PRINS

Gene Summary

Gene:PRINS; psoriasis associated non-protein coding RNA induced by stress
Aliases: NCRNA00074
Location:10p12.1
Summary:-
Databases:HGNC, GeneCard, Gene
Source:NCBIAccessed: 14 March, 2017

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 14 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 14 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: PRINS (cancer-related)

Blokzijl F, de Ligt J, Jager M, et al.
Tissue-specific mutation accumulation in human adult stem cells during life.
Nature. 2016; 538(7624):260-264 [PubMed] Related Publications
The gradual accumulation of genetic mutations in human adult stem cells (ASCs) during life is associated with various age-related diseases, including cancer. Extreme variation in cancer risk across tissues was recently proposed to depend on the lifetime number of ASC divisions, owing to unavoidable random mutations that arise during DNA replication. However, the rates and patterns of mutations in normal ASCs remain unknown. Here we determine genome-wide mutation patterns in ASCs of the small intestine, colon and liver of human donors with ages ranging from 3 to 87 years by sequencing clonal organoid cultures derived from primary multipotent cells. Our results show that mutations accumulate steadily over time in all of the assessed tissue types, at a rate of approximately 40 novel mutations per year, despite the large variation in cancer incidence among these tissues. Liver ASCs, however, have different mutation spectra compared to those of the colon and small intestine. Mutational signature analysis reveals that this difference can be attributed to spontaneous deamination of methylated cytosine residues in the colon and small intestine, probably reflecting their high ASC division rate. In liver, a signature with an as-yet-unknown underlying mechanism is predominant. Mutation spectra of driver genes in cancer show high similarity to the tissue-specific ASC mutation spectra, suggesting that intrinsic mutational processes in ASCs can initiate tumorigenesis. Notably, the inter-individual variation in mutation rate and spectra are low, suggesting tissue-specific activity of common mutational processes throughout life.

Gore AC, Chappell VA, Fenton SE, et al.
EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals.
Endocr Rev. 2015; 36(6):E1-E150 [PubMed] Free Access to Full Article Related Publications
The Endocrine Society's first Scientific Statement in 2009 provided a wake-up call to the scientific community about how environmental endocrine-disrupting chemicals (EDCs) affect health and disease. Five years later, a substantially larger body of literature has solidified our understanding of plausible mechanisms underlying EDC actions and how exposures in animals and humans-especially during development-may lay the foundations for disease later in life. At this point in history, we have much stronger knowledge about how EDCs alter gene-environment interactions via physiological, cellular, molecular, and epigenetic changes, thereby producing effects in exposed individuals as well as their descendants. Causal links between exposure and manifestation of disease are substantiated by experimental animal models and are consistent with correlative epidemiological data in humans. There are several caveats because differences in how experimental animal work is conducted can lead to difficulties in drawing broad conclusions, and we must continue to be cautious about inferring causality in humans. In this second Scientific Statement, we reviewed the literature on a subset of topics for which the translational evidence is strongest: 1) obesity and diabetes; 2) female reproduction; 3) male reproduction; 4) hormone-sensitive cancers in females; 5) prostate; 6) thyroid; and 7) neurodevelopment and neuroendocrine systems. Our inclusion criteria for studies were those conducted predominantly in the past 5 years deemed to be of high quality based on appropriate negative and positive control groups or populations, adequate sample size and experimental design, and mammalian animal studies with exposure levels in a range that was relevant to humans. We also focused on studies using the developmental origins of health and disease model. No report was excluded based on a positive or negative effect of the EDC exposure. The bulk of the results across the board strengthen the evidence for endocrine health-related actions of EDCs. Based on this much more complete understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability, these findings can be much better translated to human health. Armed with this information, researchers, physicians, and other healthcare providers can guide regulators and policymakers as they make responsible decisions.

Gore AC, Chappell VA, Fenton SE, et al.
Executive Summary to EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals.
Endocr Rev. 2015; 36(6):593-602 [PubMed] Free Access to Full Article Related Publications
This Executive Summary to the Endocrine Society's second Scientific Statement on environmental endocrine-disrupting chemicals (EDCs) provides a synthesis of the key points of the complete statement. The full Scientific Statement represents a comprehensive review of the literature on seven topics for which there is strong mechanistic, experimental, animal, and epidemiological evidence for endocrine disruption, namely: obesity and diabetes, female reproduction, male reproduction, hormone-sensitive cancers in females, prostate cancer, thyroid, and neurodevelopment and neuroendocrine systems. EDCs such as bisphenol A, phthalates, pesticides, persistent organic pollutants such as polychlorinated biphenyls, polybrominated diethyl ethers, and dioxins were emphasized because these chemicals had the greatest depth and breadth of available information. The Statement also included thorough coverage of studies of developmental exposures to EDCs, especially in the fetus and infant, because these are critical life stages during which perturbations of hormones can increase the probability of a disease or dysfunction later in life. A conclusion of the Statement is that publications over the past 5 years have led to a much fuller understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability. These findings will prove useful to researchers, physicians, and other healthcare providers in translating the science of endocrine disruption to improved public health.

Harmsen MG, Hermens RP, Prins JB, et al.
How medical choices influence quality of life of women carrying a BRCA mutation.
Crit Rev Oncol Hematol. 2015; 96(3):555-68 [PubMed] Related Publications
Germline mutations in BRCA1 and BRCA2 genes were discovered twenty years ago. Female BRCA mutation carriers have an increased risk of breast and ovarian cancer at a relatively young age. Several choices have to be made with respect to cancer risk management, and consequences of these choices may affect quality of life. A review of the literature was performed to evaluate quality of life in unaffected BRCA mutation carriers and the influence of these medical choices. Overall, general quality of life appears not to be permanently affected in BRCA mutation carriers or by their choices. Risk-reducing salpingo-oophorectomy and its subsequent premature menopause affect (menopause specific) quality of life most. Hormone replacement therapy does not fully alleviate climacteric symptoms and therefore, there is a strong need for alternative strategies to reduce ovarian cancer risk and/or for improvements in postoperative care. Future research should focus on these needs.

