥3 months) and binary variables (≥1 vs. <1 month, ≥2 vs. <2 months, and ≥3 vs. <3 months). Outcomes included cancer-specific and overall survival. Covariates included age at diagnosis, sex, race, marital status, tumor size, grade, surgery type, chemotherapy, radiotherapy, and study period. Kaplan-Meier survival curves and Cox proportional hazards regression models were applied to examine the survival differences. RESULTS: With a median follow-up time of 51 months, a total of 40,612 patients were analyzed, including 40.1% adenocarcinoma and 24.5% squamous or epidermoid carcinoma. The proportion of patients receiving surgery <1, 1-2, 2-3, and ≥3 months from diagnosis were 34.2%, 33.9%, 19.8%, and 12.1%, respectively. Delayed surgery was associated with worse cancer-specific and overall survival for all lung cancers, adenocarcinoma, squamous or epidermoid, bronchioloalveolar, and large cell carcinoma (20-40% increased risk). Dose-dependent effects (longer delay, worse survival) were observed in all lung cancers, adenocarcinoma, and squamous and epidermoid carcinoma. No significant association between surgery delay and survival was observed in adenosquamous, carcinoid, and small cell carcinoma. CONCLUSIONS: Our findings support the guidelines of undertaking surgery within 1 month from diagnosis in patients with stage I-IIA lung cancer. The observed dose-dependent effects emphasize the clinical importance of early surgery. Future studies with larger sample size of less frequent histologic subtypes are warranted to provide more evidence for histology-specific lung cancer treatment guidelines.

Racial differences in the risk of second primary bladder cancer following radiation therapy among localized prostate cancer patients.

OBJECTIVES: To investigate the race-specific second primary bladder cancer (SPBC) risk following prostatic irradiation. METHODS: Louisiana residents who were diagnosed with localized prostate cancer (PCa) in 1996-2013 and received surgery or radiation were included. Patients were followed until SPBC diagnosis, death, or Dec. 2018. The exposure variable was type of treatment (radiation only vs. surgery only). The outcome was time from PCa diagnosis to SPBC diagnosis, stratified by race. Fine and Gray's competing risk model was applied with death as a competing event and adjustment of sociodemographic and tumor characteristics. We used 5 years and 10 years as lag time in the analyses. RESULTS: A total of 26,277 PCa patients with a median follow-up of 10.7 years were analyzed, including 18,598 white and 7679 black patients. About 42.9 % of whites and 45.7 % of blacks received radiation. SPBC counted for 1.84 % in the radiation group and 0.90 % in the surgery group among white patients and for 0.91 % and 0.58 %, respectively, among black patients. The adjusted subdistribution hazard ratio of SPBC was 1.80 (95 % CI: 1.30-2.48) for radiation recipients compared to surgery recipients among white patients; 1.93 (95 % CI: 1.36-2.74) if restricted to external beam radiation therapy (EBRT). The SPBC risk was not significantly different between irradiated and surgically treated among blacks. CONCLUSIONS: The SPBC risk is almost two-fold among white irradiated PCa patients compared to their counterparts treated surgically. Our findings highlight the need for enhanced surveillance for white PCa survivors receiving radiotherapy, especially those received EBRT.

Racial Disparity and Social Determinants in Receiving Timely Surgery Among Stage I-IIIA Non-small Cell Lung Cancer Patients in a U.S. Southern State.

Delayed surgery is associated with worse lung cancer outcomes. Social determinants can influence health disparities. This study aimed to examine the potential racial disparity and the effects from social determinants on receipt of timely surgery among lung cancer patients in Louisiana, a southern state in the U.S. White and black stage I-IIIA non-small cell lung cancer patients diagnosed in Louisiana between 2004 and 2016, receiving surgical lobectomy or a more extensive surgery, were selected. Diagnosis-to-surgery interval >6 weeks were considered as delayed surgery. Social determinants included marital status, insurance, census tract level poverty, and census tract level urbanicity. Multivariable logistic regression and generalized multiple mediation analysis were conducted. A total of 3,616 white (78.9%) and black (21.1%) patients were identified. The median time interval from diagnosis to surgery was 27 days in whites and 42 days in blacks (P < 0.0001). About 28.7% of white and 48.4% of black patients received delayed surgery (P < 0.0001). Black patients had almost two-fold odds of receiving delayed surgery than white patients (adjusted odds ratio: 1.91; 95% confidence interval: 1.59-2.30). Social determinants explained about 26% of the racial disparity in receiving delayed surgery. Having social support, private insurance, and living in census tracts with lower poverty level were associated with improved access to timely surgery. The census tract level poverty level a stronger effect on delayed surgery in black patients than in white patients. Tailored interventions to improve the timely treatment in NSCLC patients, especially black patients, are needed in the future.

