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bioRxiv2018

PIK3C2B promotes epithelial to mesenchymal transition and EGFR inhibitors insensitivity in epidermal squamous cell carcinoma.

While the class I of PI3Ks has been deeply studied due to its clear implication in cancer development, little is known about the class II of PI3Ks. However, recent accumulation of data is now revealing that PI3KC2{beta}, one isoform of this class of PI3Ks, may also play a role in cancer. Specifically, recent studies have suggested an implication of PI3KC2{beta} in metastasis formation through the promotion of epithelial to mesenchymal transition (EMT). Here, we report that the overexpression of PI3KC2{beta} in the epidermal squamous cell carcinoma (ESCC) cells A431 promotes apparent EMT transformation. We further confirm this EMT by showing modification in several biochemical markers (E-cadherin, {beta}-catenin, Snail, Twist1 and Vimentin). Furthermore, an intracellular co-localization of E-cadherin, {beta}-catenin and EGFR was observed. This transformation decreased EGFR signaling and the sensitivity to inhibitors targeting this receptor. To confirm our results, we have used the colon adenocarcinoma cells HT29 and induced overexpression of PI3KC2{beta} in these cells. We could recapitulate in this model some of our major findings regarding EMT in the PI3KC2{beta} overexpressing A431 cells. Taken together, these data support a role of PI3KC2{beta} in promoting EMT.

cancer biology↗

bioRxiv2018

Drosophila Hox genes induce melanised pseudo-tumours when misexpressed in hemocytes

Homeotic genes are the key early determinants of cell identity along the anterior-posterior body axis across bilaterians. More recently, however, several late non-homeotic functions of hox genes have emerged in a variety of organogenesis processes, including in mammals. Being crucial factors in determining cell identity and organogenesis, the misregulation of hox genes is likely to be associated with defects in these processes. Several studies have reported misexpression of hox genes in a variety of malignancies including acute myeloid leukaemia. Considering that Drosophila is a well-established model for the study of haematopoiesis, we ectopically expressed the hox genes, Dfd, Ubx, abd-A and Abd-B, to ask if and how it will alter the process of haematopoiesis. We observed black melanised spots circulating in the viscera of the larvae and extensive lethality at during the pupal stage in these conditions. Such abnormalities are the hallmark of dysregulated haematopoiesis. We also observed an increase in blood cell number as well as their enhanced differentiation into lamellocytes. Our study opens a new possibility of addressing the function hox genes in normal and leukemogenic hematopoiesis with potential implications in downstream targets for diagnostic markers and therapy.\n\nSummaryDrosophila Hox genes, when expressed in blood cells, are leukemogenic, induce cell autonomous proliferation and differentiation. This reinforces previous studies in vertebrates and allows for Hox induced leukaemia to be studied in Drosophila.

cancer biology↗

bioRxiv2018

Profiling of urine bacterial DNA to identify an oncobiome in a mouse model of bladder cancer

IntroductionRecurrent urinary tract infections have been linked to increased risk of bladder cancer, suggesting a potential role of the urinary microbiome in bladder cancer pathogenesis.\n\nObjectiveCompare the urinary microbiomes in mice with and without bladder.\n\nMethodsLongitudinal study of mice exposed to a dilute bladder-specific carcinogen (0.05% n-butyl-n-(4-hydroxybutyl) nitrosamine, BBN mice, n=10), and control mice (n=10). Urine was sampled monthly from individual mice for 4 months. Microbial DNA was extracted from the urine, and the V4 region of the 16S rRNA gene sequenced. Animals were sacrificed and their bladders harvested for histopathology. Bladder sections were graded by a blinded pathologist. The composition and diversity of the urinary microbiome were compared between the BBN and control mice. Metabolic pathway analysis was completed using PICRUST.\n\nResultsBladder histology in the BBN group showed normal tissue with inflammation (BBN-normal, n=5), precancerous pathologies, (BBN-precancerous, n=3), and invasive cancer (BBN-cancer, n=2). Alpha diversity did not differ between the mice exposed to BBN and the control mice at any timepoint. There were no differences in the urinary microbiomes between the BBN and control mice at baseline. At month 4, mice exposed to BBN had higher proportion of both Gardnerella and Bifidobacterium compared to control mice. There were no differences in proportions of specific bacteria between either the BBN-precancer or BBN-cancer and controls at month 4. However, the BBN-normal mice had higher proportions of Gardnerella, Haemophilus, Bifidobacterium, and Ureaplasma Actinobaculum, and lower proportions of Actinomyces, compared to control mice at month 4. Functional pathway analysis demonstrated increases in genes related to purine metabolism, phosphotransferase systems, peptidases, protein folding, and bacterial toxins in the BBN-mice compared to control mice at month 4.\n\nConclusionMice exposed to 4 months of BBN, a bladder-specific carcinogen, have distinct urine microbial profiles compared to control mice.