Ho SM, Cheong A, Lam HM, et al.
Exposure of Human Prostaspheres to Bisphenol A Epigenetically Regulates SNORD Family Noncoding RNAs via Histone Modification.
Endocrinology. 2015; 156(11):3984-95 [PubMed] Free Access to Full Article Related Publications
Bisphenol A (BPA) is a ubiquitous endocrine disruptor exerting lifelong effects on gene expression in rodent prostate cancer (PCa) models. Here, we aimed to determine whether epigenetic events mediating the action of BPA on human prostaspheres enriched in epithelial stem-like/progenitor cells is linked to PCa. We performed genome-wide transcriptome and methylome analyses to identify changes in prostaspheres treated with BPA (10 nM, 200 nM, and 1000 nM) or estradiol-17β (E2) (0.1 nM) for 7 days and validated changes in expression, methylation, and histone marks in parallel-treated prostaspheres. BPA/E2-treatment altered expression of 91 genes but not the methylation status of 485,000 CpG sites in BPA/E2-treated prostaspheres. A panel of 26 genes was found repressed in all treatment groups. Fifteen of them were small nucleolar RNAs with C/D motif (SNORDs), which are noncoding, small nucleolar RNAs known to regulate ribosomal RNA assembly and function. Ten of the most down-regulated SNORDs were further studied. All 10 were confirmed repressed by BPA, but only 3 ratified as E2-repressed. SNORD suppression showed no correlation with methylation status changes in CpG sites in gene regulatory regions. Instead, BPA-induced gene silencing was found to associate with altered recruitments of H3K9me3, H3K4me3, and H3K27me3 to 5'-regulatory/exonic sequences of 5 SNORDs. Expression of 4 out of these 5 SNORDs (SNORD59A, SNORD82, SNORD116, and SNORD117) was shown to be reduced in PCa compared with adjacent normal tissue. This study reveals a novel and unique action of BPA in disrupting expression of PCa-associated SNORDs and a putative mechanism for reprogramming the prostasphere epigenome via histone modification.

Fu X, Chin RM, Vergnes L, et al.
2-Hydroxyglutarate Inhibits ATP Synthase and mTOR Signaling.
Cell Metab. 2015; 22(3):508-15 [PubMed] Free Access to Full Article Related Publications
We discovered recently that the central metabolite α-ketoglutarate (α-KG) extends the lifespan of C. elegans through inhibition of ATP synthase and TOR signaling. Here we find, unexpectedly, that (R)-2-hydroxyglutarate ((R)-2HG), an oncometabolite that interferes with various α-KG-mediated processes, similarly extends worm lifespan. (R)-2HG accumulates in human cancers carrying neomorphic mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes. We show that, like α-KG, both (R)-2HG and (S)-2HG bind and inhibit ATP synthase and inhibit mTOR signaling. These effects are mirrored in IDH1 mutant cells, suggesting a growth-suppressive function of (R)-2HG. Consistently, inhibition of ATP synthase by 2-HG or α-KG in glioblastoma cells is sufficient for growth arrest and tumor cell killing under conditions of glucose limitation, e.g., when ketone bodies (instead of glucose) are supplied for energy. These findings inform therapeutic strategies and open avenues for investigating the roles of 2-HG and metabolites in biology and disease.

Hartley ML, Bade NA, Prins PA, et al.
Pancreatic cancer, treatment options, and GI-4000.
Hum Vaccin Immunother. 2015; 11(4):931-7 [PubMed] Free Access to Full Article Related Publications
Although pancreatic cancer is but the eleventh most prevalent cancer in the US, it is predicted that of all the patients newly diagnosed with this disease in 2014, only 27% will still be alive at the end of the first year, which is reduced to 6% after 5 years. The choice of chemotherapy in the treatment of pancreatic cancer is dependent on disease stage and patient performance status but, in general, the most widely used approved regimens include 5-fluorouracil (5-FU) combinations and gemcitabine combinations. Recent therapeutic strategies have resulted in an improvement in survival of patients with pancreatic cancer but the magnitude of change is disappointing and vast improvements are still needed. The goal of immunotherapy is to enhance and guide the body's immune system to recognize tumor-specific antigens and mount an attack against the disease. Among newer immune therapies, GI-4000 consists of 4 different targeted molecular immunogens, each containing a different Ras protein (antigen) encoded by the most commonly found mutant RAS genes in solid tumors-RAS mutations exist in over 90% of pancreatic ductal adenocarcinomas. We will review pancreatic cancer epidemiology and its current treatment options, and consider the prospects of immunotherapy, focusing on GI-4000. We discuss the potential mechanism of action of GI-4000, and the performance of this vaccination series thus far in early phase clinical trials.

Visser A, Bos WC, Prins JB, et al.
Breast self-examination education for BRCA mutation carriers by clinical nurse specialists.
Clin Nurse Spec. 2015 May-Jun; 29(3):E1-7 [PubMed] Related Publications
PURPOSE: Breast self-examination (BSE) may be beneficial for women with a BRCA1 or BRCA2 mutation. Therefore, these women are often advised to perform BSE. However, only 20% to 35% is performing BSE monthly, and proficiency levels are low. Recently diagnosed carriers are educated by a specially trained clinical nurse specialist (CNS) on how to perform BSE, as part of the yearly surveillance. Clinical nurse specialists are already commonly involved in breast cancer care. However, CNSs are not yet involved in the counseling of BRCA mutation carriers. The aim of this RCT was 2-fold: (1) to evaluate the feasibility of CNS-led BSE education (based on the Health Belief Model) as part of BRCA surveillance and (2) to evaluate the effects and feasibility of additional written information leaflets concerning BSE.
METHODS: Thirty-seven female BRCA1 or BRCA2 mutation carriers were randomized into the intervention or control group. Women in both groups were educated about BSE by a specially trained CNS during the yearly visit to the outpatient clinic. The intervention group received additional written BSE instructions. After 3 months, 29 patients filled out a questionnaire, covering demographic characteristics, BSE behavior, and patient satisfaction.
RESULTS: The BSE frequencies did not significantly differ between both groups. A significant increase in the self-reported frequency of BSE after CNS-led education (P < .001) was shown. Before the education, the main reason for not performing BSE was that women had felt unable to perform BSE (42.9%). Patient satisfaction with the CNS-led education was high.
CONCLUSION: CNS-led BSE education is feasible for the yearly breast surveillance of BRCA mutation carriers. In addition, a leaflet was shown to be useful as an additional source of information for patients.
IMPLICATIONS: These results indicate that it is feasible to involve a CNS in the yearly surveillance of BRCA mutation carriers, which could be a solution for the continuous increased demand for care, while providing continuing high-quality care.