Breast Cancer Type Classification Using Machine Learning.

BACKGROUND: Breast cancer is a heterogeneous disease defined by molecular types and subtypes. Advances in genomic research have enabled use of precision medicine in clinical management of breast cancer. A critical unmet medical need is distinguishing triple negative breast cancer, the most aggressive and lethal form of breast cancer, from non-triple negative breast cancer. Here we propose use of a machine learning (ML) approach for classification of triple negative breast cancer and non-triple negative breast cancer patients using gene expression data. METHODS: We performed analysis of RNA-Sequence data from 110 triple negative and 992 non-triple negative breast cancer tumor samples from The Cancer Genome Atlas to select the features (genes) used in the development and validation of the classification models. We evaluated four different classification models including Support Vector Machines, K-nearest neighbor, Naïve Bayes and Decision tree using features selected at different threshold levels to train the models for classifying the two types of breast cancer. For performance evaluation and validation, the proposed methods were applied to independent gene expression datasets. RESULTS: Among the four ML algorithms evaluated, the Support Vector Machine algorithm was able to classify breast cancer more accurately into triple negative and non-triple negative breast cancer and had less misclassification errors than the other three algorithms evaluated. CONCLUSIONS: The prediction results show that ML algorithms are efficient and can be used for classification of breast cancer into triple negative and non-triple negative breast cancer types.

Elucidation of the Genomic-Epigenomic Interaction Landscape of Aggressive Prostate Cancer.

BACKGROUND: Majority of prostate cancer (PCa) deaths are attributed to localized high-grade aggressive tumours which progress rapidly to metastatic disease. A critical unmet need in clinical management of PCa is discovery and characterization of the molecular drivers of aggressive tumours. The development and progression of aggressive PCa involve genetic and epigenetic alterations occurring in the germline, somatic (tumour), and epigenomes. To date, interactions between genes containing germline, somatic, and epigenetic mutations in aggressive PCa have not been characterized. The objective of this investigation was to elucidate the genomic-epigenomic interaction landscape in aggressive PCa to identify potential drivers aggressive PCa and the pathways they control. We hypothesized that aggressive PCa originates from a complex interplay between genomic (both germline and somatic mutations) and epigenomic alterations. We further hypothesized that these complex arrays of interacting genomic and epigenomic factors affect gene expression, molecular networks, and signaling pathways which in turn drive aggressive PCa. METHODS: We addressed these hypotheses by performing integrative data analysis combining information on germline mutations from genome-wide association studies with somatic and epigenetic mutations from The Cancer Genome Atlas using gene expression as the intermediate phenotype. RESULTS: The investigation revealed signatures of genes containing germline, somatic, and epigenetic mutations associated with aggressive PCa. Aberrant DNA methylation had effect on gene expression. In addition, the investigation revealed molecular networks and signalling pathways enriched for germline, somatic, and epigenetic mutations including the STAT3, PTEN, PCa, ATM, AR, and P53 signalling pathways implicated in aggressive PCa. CONCLUSIONS: The study demonstrated that integrative analysis combining diverse omics data is a powerful approach for the discovery of potential clinically actionable biomarkers, therapeutic targets, and elucidation of oncogenic interactions between genomic and epigenomic alterations in aggressive PCa.

Delineation of the Germline and Somatic Mutation Interaction Landscape in Triple-Negative and Non-Triple-Negative Breast Cancer.

BACKGROUND: Breast cancer development and progression involve both germline and somatic mutations. High-throughput genotyping and next-generation sequencing technologies have enabled discovery of genetic risk variants and acquired somatic mutations driving the disease. However, the possible oncogenic interactions between germline genetic risk variants and somatic mutations in triple-negative breast cancer (TNBC) and non-triple-negative breast cancer (non-TNBC) have not been characterized. Here, we delineated the possible oncogenic interactions between genes containing germline and somatic mutations in TNBC and non-TNBC and investigated whether there are differences in gene expression and mutation burden between the two types of breast cancer. METHODS: We addressed this problem by integrating germline mutation information from genome-wide association studies with somatic mutation information from next-generation sequencing using gene expression data as the intermediated phenotype. We performed network and pathway analyses to discover molecular networks and signalling pathways enriched for germline and somatic mutations. RESULTS: The investigation revealed signatures of differentially expressed and differentially somatic mutated genes between TNBC and non-TNBC. Network and pathway analyses revealed functionally related genes interacting in gene regulatory networks and multiple signalling pathways enriched for germline and somatic mutations for each type of breast cancer. Among the signalling pathways discovered included the DNA repair and Androgen and ATM signalling pathways for TNBC and the DNA damage response, molecular mechanisms of cancer, and ATM and GP6 signalling pathways for non-TNBC. CONCLUSIONS: The results show that integrative genomics is a powerful approach for delineating oncogenic interactions between genes containing germline and genes containing somatic mutations in TNBC and non-TNBC and establishes putative functional bridges between genetic and somatic alterations and the pathways they control in the two types of breast cancer.