cancer biology↗

bioRxiv2018

Lineage tracing of Notch1-expressing cells in intestinal tumours reveals a distinct population of cancer stem cells.

Colon tumours are hierarchically organized and contain multipotent self-renewing cells, called Cancer Stem Cells (CSCs). We have previously shown that the Notch1 receptor is expressed in Intestinal Stem Cells (ISCs); given the critical role played by Notch signalling in promoting intestinal tumourigenesis, we explored Notch1 expression in tumours. Combining lineage tracing in two tumour models with transcriptomic analyses, we found that Notch1 + tumour cells are undifferentiated, proliferative and capable of indefinite self-renewal and of generating a heterogeneous clonal progeny. Molecularly, the transcriptional signature of Notch1+ tumour cells highly correlates with ISCs, suggestive of their origin from normal crypt cells. Surprisingly, Notch1+ expression labels a subset of CSCs that show reduced levels of Lgr5, a reported CSCs marker. The existence of distinct stem cell populations within intestinal tumours highlights the necessity of better understanding their hierarchy and behaviour, to identify the correct cellular targets for therapy.

cancer biology↗

bioRxiv2018

Analysis of head and neck carcinoma progression reveals novel and relevant stage-specific genetic changes associated with immortalisation and malignancy.

Head and neck squamous cell carcinoma (HNSCC) is a widely prevalent cancer globally with high mortality and morbidity. We report here changes in the genomic landscape in the development of HNSCC from potentially premalignant lesions (PPOLS) to malignancy and lymph node metastases. Frequent likely pathological mutations are restricted to a relatively small set of genes including TP53, CDKN2A, FBXW7, FAT1, NOTCH1 and KMT2D; these arise early in tumour progression and are present in PPOLs with NOTCH1 mutations restricted to cell lines from lesions that subsequently progressed to HNSCC. The most frequent genetic changes are of consistent somatic copy number alterations (SCNA). The earliest SCNAs involved deletions of CSMD1 (8p23.2), FHIT (3p14.2) and CDKN2A (9p21.3) together with gains of chromosome 20. CSMD1 deletions or promoter hypermethylation were present in all of the immortal PPOLs and occurred at high frequency in the immortal HNSCC cell lines (promoter hypermethylation ~63%, hemizygous deletions ~75%, homozygous deletions ~18%). Forced expression of CSMD1 in the HNSCC cell line H103 showed significant suppression of proliferation (p=0.0053) and invasion in vitro (p=5.98X10-5) supporting a role for CSMD1 inactivation in early head and neck carcinogenesis. In addition, knockdown of CSMD1 in the CSMD1-expressing BICR16 cell line showed significant stimulation of invasion in vitro (p=1.82 x 10-5) but not cell proliferation (p=0.239). HNSCC with and without nodal metastases showed some clear differences including high copy number gains of CCND1, hsa-miR-548k and TP63 in the metastases group. GISTIC peak SCNA regions showed significant enrichment (adj P<0.01) of genes in multiple KEGG cancer pathways at all stages with disruption of an increasing number of these involved in the progression to lymph node metastases. Sixty-seven genes from regions with statistically significant differences in SCNA/LOH frequency between immortal PPOL and HNSCC cell lines showed correlation with expression including 5 known cancer drivers.\n\nLay SummaryCancers affecting the head and neck region are relatively common. A large percentage of these are of one particular type; these are generally detected late and are associated with poor prognosis. Early detection and treatment dramatically improve survival and reduces the damage associated with the cancer and its treatment. Cancers arise and progress because of changes in the genetic material of the cells. This study focused on identifying such changes in these cancers particularly in the early stages of development, which are not fully known. Identification of these changes is important in developing new treatments as well as markers of behaviour of cancers and also the early or premalignant lesions. We used a well-characterised panel of cell lines generated from premalignant lesions as well as cancers, to identify mutations in genes, and an increase or decrease in number of copies of genes. We mapped new and previously identified changes in these cancers to specific stages in the development of these cancers and their spread. We additionally report here for the first time, alterations in CSMD1 gene in early premalignant lesions; we further show that this is likely to result in increased ability of the cells to spread and possibly, multiply faster as well.