Welch JD, Baran-Gale J, Perou CM, et al.
Pseudogenes transcribed in breast invasive carcinoma show subtype-specific expression and ceRNA potential.
BMC Genomics. 2015; 16:113 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Recent studies have shown that some pseudogenes are transcribed and contribute to cancer when dysregulated. In particular, pseudogene transcripts can function as competing endogenous RNAs (ceRNAs). The high similarity of gene and pseudogene nucleotide sequence has hindered experimental investigation of these mechanisms using RNA-seq. Furthermore, previous studies of pseudogenes in breast cancer have not integrated miRNA expression data in order to perform large-scale analysis of ceRNA potential. Thus, knowledge of both pseudogene ceRNA function and the role of pseudogene expression in cancer are restricted to isolated examples.
RESULTS: To investigate whether transcribed pseudogenes play a pervasive regulatory role in cancer, we developed a novel bioinformatic method for measuring pseudogene transcription from RNA-seq data. We applied this method to 819 breast cancer samples from The Cancer Genome Atlas (TCGA) project. We then clustered the samples using pseudogene expression levels and integrated sample-paired pseudogene, gene and miRNA expression data with miRNA target prediction to determine whether more pseudogenes have ceRNA potential than expected by chance.
CONCLUSIONS: Our analysis identifies with high confidence a set of 440 pseudogenes that are transcribed in breast cancer tissue. Of this set, 309 pseudogenes exhibit significant differential expression among breast cancer subtypes. Hierarchical clustering using only pseudogene expression levels accurately separates tumor samples from normal samples and discriminates the Basal subtype from the Luminal and Her2 subtypes. Correlation analysis shows more positively correlated pseudogene-parent gene pairs and negatively correlated pseudogene-miRNA pairs than expected by chance. Furthermore, 177 transcribed pseudogenes possess binding sites for co-expressed miRNAs that are also predicted to target their parent genes. Taken together, these results increase the catalog of putative pseudogene ceRNAs and suggest that pseudogene transcription in breast cancer may play a larger role than previously appreciated.

Erickson KL, Hickey MJ, Kato Y, et al.
Radial mobility and cytotoxic function of retroviral replicating vector transduced, non-adherent alloresponsive T lymphocytes.
J Vis Exp. 2015; (96) [PubMed] Free Access to Full Article Related Publications
We report a novel adaptation of the Radial Monolayer Cell Migration assay, first reported to measure the radial migration of adherent tumor cells on extracellular matrix proteins, for measuring the motility of fluorescently-labeled, non-adherent human or murine effector immune cells. This technique employs a stainless steel manifold and 10-well Teflon slide to focally deposit non-adherent T cells into wells prepared with either confluent tumor cell monolayers or extracellular matrix proteins. Light and/or multi-channel fluorescence microscopy is used to track the movement and behavior of the effector cells over time. Fluorescent dyes and/or viral vectors that code for fluorescent transgenes are used to differentially label the cell types for imaging. This method is distinct from similar-type in vitro assays that track horizontal or vertical migration/invasion utilizing slide chambers, agar or transwell plates. The assay allows detailed imaging data to be collected with different cell types distinguished by specific fluorescent markers; even specific subpopulations of cells (i.e., transduced/nontransduced) can be monitored. Surface intensity fluorescence plots are generated using specific fluorescence channels that correspond to the migrating cell type. This allows for better visualization of the non-adherent immune cell mobility at specific times. It is possible to gather evidence of other effector cell functions, such as cytotoxicity or transfer of viral vectors from effector to target cells, as well. Thus, the method allows researchers to microscopically document cell-to-cell interactions of differentially-labeled, non-adherent with adherent cells of various types. Such information may be especially relevant in the assessment of biologically-manipulated or activated immune cell types, where visual proof of functionality is desired with tumor target cells before their use for cancer therapy.


Comprehensive genomic characterization of head and neck squamous cell carcinomas.
Nature. 2015; 517(7536):576-82 [PubMed] Free Access to Full Article Related Publications
The Cancer Genome Atlas profiled 279 head and neck squamous cell carcinomas (HNSCCs) to provide a comprehensive landscape of somatic genomic alterations. Here we show that human-papillomavirus-associated tumours are dominated by helical domain mutations of the oncogene PIK3CA, novel alterations involving loss of TRAF3, and amplification of the cell cycle gene E2F1. Smoking-related HNSCCs demonstrate near universal loss-of-function TP53 mutations and CDKN2A inactivation with frequent copy number alterations including amplification of 3q26/28 and 11q13/22. A subgroup of oral cavity tumours with favourable clinical outcomes displayed infrequent copy number alterations in conjunction with activating mutations of HRAS or PIK3CA, coupled with inactivating mutations of CASP8, NOTCH1 and TP53. Other distinct subgroups contained loss-of-function alterations of the chromatin modifier NSD1, WNT pathway genes AJUBA and FAT1, and activation of oxidative stress factor NFE2L2, mainly in laryngeal tumours. Therapeutic candidate alterations were identified in most HNSCCs.