Unraveling the Genomic-Epigenomic Interaction Landscape in Triple Negative and Non-Triple Negative Breast Cancer.

BACKGROUND: The recent surge of next generation sequencing of breast cancer genomes has enabled development of comprehensive catalogues of somatic mutations and expanded the molecular classification of subtypes of breast cancer. However, somatic mutations and gene expression data have not been leveraged and integrated with epigenomic data to unravel the genomic-epigenomic interaction landscape of triple negative breast cancer (TNBC) and non-triple negative breast cancer (non-TNBC). METHODS: We performed integrative data analysis combining somatic mutation, epigenomic and gene expression data from The Cancer Genome Atlas (TCGA) to unravel the possible oncogenic interactions between genomic and epigenomic variation in TNBC and non-TNBC. We hypothesized that within breast cancers, there are differences in somatic mutation, DNA methylation and gene expression signatures between TNBC and non-TNBC. We further hypothesized that genomic and epigenomic alterations affect gene regulatory networks and signaling pathways driving the two types of breast cancer. RESULTS: The investigation revealed somatic mutated, epigenomic and gene expression signatures unique to TNBC and non-TNBC and signatures distinguishing the two types of breast cancer. In addition, the investigation revealed molecular networks and signaling pathways enriched for somatic mutations and epigenomic changes unique to each type of breast cancer. The most significant pathways for TNBC were: retinal biosynthesis, BAG2, LXR/RXR, EIF2 and P2Y purigenic receptor signaling pathways. The most significant pathways for non-TNBC were: UVB-induced MAPK, PCP, Apelin endothelial, Endoplasmatic reticulum stress and mechanisms of viral exit from host signaling Pathways. CONCLUSION: The investigation revealed integrated genomic, epigenomic and gene expression signatures and signing pathways unique to TNBC and non-TNBC, and a gene signature distinguishing the two types of breast cancer. The study demonstrates that integrative analysis of multi-omics data is a powerful approach for unravelling the genomic-epigenomic interaction landscape in TNBC and non-TNBC.

Mapping the Germline and Somatic Mutation Interaction Landscape in Indolent and Aggressive Prostate Cancers.

BACKGROUND: A majority of prostate cancers (PCas) are indolent and cause no harm even without treatment. However, a significant proportion of patients with PCa have aggressive tumors that progress rapidly to metastatic disease and are often lethal. PCa develops through somatic mutagenesis, but emerging evidence suggests that germline genetic variation can markedly contribute to tumorigenesis. However, the causal association between genetic susceptibility and tumorigenesis has not been well characterized. The objective of this study was to map the germline and somatic mutation interaction landscape in indolent and aggressive tumors and to discover signatures of mutated genes associated with each type and distinguishing the two types of PCa. MATERIALS AND METHODS: We integrated germline mutation information from genome-wide association studies (GWAS) with somatic mutation information from The Cancer Genome Atlas (TCGA) using gene expression data from TCGA on indolent and aggressive PCas as the intermediate phenotypes. Germline and somatic mutated genes associated with each type of PCa were functionally characterized using network and pathway analysis. RESULTS: We discovered gene signatures containing germline and somatic mutations associated with each type and distinguishing the two types of PCa. We discovered multiple gene regulatory networks and signaling pathways enriched with germline and somatic mutations including axon guidance, RAR, WINT, MSP-RON, STAT3, PI3K, TR/RxR, and molecular mechanisms of cancer, NF-kB, prostate cancer, GP6, androgen, and VEGF signaling pathways for indolent PCa and MSP-RON, axon guidance, RAR, adipogenesis, and molecular mechanisms of cancer and NF-kB signaling pathways for aggressive PCa. CONCLUSION: The investigation revealed germline and somatic mutated genes associated with indolent and aggressive PCas and distinguishing the two types of PCa. The study revealed multiple gene regulatory networks and signaling pathways dysregulated by germline and somatic alterations. Integrative analysis combining germline and somatic mutations is a powerful approach to mapping germline and somatic mutation interaction landscape.