cancer biology↗

bioRxiv2018

Design, optimization and validation of genes commonly used in expression studies on DMH/AOM rat colon carcinogenesis model

Colorectal cancer (CRC), also known as colon cancer, is the third most common form of cancer worldwide in men and the second in women and is characterized by several genetic alterations, among them the expression of several genes. 1,2-dimethylhydrazine (DMH) and its metabolite azoxymethane (AOM) are procarcinogens commonly used to induce colon cancer in rats (DMH/AOM rat model). This rat model has been used to study changes in mRNA expression in genes involved in this pathological condition. However, a lack of proper detailed PCR primer design in the literature limits the reproducibility of the published data.\n\nThe present study aims to design, optimize and validate the qPCR, in accordance with the MIQE (Minimum Information for Publication of Quantitative Real-Time PCR Experiments) guidelines, for seventeen genes commonly used in the DMH/AOM rat model of CRC (Apc, Aurka, Bax, Bcl2, {beta}-catenin, Ccnd1, Cdnk-1A, Cox2, Gsk3beta, IL-33, iNOs, Nrf2, p53, RelA, Smad4, Tnfa and Vegfa) and two reference genes (Actb or {beta}-actin and B2m). The specificity of all primer pairs was empirically validated on agarose gel, and furthermore, the melting curve inspection was checked as was their efficiency (%) ranging from 90 to 110 with a correlation coefficient of r2 > 0.980. Finally, a pilot study was performed to compare the robustness of two candidate reference genes.

cancer biology↗

bioRxiv2018

Integrative data analysis predicts YY1 as a Cis-regulator in the 3D Cell Culture Models of MCF10A at the Stiffness Level of High Mammographic Density

Previous studies have shown that in 3D cell culture models of human mammary cells (HMEC) (i) colony organizations are heterogeneous, and (ii) ERBB2 is overexpressed in MCF10A when the stiffness of the microenvironment is increased to that of high mammographic density (MD). The goal of the current study is to identify transcription factors that regulate processes associated with the increased stiffness of the microenvironment. Two HMEC premalignant lines of MCF7 and 184A1 are cultured in 3D, colonies are imaged using confocal microscopy, and colony organizations and heterogeneity are quantified as a function of the stiffness of the microenvironment. In parallel and surrogate assays, colony organizations are profiled by transcriptomics. Transcriptome data are enriched by correlative analysis with the computed morphometric indices, from 3D culture, and a subset of transcriptome data is selected. This subset is then processed with Model-based Analysis of Regulation of Gene Expression (MARGE) and publicly available ChIP-seq data to predict regulatory transcription factors. The integrative analysis indicated that YY1 regulates ERBB2 in the 3D cell culture of MCF10A when the stiffness of the microenvironment is increased to that of high MD. Subsequent experimental validation confirmed that YY1 is only expressed at the high stiffness value of the microenvironment concomitant with the overexpression of ERBB2 in MCF10A. Furthermore, using ERBB2 positive SKBR3 cell line, co-expression of YY1 and ERBB2 is absent, which indicates that YY1 regulates tumorigenicity through multiple pathways.\n\nAuthors summaryMCF10A is a premalignant immortalized human mammary cell that has been isolated from a patient with fibrocystic and lost several barriers toward transformation. In an earlier study, we showed that ERBB2 is upregulated in 3D cultures of MCF10A when the stiffness of the microenvironment is increased to that of high mammographic density. Here, we leverage publicly available ChIP-seq data to predict and validate the cis-regulator of ERBB2. Our integrated experimental and computation protocol provides a pathway for elucidating regulators that can potentially be targeted for intervention.

cancer biology↗

bioRxiv2018

Long non-coding RNAs defining major subtypes of B cell precursor acute lymphoblastic leukemia