Hartley ML, Bade NA, Prins PA, et al.
Pancreatic cancer, treatment options, and GI-4000.
Hum Vaccin Immunother. 2014; 10(11):3347-53 [PubMed] Free Access to Full Article Related Publications
Although pancreatic cancer is but the eleventh most prevalent cancer in the US, it is predicted that of all the patients newly diagnosed with this disease in 2014, only 27% will still be alive at the end of the first year and only 6% will make it past 5 years. The choice of chemotherapy in the treatment of pancreatic cancer is dependent on disease stage and patient performance status but, in general, the most widely used approved regimens include 5-fluorouracil (5-FU) combinations and gemcitabine combinations. Recent therapeutic strategies have resulted in an improvement in survival of patients with pancreatic cancer but the magnitude of change is disappointing and vast improvements are still needed. The goal of immunotherapy is to enhance and guide the body's immune system to recognize tumor-specific antigens and mount an attack against the disease. Among newer immune therapies, GI-4000 consists of 4 different targeted molecular immunogens, each containing a different Ras protein (antigen) encoded by the most commonly found mutant RAS genes in solid tumors--RAS mutations exist in over 90% of pancreatic ductal adenocarcinomas. We will review pancreatic cancer epidemiology and its current treatment options, and consider the prospects of immunotherapy, focusing on GI-4000. We discuss the potential mechanism of action of GI-4000, and the performance of this vaccination series thus far in early phase clinical trials.


Integrated genomic characterization of papillary thyroid carcinoma.
Cell. 2014; 159(3):676-90 [PubMed] Free Access to Full Article Related Publications
Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Here, we describe the genomic landscape of 496 PTCs. We observed a low frequency of somatic alterations (relative to other carcinomas) and extended the set of known PTC driver alterations to include EIF1AX, PPM1D, and CHEK2 and diverse gene fusions. These discoveries reduced the fraction of PTC cases with unknown oncogenic driver from 25% to 3.5%. Combined analyses of genomic variants, gene expression, and methylation demonstrated that different driver groups lead to different pathologies with distinct signaling and differentiation characteristics. Similarly, we identified distinct molecular subgroups of BRAF-mutant tumors, and multidimensional analyses highlighted a potential involvement of oncomiRs in less-differentiated subgroups. Our results propose a reclassification of thyroid cancers into molecular subtypes that better reflect their underlying signaling and differentiation properties, which has the potential to improve their pathological classification and better inform the management of the disease.

Parfenov M, Pedamallu CS, Gehlenborg N, et al.
Characterization of HPV and host genome interactions in primary head and neck cancers.
Proc Natl Acad Sci U S A. 2014; 111(43):15544-9 [PubMed] Free Access to Full Article Related Publications
Previous studies have established that a subset of head and neck tumors contains human papillomavirus (HPV) sequences and that HPV-driven head and neck cancers display distinct biological and clinical features. HPV is known to drive cancer by the actions of the E6 and E7 oncoproteins, but the molecular architecture of HPV infection and its interaction with the host genome in head and neck cancers have not been comprehensively described. We profiled a cohort of 279 head and neck cancers with next generation RNA and DNA sequencing and show that 35 (12.5%) tumors displayed evidence of high-risk HPV types 16, 33, or 35. Twenty-five cases had integration of the viral genome into one or more locations in the human genome with statistical enrichment for genic regions. Integrations had a marked impact on the human genome and were associated with alterations in DNA copy number, mRNA transcript abundance and splicing, and both inter- and intrachromosomal rearrangements. Many of these events involved genes with documented roles in cancer. Cancers with integrated vs. nonintegrated HPV displayed different patterns of DNA methylation and both human and viral gene expressions. Together, these data provide insight into the mechanisms by which HPV interacts with the human genome beyond expression of viral oncoproteins and suggest that specific integration events are an integral component of viral oncogenesis.

Giangreco AA, Dambal S, Wagner D, et al.
Differential expression and regulation of vitamin D hydroxylases and inflammatory genes in prostate stroma and epithelium by 1,25-dihydroxyvitamin D in men with prostate cancer and an in vitro model.
J Steroid Biochem Mol Biol. 2015; 148:156-65 [PubMed] Free Access to Full Article Related Publications
Previous work on vitamin D in the prostate has focused on the prostatic epithelium, from which prostate cancer arises. Prostatic epithelial cells are surrounded by stroma, which has well-established regulatory control over epithelial proliferation, differentiation, and the inflammatory response. Here we examined the regulation of vitamin D-related genes and inflammatory genes by 1α,25-dihydroxyvitamin D3 (1,25(OH)2D) in laser-capture microdissected prostate tissue from a vitamin D3 clinical trial and in an in vitro model that facilitates stromal-epithelial crosstalk. Analysis of the trial tissues showed that VDR was present in both cell types, whereas expression of the hydroxylases was the highest in the epithelium. Examination of gene expression by prostatic (1,25(OH)2D) concentrations showed that VDR was significantly lower in prostate tissues with the highest concentration of 1,25(OH)2D, and down-regulation of VDR by 1,25(OH) 2D was confirmed in the primary cell cultures. Analysis of inflammatory genes in the patient tissues revealed that IL-6 expression was the highest in the prostate stroma while PTGS2 (COX2) levels were lowest in the prostate cancer tissues from men in the highest tertile of prostatic 1,25(OH)2D. In vitro, TNF-α, IL-6 and IL-8 were suppressed by 1,25 (OH)2D in the primary epithelial cells, whereas TNF-α and PTGS2 were suppressed by 1,25(OH) 2D in the stromal cells. Importantly, the ability of 1,25(OH)2D to alter pro-inflammatory-induced changes in epithelial cell growth were dependent on the presence of the stromal cells. In summary, whereas both stromal and epithelial cells of the prostate express VDR and can presumably respond to 1,25(OH)2D, the prostatic epithelium appears to be the main producer of 1,25(OH)2D. Further, while the prostate epithelium was more responsive to the anti-inflammatory activity of 1,25 (OH)2D than stromal cells, stroma-epithelial crosstalk enhanced the phenotypic effects of 1,25(OH)2D and the inflammatory process in the prostate gland.