Deconvolution of the Genomic and Epigenomic Interaction Landscape of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer. Emerging evidenced suggests that both genetics and epigenetic factors play a role in the pathogenesis of TNBC. However, oncogenic interactions and cooperation between genomic and epigenomic variation have not been characterized. The objective of this study was to deconvolute the genomic and epigenomic interaction landscape in TNBC using an integrative genomics approach, which integrates information on germline, somatic, epigenomic and gene expression variation. We hypothesized that TNBC originates from a complex interplay between genomic (both germline and somatic variation) and epigenomic variation. We further hypothesized that these complex arrays of interacting genomic and epigenomic factors affect entire molecular networks and signaling pathways which, in turn, drive TNBC. We addressed these hypotheses using germline variation from genome-wide association studies and somatic, epigenomic and gene expression variation from The Cancer Genome Atlas (TCGA). The investigation revealed signatures of functionally related genes containing germline, somatic and epigenetic variations. DNA methylation had an effect on gene expression. Network and pathway analysis revealed molecule networks and signaling pathways enriched for germline, somatic and epigenomic variation, among them: Role of BRCA1 in DNA Damage Response, Hereditary Breast Cancer Signaling, Molecular Mechanisms of Cancer, Estrogen-Dependent Breast Cancer, p53, MYC Mediated Apoptosis, and PTEN Signaling pathways. The investigation revealed that integrative genomics is a powerful approach for deconvoluting the genomic-epigenomic interaction landscape in TNBC. Further studies are needed to understand the biological mechanisms underlying oncogenic interactions between genomic and epigenomic factors in TNBC.

Interactions between Germline and Somatic Mutated Genes in Aggressive Prostate Cancer.

Prostate cancer (PCa) is the most common diagnosed malignancy and the second leading cause of cancer-related deaths among men in the USA. Advances in high-throughput genotyping and next generation sequencing technologies have enabled discovery of germline genetic susceptibility variants and somatic mutations acquired during tumor formation. Emerging evidence indicates that germline variations may interact with somatic events in carcinogenesis. However, the possible oncogenic interactions and cooperation between germline and somatic variation and their role in aggressive PCa remain largely unexplored. Here we investigated the possible oncogenic interactions and cooperation between genes containing germline variation from genome-wide association studies (GWAS) and genes containing somatic mutations from tumor genomes of 305 men with aggressive tumors and 52 control samples from The Cancer Genome Atlas (TCGA). Network and pathway analysis were performed to identify molecular networks and biological pathways enriched for germline and somatic mutations. The analysis revealed 90 functionally related genes containing both germline and somatic mutations. Transcriptome analysis revealed a 61-gene signature containing both germline and somatic mutations. Network analysis revealed molecular networks of functionally related genes and biological pathways including P53, STAT3, NKX3-1, KLK3, and Androgen receptor signaling pathways enriched for germline and somatic mutations. The results show that integrative analysis is a powerful approach to uncovering the possible oncogenic interactions and cooperation between germline and somatic mutations and understanding the broader biological context in which they operate in aggressive PCa.

Integrating germline and somatic variation information using genomic data for the discovery of biomarkers in prostate cancer.

BACKGROUND: Prostate cancer (PCa) is the most common diagnosed malignancy and the second leading cause of cancer-related deaths among men in the United States. High-throughput genotyping has enabled discovery of germline genetic susceptibility variants (herein referred to as germline mutations) associated with an increased risk of developing PCa. However, germline mutation information has not been leveraged and integrated with information on acquired somatic mutations to link genetic susceptibility to tumorigenesis. The objective of this exploratory study was to address this knowledge gap. METHODS: Germline mutations and associated gene information were derived from genome-wide association studies (GWAS) reports. Somatic mutation and gene expression data were derived from 495 tumors and 52 normal control samples obtained from The Cancer Genome Atlas (TCGA). We integrated germline and somatic mutation information using gene expression data. We performed enrichment analysis to discover molecular networks and biological pathways enriched for germline and somatic mutations. RESULTS: We discovered a signature of 124 genes containing both germline and somatic mutations. Enrichment analysis revealed molecular networks and biological pathways enriched for germline and somatic mutations, including, the PDGF, P53, MYC, IGF-1, PTEN and Androgen receptor signaling pathways. CONCLUSION: Integrative genomic analysis links genetic susceptibility to tumorigenesis in PCa and establishes putative functional bridges between the germline and somatic variation, and the biological pathways they control.

Integrating Germline and Somatic Mutation Information for the Discovery of Biomarkers in Triple-Negative Breast Cancer.