Recent studies implicated that long non-coding RNAs (lncRNAs) may play a role in the progression and development of acute lymphoblastic leukemia, however, this role is not yet clear. In order to unravel the role of lncRNAs associated with B-cell precursor Acute Lymphoblastic Leukemia (BCP-ALL) subtypes, we performed transcriptome sequencing and DNA methylation array across 82 BCP-ALL samples from three molecular subtypes (DUX4, Ph-like, and Near Haploid or High Hyperdiploidy). Unsupervised clustering of BCP-ALL samples on the basis of their lncRNAs on transcriptome and DNA methylation profiles revealed robust clusters separating three molecular subtypes. Using extensive computational analysis, we developed a comprehensive catalog of 1235 aberrantly dysregulated BCP-ALL subtype-specific lncRNAs with altered expression and methylation patterns from three subtypes of BCP-ALL. By analyzing the co-expression of subtype-specific lncRNAs and protein-coding genes, we inferred key molecular processes in BCP-ALL subtypes. A strong correlation was identified between the DUX4 specific lncRNAs and activation of TGF-{beta} and Hippo signaling pathways. Similarly, Ph-like specific lncRNAs were correlated with genes involved in activation of PI3K-AKT, mTOR, and JAK-STAT signaling pathways. Interestingly, the relapse-specific differentially expressed lncRNAs correlated with the activation of metabolic and signaling pathways. Finally, we showed a set of epigenetically altered lncRNAs facilitating the expression of tumor genes located at their cis location. Overall, our study provides a comprehensive set of novel subtype and relapse-specific lncRNAs in BCP-ALL. Our findings suggest a wide range of molecular pathways are associated with lncRNAs in BCP-ALL subtypes and provide a foundation for functional investigations that could lead to new therapeutic approaches.\n\nAuthor SummaryAcute lymphoblastic leukemia is a heterogeneous blood cancer, with multiple molecular subtypes, and with high relapse rate. We are far from the complete understanding of the rationale behind these subtypes and high relapse rate. Long non-coding (lncRNAs) has emerged as a novel class of RNA due to its diverse mechanism in cancer development and progression. LncRNAs does not code for proteins and represent around 70% of human transcripts. Recently, there are a number of studies used lncRNAs expression profile in the classification of various cancers subtypes and displayed their correlation with genomic, epigenetic, pathological and clinical features in diverse cancers. Therefore, lncRNAs can account for heterogeneity and has independent prognostic value in various cancer subtypes. However, lncRNAs defining the molecular subtypes of BCP-ALL are not portrayed yet. Here, we describe a set of relapse and subtype-specific lncRNAs from three major BCP-ALL subtypes and define their potential functions and epigenetic regulation. Our data uncover the diverse mechanism of action of lncRNAs in BCP-ALL subtypes defining how lncRNAs are involved in the pathogenesis of disease and the relevance in the stratification of BCP-ALL subtypes.

cancer biology↗

bioRxiv2018

FAM35A co-operates with REV7 to coordinate DNA double-strand break repair pathway choice.

DNA double-strand breaks (DSBs) can be repaired by two major pathways: non-homologous end-joining (NHEJ) and homologous recombination (HR). DNA repair pathway choice is governed by the opposing activities of 53BP1, in complex with its effectors RIF1 and REV7, and BRCA1. However, it remains unknown how the 53BP1/RIF1/REV7 complex stimulates NHEJ and restricts HR to the S/G2 phases of the cell cycle. Using a mass spectrometry (MS)-based approach, we identify 11 high-confidence REV7 interactors and elucidate the role of a previously undescribed factor, FAM35A/SHDL2, as a novel effector of REV7 in the NHEJ pathway. FAM35A depletion impairs NHEJ-mediated DNA repair and compromises antibody diversification by class switch recombination (CSR) in B-cells. FAM35A accumulates at DSBs in a 53BP1-, RIF1- and REV7-dependent manner and antagonizes HR by limiting DNA end resection. In fact, FAM35A is part of a larger complex composed of REV7 and another previously uncharacterized protein, C20orf196/SHDL1, which promotes NHEJ and limits HR. Together, these results establish FAM35A as a novel effector of REV7 in controlling the decision-making process during DSB repair.

cancer biology↗

bioRxiv2018

Metabolic adaptability in metastatic breast cancer by AKR1B10-dependent balancing of glycolysis and fatty acid oxidation