Li S, Chowdhury R, Liu F, et al.
Tumor-suppressive miR148a is silenced by CpG island hypermethylation in IDH1-mutant gliomas.
Clin Cancer Res. 2014; 20(22):5808-22 [PubMed] Free Access to Full Article Related Publications
PURPOSE: IDH1/2-mutant gliomas harbor a distinct glioma-CpG island methylation phenotype (G-CIMP) that may promote the initiation and progression of secondary pathway gliomas by silencing tumor-suppressive genes. The potential role of tumor-suppressive microRNAs (miRNA; miR) in this process is not understood.
EXPERIMENTAL DESIGN: To identify potential tumor-suppressive miRNA hypermethylated in glioma, the methylation profiles of IDH1/2(WT) gliomas (n = 11) and IDH1(MUT) glioma (n = 20) were compared by using massively parallel reduced representation bisulfite sequencing (RRBS). The methylation status of selected miRNA was validated by using targeted bisulfite sequencing (BiSEQ) in a large cohort of glioma tissue samples including 219 IDH1(WT) and 72 IDH1/2(MUT) samples. The expression of selected miRNAs was determined by using the TaqMan qPCR. Functional analyses of miR148a were conducted and target genes were identified.
RESULTS: We identify miR148a as a novel, G-CIMP-associated miRNA whose methylation is tightly correlated with IDH1 mutation and associated with improved survival in patients with malignant glioma. We confirm that downregulation of miR148a can occur via DNA methylation. We demonstrate that IDH1 mutation provides a mechanism of miR148a methylation and downregulation, and that restoration of miR148a reduced tumorigenic properties of glioma cells, possibly by targeting DNMT1.
CONCLUSIONS: We identify miR148a as a novel G-CIMP-associated miRNA, and provide results suggesting that miR148a restoration may have therapeutic implications.


Comprehensive molecular profiling of lung adenocarcinoma.
Nature. 2014; 511(7511):543-50 [PubMed] Free Access to Full Article Related Publications
Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.

Wielders EA, Hettinger J, Dekker R, et al.
Functional analysis of MSH2 unclassified variants found in suspected Lynch syndrome patients reveals pathogenicity due to attenuated mismatch repair.
J Med Genet. 2014; 51(4):245-53 [PubMed] Related Publications
BACKGROUND: Lynch syndrome, an autosomal-dominant disorder characterised by high colorectal and endometrial cancer risks, is caused by inherited mutations in DNA mismatch repair (MMR) genes. Mutations fully abrogating gene function are unambiguously disease causing. However, missense mutations often have unknown functional implications, hampering genetic counselling. We have applied a novel approach to study three MSH2 unclassified variants (UVs) found in Dutch families with suspected Lynch syndrome.
METHODS: The three mutations were recreated in the endogenous Msh2 gene in mouse embryonic stem cells by oligonucleotide-directed gene modification. The effect of the UVs on MMR activity was then tested using a set of functional assays interrogating the main MMR functions.
RESULTS: We recreated and functionally tested three MSH2 UVs: MSH2-Y165D (c.493T>G), MSH2-Q690E (c.2068C>G) and MSH2-M813V (c.2437A>G). We observed reduced levels of MSH2-Y165D and MSH2-Q690E but not MSH2-M813V proteins. MSH2-M813V was able to support all MMR functions similar to wild-type MSH2, whereas MSH2-Y165D and MSH2-Q690E showed partial defects.
CONCLUSIONS: Based on the results from our functional assays, we conclude that the MSH2-M813V variant is not disease causing. The MSH2-Y165D and MSH2-Q690E variants affect MMR function and are therefore likely the underlying cause of familial cancer predisposition. Since the MMR defect is partial, these variants may represent low penetrance alleles.

Prins GS, Hu WY, Shi GB, et al.
Bisphenol A promotes human prostate stem-progenitor cell self-renewal and increases in vivo carcinogenesis in human prostate epithelium.
Endocrinology. 2014; 155(3):805-17 [PubMed] Free Access to Full Article Related Publications
Previous studies in rodent models have shown that early-life exposure to bisphenol A (BPA) reprograms the prostate and enhances its susceptibility to hormonal carcinogenesis with aging. To determine whether the human prostate is similarly sensitive to BPA, the current study used human prostate epithelial stem-like cells cultured from prostates of young, disease-free donors. Similar to estradiol-17β (E2), BPA increased stem-progenitor cell self-renewal and expression of stem-related genes in a dose-dependent manner. Further, 10 nM BPA and E2 possessed equimolar membrane-initiated signaling with robust induction of p-Akt and p-Erk at 15 minutes. To assess in vivo carcinogenicity, human prostate stem-progenitor cells combined with rat mesenchyme were grown as renal grafts in nude mice, forming normal human prostate epithelium at 1 month. Developmental BPA exposure was achieved through oral administration of 100 or 250 μg BPA/kg body weight to hosts for 2 weeks after grafting, producing free BPA levels of 0.39 and 1.35 ng/mL serum, respectively. Carcinogenesis was driven by testosterone plus E2 treatment for 2 to 4 months to model rising E2 levels in aging men. The incidence of high-grade prostate intraepithelial neoplasia and adenocarcinoma markedly increased from 13% in oil-fed controls to 33% to 36% in grafts exposed in vivo to BPA (P < .05). Continuous developmental BPA exposure through in vitro (200 nM) plus in vivo (250 μg/kg body weight) treatments increased high-grade prostate intraepithelial neoplasia/cancer incidence to 45% (P < .01). Together, the present findings demonstrate that human prostate stem-progenitor cells are direct BPA targets and that developmental exposure to BPA at low doses increases hormone-dependent cancer risk in the human prostate epithelium.