Recent advances in high-throughput genotyping and the recent surge of next generation sequencing of the cancer genomes have enabled discovery of germline mutations associated with an increased risk of developing breast cancer and acquired somatic mutations driving the disease. Emerging evidence indicates that germline mutations may interact with somatic mutations to drive carcinogenesis. However, the possible oncogenic interactions and cooperation between germline and somatic alterations in triple-negative breast cancer (TNBC) have not been characterized. The objective of this study was to investigate the possible oncogenic interactions and cooperation between genes containing germline and somatic mutations in TNBC. Our working hypothesis was that genes containing germline mutations associated with an increased risk developing breast cancer also harbor somatic mutations acquired during tumorigenesis, and that these genes are functionally related. We further hypothesized that TNBC originates from a complex interplay among and between genes containing germline and somatic mutations, and that these complex array of interacting genetic factors affect entire molecular networks and biological pathways which in turn drive the disease. We tested this hypothesis by integrating germline mutation information from genome-wide association studies (GWAS) with somatic mutation information on TNBC from The Cancer Genome Atlas (TCGA) using gene expression data from 110 patients with TNBC and 113 controls. We discovered a signature of 237 functionally related genes containing both germline and somatic mutations. We discovered molecular networks and biological pathways enriched for germline and somatic mutations. The top pathways included the hereditary breast cancer and role of BRCA1 in DNA damage response signaling pathways. In conclusion, this is the first large-scale and comprehensive analysis delineating possible oncogenic interactions and cooperation among and between genes containing germline and somatic mutations in TNBC. Genetic and somatic mutations, along with the genes discovered in this study, will require experimental functional validation in different ethnic populations. Functionally validated genetic and somatic variants will have important implications for the development of novel precision prevention strategies and discovery of prognostic markers in TNBC.

Whole Genome Transcriptome Analysis of the Association between Obesity and Triple-Negative Breast Cancer in Caucasian Women.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer, with poor outcomes. The molecular basis of TNBC remains poorly understood. The objective of this exploratory study was to investigate the association between obesity and TNBC in premenopausal and postmenopausal Caucasian women using transcription profiling. METHODS: We compared gene expression levels of tumor samples drawn from normal weight, overweight, and obese pre and postmenopausal women diagnosed with TNBC. We performed hierarchical clustering to assess similarity in patterns of gene expression profiles, and conducted network and pathway analysis to identify molecular networks and biological pathways. RESULTS: We discovered gene signatures distinguishing normal weight from obese, normal weight from overweight, and overweight from obese individuals in both premenopausal and postmenopausal women. The analysis revealed molecular networks and biological pathways associating obesity with TNBC. The discovered pathways included the unfolded protein response, endoplasmic reticulum stress, B cell receptor, and autophagy signaling pathways in obese premenopausal women; and the integrin, axonal guidance, ERK/MAPK (extracellular-signal-regulated kinase/mitogen activated protein kinase) and glutathione biosynthesis signaling pathways in obese postmenopausal women. CONCLUSIONS: The results suggest that both overweight and obese status are associated with TNBC, highlighting the need for conformation of these results in independent studies.

Seasonality in the adverse outcomes in weight loss surgeries.

BACKGROUND: Weight loss surgery is a common procedure in the United States. OBJECTIVE: As weight loss surgery is largely an elective procedure for which patients and physicians can choose the timing, it could be helpful to explore the seasonality pattern of its perioperative adverse outcomes to help decide the timing of this surgery. SETTING: United States. METHODS: We used an obese adult sample (age ≥20 yr) of patients who underwent weight loss surgeries from the Premier Healthcare Database from 2011 to 2014. The International Classification of Diseases, Ninth Revision Clinical Modification procedure codes were used to identify weight loss surgery cases. Binary variables are used for 4 adverse outcomes, including hospital mortality, sepsis, deep vein thrombosis (DVT), and pulmonary embolism. The associations between the adverse outcomes and season of surgery were examined using logistic regressions, adjusting for age, sex, race, marital status, surgery types, body mass index, the Charlson co-morbidity index, and region. RESULTS: A total of 69,365 weight loss surgeries were identified for the analytic sample. The overall rate was .27% for hospital mortality, .16% for DVT, .10% for pulmonary embolism, and .20% for sepsis. For DVT, adjusted odds ratio for the fall was 2.68 (95% confidence interval: 1.39-5.19) and the odds ratio for the winter was 2.26 (95% confidence interval: 1.09-4.27) compared with the summer. For sepsis, adjusted odds ratio for the spring was 1.83 (95% confidence interval: 1.07-3.12) compared with that of the summer. The seasonality pattern was not statistically significant for hospital mortality and pulmonary embolism. CONCLUSION: DVT and sepsis are more likely to occur in colder seasons compared with the summer season, although the crude rates of these adverse events were low.