The different stages of the metastatic cascade present distinct metabolic challenges to tumour cells and an altered tumour metabolism associated with successful metastatic colonisation provides a therapeutic vulnerability in disseminated disease. We identify the aldo-keto reductase AKR1B10 as a metastasis enhancer that has little impact on primary tumour growth or dissemination but promotes effective tumour growth in secondary sites and, in human disease, is associated with an increased risk of distant metastatic relapse. AKR1B10High tumour cells have reduced glycolytic capacity and dependency on glucose as fuel source but increased utilisation of fatty acid oxidation. Conversely, in both 3D tumour spheroid assays and in vivo metastasis assays, inhibition of fatty acid oxidation blocks AKR1B10High-enhanced metastatic colonisation with no impact on AKR1B10Low cells. Finally, mechanistic analysis supports a model in which AKR1B10 serves to limit the toxic side effects of oxidative stress thereby sustaining fatty acid oxidation in metabolically challenging metastatic environments.

cancer biology↗

bioRxiv2018

gpps: An ILP-based approach for inferringcancer progression with mutation losses fromsingle cell data

MotivationIn recent years, the well-known Infinite Sites Assumption (ISA) has been a fundamental feature of computational methods devised for reconstructing tumor phylogenies and inferring cancer progression where mutations are accumulated through histories. However, some recent studies leveraging Single Cell Sequencing (SCS) techniques have shown evidence of mutation losses in several tumor samples [19], making the inference problem harder.\n\nResultsWe present a new tool, gpps, that reconstructs a tumor phylogeny from single cell data, allowing each mutation to be lost at most a fixed number of times.\n\nAvailabilityThe General Parsimony Phylogeny from Single cell (gpps) tool is open source and available at https://github.com/AlgoLab/gppf.

cancer biology↗

bioRxiv2018

Pharmacologic activation of G protein-coupled estrogen receptor inhibits pancreatic ductal adenocarcinoma

Female sex is associated with lower incidence and improved clinical outcomes for many cancer types, including pancreatic ductal adenocarcinoma (PDAC). Although the mechanisms responsible for this sex difference are unknown, recent data suggests nonclassical estrogen signaling through the G Protein-coupled Estrogen Receptor (GPER) is likely involved. Here we used murine syngeneic tumor models and human xenografts to test whether GPER signaling inhibits pancreatic ductal adenocarcinoma (PDAC). Activation of GPER with the specific, small molecule agonist G-1 inhibited PDAC proliferation, depleted c-Myc and programmed death ligand 1 (PD-L1), and increased tumor cell immunogenicity. Systemically delivered G-1 was well tolerated in PDAC bearing mice, significantly prolonged survival, and markedly increased the efficacy of PD-1 targeted immune therapy. We detected GPER protein in a majority of spontaneous human PDAC tumors. These data, coupled with the wide tissue distribution of GPER, and our previous work showing that G-1 inhibits melanoma, suggest that GPER agonists may be useful against many different cancer types.

cancer biology↗

bioRxiv2018

Comprehensive analysis of potential immunotherapy genomic biomarkers in 1,000 Chinese patients with cancer

BackgroundTumor mutation burden (TMB), DNA mismatch repair deficiency (dMMR), microsatellite instability (MSI), and PD-L1 amplification (PD-L1 AMP) may predict the efficacy of PD-1/PD-L1 blockade. In this study, we aimed to characterize the distributions of these biomarkers in over 1,000 Chinese patients with cancer.\n\nMethodsTMB, MSI, dMMR, and PD-L1 AMP were determined based on whole-exome sequencing of tumor/blood samples from > 1,000 Chinese patients with cancer.\n\nResultsIncidence rates among 953 Chinese patients with cancer showing high TMB (TMB-H), high MSI (MSI-H), dMMR and PD-L1 AMP were 35%, 4%, 0.53% and 3.79%, respectively. We found higher rates of TMB-H among hepatocellular carcinoma, breast cancer, and esophageal cancer patients than was reported for The Cancer Genome Atlas data. Lung cancer patients with EGFR mutations had significantly lower TMB values than those with wild-type EGFR, and increased TMB was significantly associated with dMMR in colorectal cancer (CRC). The frequency of tumors with MSI-H was highest in CRC (14%) and gastric cancer (4%). PD-L1 AMP occurred most frequently in lung squamous cell carcinoma (14.3%) and HER2-positive breast cancer (8.8%). Most MSI-H and dMMR cases exhibited TMB-H, but the overlap among the other biomarkers was low.\n\nConclusionWhile MSI and dMMR are associated with higher mutational loads, correlations between TMB-H and other biomarkers, between MSI-H and dMMR, and between PD-L1 AMP and other biomarkers were low, indicating different underlying causes of the four biomarkers. Thus, it is recommended that all four biomarkers be assessed for certain cancers before administration of PD-1/PD-L1 blockade treatment.