Lisanti S, Omar WA, Tomaszewski B, et al.
Comparison of methods for quantification of global DNA methylation in human cells and tissues.
PLoS One. 2013; 8(11):e79044 [PubMed] Free Access to Full Article Related Publications
DNA methylation is a key epigenetic modification which, in mammals, occurs mainly at CpG dinucleotides. Most of the CpG methylation in the genome is found in repetitive regions, rich in dormant transposons and endogenous retroviruses. Global DNA hypomethylation, which is a common feature of several conditions such as ageing and cancer, can cause the undesirable activation of dormant repeat elements and lead to altered expression of associated genes. DNA hypomethylation can cause genomic instability and may contribute to mutations and chromosomal recombinations. Various approaches for quantification of global DNA methylation are widely used. Several of these approaches measure a surrogate for total genomic methyl cytosine and there is uncertainty about the comparability of these methods. Here we have applied 3 different approaches (luminometric methylation assay, pyrosequencing of the methylation status of the Alu repeat element and of the LINE1 repeat element) for estimating global DNA methylation in the same human cell and tissue samples and have compared these estimates with the "gold standard" of methyl cytosine quantification by HPLC. Next to HPLC, the LINE1 approach shows the smallest variation between samples, followed by Alu. Pearson correlations and Bland-Altman analyses confirmed that global DNA methylation estimates obtained via the LINE1 approach corresponded best with HPLC-based measurements. Although, we did not find compelling evidence that the gold standard measurement by HPLC could be substituted with confidence by any of the surrogate assays for detecting global DNA methylation investigated here, the LINE1 assay seems likely to be an acceptable surrogate in many cases.

Simon JM, Hacker KE, Singh D, et al.
Variation in chromatin accessibility in human kidney cancer links H3K36 methyltransferase loss with widespread RNA processing defects.
Genome Res. 2014; 24(2):241-50 [PubMed] Free Access to Full Article Related Publications
Comprehensive sequencing of human cancers has identified recurrent mutations in genes encoding chromatin regulatory proteins. For clear cell renal cell carcinoma (ccRCC), three of the five commonly mutated genes encode the chromatin regulators PBRM1, SETD2, and BAP1. How these mutations alter the chromatin landscape and transcriptional program in ccRCC or other cancers is not understood. Here, we identified alterations in chromatin organization and transcript profiles associated with mutations in chromatin regulators in a large cohort of primary human kidney tumors. By associating variation in chromatin organization with mutations in SETD2, which encodes the enzyme responsible for H3K36 trimethylation, we found that changes in chromatin accessibility occurred primarily within actively transcribed genes. This increase in chromatin accessibility was linked with widespread alterations in RNA processing, including intron retention and aberrant splicing, affecting ∼25% of all expressed genes. Furthermore, decreased nucleosome occupancy proximal to misspliced exons was observed in tumors lacking H3K36me3. These results directly link mutations in SETD2 to chromatin accessibility changes and RNA processing defects in cancer. Detecting the functional consequences of specific mutations in chromatin regulatory proteins in primary human samples could ultimately inform the therapeutic application of an emerging class of chromatin-targeted compounds.

Kegelaers D, Merckx W, Odeurs P, et al.
Disclosure pattern and follow-up after the molecular diagnosis of BRCA/CHEK2 mutations.
J Genet Couns. 2014; 23(2):254-61 [PubMed] Related Publications
Five to 10% of all breast cancer cases are due to mutations of high penetrance susceptibility genes, especially BRCA1 and BRCA2. In families with known BRCA mutations, disclosure of genetic test results could induce relatives to undergo genetic testing themselves and adopt cancer risk management strategies, if necessary. This study examines disclosure patterns of individuals tested for mutations in the BRCA1, BRCA2 and CHEK2 genes to first-degree relatives with emphasis on a possible gender difference. It also assesses which management strategy is preferred by mutation-positive women in Belgium and the influence of psychological characteristics on communication and choice of management strategy. Ninety-nine adults from BRCA/CHEK2 families, selected from the Centre of Medical Genetics of Antwerp, were included in the study. They were provided with medical and psychological questionnaires, the latter being the Self-Assessment Questionnaire, which is the Dutch version of the Spielberger State-Trait Anxiety Inventory and the Dutch version of the Coping Inventory for Stressful Situations (CISS-NL). The survey focused on disclosure, coping and management strategies with special attention on possible gender differences. The influence of socio-demographic and medical data on disclosure and cancer risk management as well as the influence of psychological features were examined by means of various statistical analyses. Ninety-nine patients were included, of whom 25 (25 %) were male. Eighty-seven percent of the participants informed all of their adult first-degree relatives about their mutation status without any gender discrimination. Seventy-eight percent of highly-educated participants informed all of their adult first-degree relatives, compared to 98 % of less formally-educated participants (p = 0.006). The majority of mutation-positive women preferred prophylactic surgery to surveillance. Psychological differences appeared to have little influence on disclosure patterns and management strategies. The gender difference seems to be less pronounced than previously assumed. A striking observation, however, is the fact that significantly more participants who were less formally-educated informed all of their adult first-degree relatives, compared to participants who were highly-educated. In our study population, most female mutation carriers opted for prophylactic surgery. Since the study population is small, further studies are needed to enhance the generalizability of these results.

Sie AS, van Zelst-Stams WA, Spruijt L, et al.
More breast cancer patients prefer BRCA-mutation testing without prior face-to-face genetic counseling.
Fam Cancer. 2014; 13(2):143-51 [PubMed] Related Publications
Currently, most breast cancer (BC) patients receive face-to-face genetic counseling (DNA-intake) prior to BRCA-mutation testing, with generic information regarding hereditary BC and BRCA-mutation testing. This prospective study evaluated a novel format: replacing the intake consultation with telephone, written and digital information sent home, and face-to-face contact following BRCA-mutation testing (DNA-direct). From August 2011 to February 2012, 161 of 233 eligible BC patients referred to our Human Genetics department chose between DNA-direct (intervention) or DNA-intake (control). Exclusion criteria were psychological problems (n = 33), difficulty with Dutch text (n = 5), known BRCA-family (n = 3), non-BRCA-referral (n = 1). 30 declined genetic counseling or study participation. Participants received questionnaires including satisfaction and psychological distress. 59 % chose DNA-direct (p = 0.03), of whom 90 % were satisfied and would choose DNA-direct again (including 6/8 BRCA-mutation carriers); although 27 % hesitated to recommend DNA-direct to other patients. General distress (GHQ-12, p = 0.001) and heredity-specific distress (IES, p = 0.02) scored lower in DNA-direct than DNA-intake, both at baseline and follow-up 2 weeks after BRCA-result disclosure; all scores remained below clinical relevance. DNA-direct participants reported higher website use (53 vs. 32 %, p = 0.01), more referrer information about personal consequences (41 vs. 20 %, p = 0.004) and lower decisional conflict (median 20 [0-88] vs. 25 [0-50], p = 0.01). Processing time in DNA-direct was reduced by 1 month. Mutation detection rate was 8 % in both groups. All BRCA-mutation carriers fulfilled current testing criteria. In conclusion, more BC patients preferred DNA-direct over intake consultation prior to BRCA-mutation testing, the majority being strongly to moderately satisfied with the procedure followed, without increased distress.

Prins MJ, Ruurda JP, van Diest PJ, et al.
Evaluation of the HER2 amplification status in oesophageal adenocarcinoma by conventional and automated FISH: a tissue microarray study.
J Clin Pathol. 2014; 67(1):26-32 [PubMed] Related Publications
INTRODUCTION: The manual fluorescence in situ hybridisation (FISH) Human Epidermal Growth Factor Receptor 2 (HER2)/CEP17 testing method is frequently used, however, it is time consuming and liable to subjectivity. Automation of FISH might increase the throughput and accuracy.
AIM: To evaluate the agreement between automated and conventional FISH with regard to a reference test silver-enhanced in situ hybridization (SISH) for HER2 amplification, as well as its prognostic significance.
MATERIAL AND METHODS: 154 oesophageal adenocarcinomas were included in a tissue microarray. HER2/CEP17 gene amplification was assessed by automated FISH and was compared with conventional HER2/CEP17 testing methods.
RESULTS: 46.8% of patients showed HER2 amplified tumours by automated FISH (ratio ≥1.8) compared with 18.1% by conventional FISH. A high automated HER2/CEP17 ratio (≥1.8) was significantly associated with worse survival (HR 1.731; 95% CI 1.075 to 2.786; p=0.024). However, agreement between automated and conventional FISH was only 72.2% and 71.4% between automated FISH and SISH, compared with 94.6% for conventional FISH/SISH. Therefore, thresholds for HER2/CEP17 amplification were sequentially raised from HER2/CEP17 ratio 1.8 till 5.0. A HER2/CEP17 ratio threshold of ≥3.6 had similar prognostic significance as conventional FISH (HR 1.880; 95% CI 1.060 to 3.332; p=0.031 vs HR 1.828; 95% CI 1.102 to 3.033; p=0.020), yielded comparable amplification rates as conventional FISH (14.3% vs 18.1%) and comparable agreement to SISH/Immunohistochemistry (IHC).
CONCLUSIONS: Automation of HER2 FISH analysis in oesophageal cancer has not been performed before. Automated HER2 is feasible, but it seems that the HER2/CEP17 threshold should be adjusted to ≥3.6 to arrive at best comparability with other methods and prognostic value.

Snoeren N, Emmink BL, Koerkamp MJ, et al.
Maspin is a marker for early recurrence in primary stage III and IV colorectal cancer.
Br J Cancer. 2013; 109(6):1636-47 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Little is known about the factors that drive metastasis formation in colorectal cancer (CRC). Here, we set out to identify genes and proteins in patients with colorectal liver metastases that correlate with early disease recurrence. Such factors may predict a propensity for metastasis in earlier stages of CRC.
METHODS: Gene expression profiling and proteomics were used to identify differentially expressed genes/proteins in resected liver metastases that recurred within 6 months following liver surgery vs those that did not recur for >24 months. Expression of the identified genes/proteins in stage II (n=243) and III (n=176) tumours was analysed by immunohistochemistry on tissue microarrays. Correlation of protein levels with stage-specific outcome was assessed by uni- and multivariable analyses.
RESULTS: Both gene expression profiling and proteomics identified Maspin to be differentially expressed in colorectal liver metastases with early (<6 months) and prolonged (>24 months) time to recurrence. Immunohistochemical analysis of Maspin expression on tumour sections revealed that it was an independent predictor of time to recurrence (log-rank P=0.004) and CRC-specific survival (P=0.000) in stage III CRC. High Maspin expression was also correlated with mucinous differentiation. In stage II CRC patients, high Maspin expression did not correlate with survival but was correlated with a right-sided tumour location.
CONCLUSION: High Maspin expression correlates with poor outcome in CRC after spread to the local lymph nodes. Therefore, Maspin may have a stage-specific function possibly related to tumour cell dissemination and/or metastatic outgrowth.

Sie AS, Prins JB, Spruijt L, et al.
Can we test for hereditary cancer at 18 years when we start surveillance at 25? Patient reported outcomes.
Fam Cancer. 2013; 12(4):675-82 [PubMed] Related Publications
DNA-testing for BRCA1/2 or Lynch syndrome is possible from the age of 18 years, although surveillance usually starts at 25. Some patients regret their decision of testing before age 25. This retrospective study evaluates whether the testing age should be above 25 years to prevent adverse effects such as regret or decisional conflict, by determining the percentage and characteristics of patients reporting these problems. 111 of 219 patients (51%) tested for BRCA1/2 mutations or Lynch syndrome between 18 and 25 years from July 1996 to February 2011, returned self-report surveys. Primary measures were regret, decisional conflict and family influence. Secondary measures included quality of life (QoL), coping style, impact of genetic testing, and risk perception. Median age was 27 [21-40] years, with 86% female. 73% was tested for BRCA1/2, 27% for Lynch syndrome. Only 3% reported regret, however 39% had moderate (32%) to severe (7%) decisional conflict. Regression analysis revealed that decisional conflict was associated with more monitoring/neutral coping style (p < 0.03) or paternal/no family mutation (p < 0.02); there were no differences in QoL, impact or risk perception. 42% were mutation carriers, showing equal decisional conflict to non-carriers. 68% would recommend testing <25 years; 77% desired surveillance <25 years if a mutation carrier. Almost no patient tested for hereditary cancer between 18 and 25 years regretted this decision. A third reported retrospective decisional conflict, especially those actively seeking information when faced with a threat and/or those with a paternal or unknown inheritance. These patients may benefit from decisional support and personalized information.