cancer biology↗

bioRxiv2018

Silencing of ANKRD12 circRNA induces molecular and functional changes associated with invasive phenotypes

Circular RNAs (circRNA) that form through non-canonical backsplicing events of pre-mRNA transcripts are evolutionarily conserved and abundantly expressed across species. However, the functional relevance of circRNAs remains a topic of debate. In this study, we identified and characterized a circular RNA derived from Exon 2 and Exon 8 of the ANKRD12 gene, termed here as circANKRD12. We show that this circRNA is abundantly expressed in breast and ovarian cancers. The circANKRD12 is RNase R resistant and predominantly localized in the cytoplasm in contrast to its source gene mRNA. We confirmed the expression of this circRNA across a variety of cancer cell lines and provide evidence for its functional relevance through downstream regulation of several tumor invasion genes. We show that silencing of circANKRD12 induces a phenotypic change by significantly regulating cell cycle, increasing invasion and migration, altering the metabolism in cancer cells. These results reveal the functional significance of circANKRD12 and provide evidence of a regulatory role for this circRNA in cancer progression.

cancer biology↗

bioRxiv2018

Gut microbiome meta-analysis reveals dysbiosis is independent of body mass index in predicting risk of obesity-associated CRC

Obesity is a risk factor for colorectal cancer (CRC), accounting for more than 14% of CRC incidence. Microbial dysbiosis and chronic inflammation are common characteristics in both obesity and CRC. Human and murine studies, together, demonstrate the significant impact of the microbiome on governing energy metabolism and CRC development; yet, little is understood about the contribution of the microbiome to development of obesity-associated CRC as compared to non-obese individuals. In this study, we conducted a meta-analysis using five publicly available stool and tissue-based 16S rRNA and whole genome sequencing (WGS) data sets of CRC microbiome studies. High-resolution analysis was employed for 16S rRNA data using Resphera Insight, which allowed us to achieve species-level information to compare with WGS. Characterization of the confounders between studies, 16S rRNA variable region, and sequencing method, did not reveal any significant effect on alpha diversity in CRC prediction. Both 16S rRNA and WGS were equally variable in their ability to predict CRC. Results from community structure and composition analysis confirmed lower diversity in obese individuals without CRC; however, no universal differences were found in diversity between obese and non-obese individuals with CRC. When examining taxonomic differences, the probability of being classified as CRC did not change significantly in obese individuals for all taxa tested. However, random forest classification was able to distinguish CRC and non-CRC stool when body mass index was added to the model. Overall, microbial dysbiosis was not a significant factor in explaining the higher risk of colon cancer among individuals with obesity.

cancer biology↗

bioRxiv2018

Application of clinical genomic sequencing among Chinese advanced cancer patients to guide precision medicine decisions

PurposeA number of studies have suggested that high-throughput genomic analyses might improve the outcomes of cancer patients. However, whether integrative information about genomic sequencing and related clinical interpretation may benefit Chinese cancer patients with stage IV disease to date has not investigated.\n\nMethodsTargeted gene panel and whole exome of tumor/blood samples in > 1,000 Chinese cancer patients were sequenced. Then we provided patients and their oncologists with the sequencing results and a clinical recommendation roadmap based on evidence-based medicine, defined as CWES. Only patients with stage IV disease who failed the previous treatment upon receiving the CWES reports were included for analyzing the impact of CWES on clinical outcomes in 1-year follow-ups.\n\nResultsWe identified the mutational signatures of 953 Chinese cancer patients, with some being unique. Approximately 88.6% of patients had clinically actionable somatic genomic alterations. We successfully followed up 22 stage IV patients. Of these, 11 patients treatment followed the CWES reports defined as group A. Eleven patients received the next treatment, but did not follow the CWES suggestions, and are defined as group B. The types of therapies before CWES were similar in the two groups. The median PFS of group A was 12 months and 45% patients failed this round of therapy. The median PFS of group B was 4 months and 91% of patients failed the treatment.\n\nConclusionThe current study suggested that CWES has the potential to help explore the clinical benefits in multiple line therapies among advanced stage tumor patients.

cancer biology↗

bioRxiv2018

Dynamics of the p53 response to ionizing and ultraviolet radiation

The tumor suppressor protein p53 compiles information about cellular stressors to make decisions on whether the cell should survive or undergo apoptosis. However, the p53 response depends on the source of damage, displaying a digital oscillatory response after ionizing radiation (IR) damage and a proportional non-oscillatory response following UV damage. We propose a mathematical model that qualitatively replicates this observed behavior. The difference in p53 dynamics in the model results from two mechanisms: IR damage is fully detected minutes after exposure while UV damage is detected over several hours; and the p53-controlled transcriptional response is dominated by inactive p53 following UV damage. In particular, we hypothesize that an unidentified positive feedback loop controlled by inactive p53 is required to maintain the qualitative high p53 response to UV damage. This work proposes an explanation for two distinct responses of p53 to DNA damage and how each response can lead to cell cycle arrest or apoptosis.\n\nAuthor summaryWe propose a mathematical model hypothesizing how the tumor suppressor protein p53 produces two contrasting dynamical responses in response to different types of DNA damage. In particular, we predict the existence of a positive feedback loop controlled by the inactive form of p53, which allows the cell to respond to slowly detected damage. The existence of differing dynamic responses by p53 has implications for our understanding of tumor development and possibly p53-related therapeutic strategies.

cancer biology↗

bioRxiv2018

TP53 mutations as potential prognostic markers for specific cancers: Analysis of data from The Cancer Genome Atlas and the International Agency for Research on Cancer TP53 Database

Mutations in the tumor suppressor gene TP53 are associated with a variety of cancers. Therefore, it is important to know the occurrence and the prognostic effects of TP53 mutations in certain cancers. Over 29,000 cases of TP53 mutations were obtained from the April 2016 release of the Internal Agency for Research on Cancer (IARC) TP53 Database, and 7,893 cancer cases were compiled in the cBioPortal for Cancer Genomics from the 33 most recent studies of The Cancer Genome Atlas (TCGA). The data was analyzed, and it was found that the majority of TP53 mutations were missense and the major mutational hotspots were located at codons 248, 273, 175, and 245 in exons 4-8 for somatic mutations with the addition of codon 337 and other mutations in exons 9-10 for germline mutations. Out of 33 TGCA studies, the effects of TP53 mutations were statistically significant in ten cancers (ovarian serous cystadenocarcinoma, lung adenocarcinoma, hepatocellular carcinoma, head and neck squamous cell carcinoma, acute myeloid leukemia, clear cell renal cell carcinoma (RCC), papillary RCC, chromophobe RCC, uterine endometrial carcinoma, and thymoma) for survival time and in six cancers (ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, hepatocellular carcinoma, chromophobe RCC, acute myeloid leukemia, and thymoma) for disease-free survival time. Also, it was found that the most common p53 mutation in hepatocellular carcinomas (R249S) was a much better indicator for poor prognosis than TP53 mutations as a whole.\n\nAuthor summaryThe TP53 gene codes for the tumor suppressor protein, p53, which is essential for DNA repair, cell cycle arrest, and apoptosis. It is commonly inactivated or partially disabled by mutations, contributing to the development of a variety of human cancers. In this study, over 29,000 cases from the April 2016 release of the International Agency for Research on Cancer TP53 Database (IARC) were analyzed to determine the distribution of mutations in the TP53 gene. Data was also collected from the 33 most recent The Cancer Genome Atlas (TCGA) studies to determine the prevalence of TP53 mutations in cancers and their effects on survival and disease-free survival time. It was found that there were statistically significant differences between cases with and without TP53 mutations in ten cancers when comparing survival time, and in six cancers when comparing disease-free survival time. This indicates that TP53 mutations are potential prognostic markers that can be used to further improve the accuracy of predicting the survival time and disease-free survival time of cancer patients.

cancer biology↗