Williams KJ, Argus JP, Zhu Y, et al.
An essential requirement for the SCAP/SREBP signaling axis to protect cancer cells from lipotoxicity.
Cancer Res. 2013; 73(9):2850-62 [PubMed] Free Access to Full Article Related Publications
The sterol regulatory element-binding proteins (SREBP) are key transcriptional regulators of lipid metabolism and cellular growth. It has been proposed that SREBP signaling regulates cellular growth through its ability to drive lipid biosynthesis. Unexpectedly, we find that loss of SREBP activity inhibits cancer cell growth and viability by uncoupling fatty acid synthesis from desaturation. Integrated lipid profiling and metabolic flux analysis revealed that cancer cells with attenuated SREBP activity maintain long-chain saturated fatty acid synthesis, while losing fatty acid desaturation capacity. We traced this defect to the uncoupling of fatty acid synthase activity from stearoyl-CoA desaturase 1 (SCD1)-mediated desaturation. This deficiency in desaturation drives an imbalance between the saturated and monounsaturated fatty acid pools resulting in severe lipotoxicity. Importantly, replenishing the monounsaturated fatty acid pool restored growth to SREBP-inhibited cells. These studies highlight the importance of fatty acid desaturation in cancer growth and provide a novel mechanistic explanation for the role of SREBPs in cancer metabolism.

Prins MJ, Ruurda JP, van Diest PJ, et al.
The significance of the HER-2 status in esophageal adenocarcinoma for survival: an immunohistochemical and an in situ hybridization study.
Ann Oncol. 2013; 24(5):1290-7 [PubMed] Related Publications
BACKGROUND: In esophageal adenocarcinoma (EAC), concordance and prognostic significance of human epidermal growth factor 2 (HER-2) protein overexpression and gene amplification are equivocal, which led us to reevaluate this by immunohistochemistry (IHC) and in situ hybridization.
METHODS: One hundred and fifty-four patients were included in a tissue micro array (TMA). HER-2 gene amplification was assessed by fluorescence and silver-enhanced in situ hybridization (FISH and SISH) and expression with the HercepTest™.
RESULTS: HER-2 was amplified in 16% by SISH and 18% by FISH. HER-2 positivity (IHC 3+ or 2+ with ISH+) was seen in 12% and overexpression (IHC 2+/3+) in 14%. Concordance was 92% between SISH/IHC, 90% between FISH/IHC and 95% between SISH/FISH. All IHC 3+ cases were amplified by SISH and in 93% by FISH. Of the IHC 2+cases, this was 33% (SISH) and 50% (FISH). Of the IHC 1+ cases, still 6% (SISH) and 8% (FISH) showed amplification. HER-2 positivity, overexpression and amplification were all associated with poor cancer-specific survival, in univariate analysis. Furthermore, HER-2 positivity and amplification (SISH) were independently associated with poor survival (hazard ratio, HR 6.343; 95% CI 1.218-36.234; P = 0.029 and HR 3.231; 95% CI 1.092-9.563; P = 0.034).
CONCLUSION: HER-2 positivity and gene amplification are fairly frequent and independently associated with poor survival.

Lodewijk L, Prins AM, Kist JW, et al.
The value of miRNA in diagnosing thyroid cancer: a systematic review.
Cancer Biomark. 2012; 11(6):229-38 [PubMed] Related Publications
Thyroid cancer is the most common endocrine neoplasm accounting for approximately 1,7% of total cancer diagnoses. The gold standard for evaluation of thyroid nodules is cytology from fine needle aspiration. In 30% of biopsies there is no conclusive diagnosis and patients undergo a diagnostic hemithyroidectomy. Somatic mutations occur frequently in thyroid cancer, the value of testing FNA biopsies on different mutation is analyzed, it improves accuracy, but their sensitivity is low. Another class of molecules with potential diagnostic value are miRNAs (miRNA, miR). MiRNAs function as gene regulators thereby controlling many cellular processes including cell growth, differentiation, proliferation, and apoptosis. Several studies have analyzed the expression of miRNAs in thyroid cancer, either by performing microarray analyses or validating a set of miRNAs. Recent reports focused on the diagnostic value of miRNAs in indeterminate FNA biopsies. In this systematic review we will provide an overview of all miRNAs found to be up- or downregulated in the different types of thyroid carcinomas, give an overview of the value of validated sets of microRNAs or single microRNAs in distinguishing malignant from benign lesions and conclude with a clinical view on future study strategies.

Hu Y, Huang Y, Du Y, et al.
DiffSplice: the genome-wide detection of differential splicing events with RNA-seq.
Nucleic Acids Res. 2013; 41(2):e39 [PubMed] Free Access to Full Article Related Publications
The RNA transcriptome varies in response to cellular differentiation as well as environmental factors, and can be characterized by the diversity and abundance of transcript isoforms. Differential transcription analysis, the detection of differences between the transcriptomes of different cells, may improve understanding of cell differentiation and development and enable the identification of biomarkers that classify disease types. The availability of high-throughput short-read RNA sequencing technologies provides in-depth sampling of the transcriptome, making it possible to accurately detect the differences between transcriptomes. In this article, we present a new method for the detection and visualization of differential transcription. Our approach does not depend on transcript or gene annotations. It also circumvents the need for full transcript inference and quantification, which is a challenging problem because of short read lengths, as well as various sampling biases. Instead, our method takes a divide-and-conquer approach to localize the difference between transcriptomes in the form of alternative splicing modules (ASMs), where transcript isoforms diverge. Our approach starts with the identification of ASMs from the splice graph, constructed directly from the exons and introns predicted from RNA-seq read alignments. The abundance of alternative splicing isoforms residing in each ASM is estimated for each sample and is compared across sample groups. A non-parametric statistical test is applied to each ASM to detect significant differential transcription with a controlled false discovery rate. The sensitivity and specificity of the method have been assessed using simulated data sets and compared with other state-of-the-art approaches. Experimental validation using qRT-PCR confirmed a selected set of genes that are differentially expressed in a lung differentiation study and a breast cancer data set, demonstrating the utility of the approach applied on experimental biological data sets. The software of DiffSplice is available at http://www.netlab.uky.edu/p/bioinfo/DiffSplice.

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