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Obon-Santacana, M., Lujan-Barroso, L., Freisling, H., Naudin, S., Boutron-Ruault, M.-C., Mancini, F. R., . . . Duell, E. J. (2020). Consumption of nuts and seeds and pancreatic ductal adenocarcinoma risk in the European Prospective Investigation into Cancer and Nutrition. International Journal of Cancer, 146(1), 76-84
Open this publication in new window or tab >>Consumption of nuts and seeds and pancreatic ductal adenocarcinoma risk in the European Prospective Investigation into Cancer and Nutrition
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2020 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 146, no 1, p. 76-84Article in journal (Refereed) Published
Abstract [en]

Four epidemiologic studies have assessed the association between nut intake and pancreatic cancer risk with contradictory results. The present study aims to investigate the relation between nut intake (including seeds) and pancreatic ductal adenocarcinoma (PDAC) risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Cox proportional hazards models were used to estimate hazards ratio (HR) and 95% confidence intervals (95% CI) for nut intake and PDAC risk. Information on intake of nuts was obtained from the EPIC country-specific dietary questionnaires. After a mean follow-up of 14 years, 476,160 participants were eligible for the present study and included 1,283 PDAC cases. No association was observed between consumption of nuts and PDAC risk (highest intake vs nonconsumers: HR, 0.89; 95% CI, 0.72-1.10; p-trend = 0.70). Furthermore, no evidence for effect-measure modification was observed when different subgroups were analyzed. Overall, in EPIC, the highest intake of nuts was not statistically significantly associated with PDAC risk.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2020
Keywords
pancreatic cancer, nuts, seeds, diet, intake, EPIC, prospective cohort study
National Category
Cancer and Oncology Nutrition and Dietetics
Identifiers
urn:nbn:se:umu:diva-165785 (URN)10.1002/ijc.32415 (DOI)000495546500011 ()31107546 (PubMedID)
Funder
Swedish Cancer SocietyRegion SkåneVästerbotten County Council
Available from: 2019-12-03 Created: 2019-12-03 Last updated: 2019-12-03Bibliographically approved
Bremer, T., Savala, J., Leesman, G., Wärnberg, F., Sund, M., Wadsten, C. & Whitworth, P. W. (2019). A biologic signature to predict ipsilateral breast event risk at 10 years for early breast cancer. Paper presented at San Antonio Breast Cancer Symposium, San Antonio, Texas, December 04-08, 2018. Cancer Research, 79(4)
Open this publication in new window or tab >>A biologic signature to predict ipsilateral breast event risk at 10 years for early breast cancer
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2019 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 79, no 4Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
American Association for Cancer Research, 2019
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-162695 (URN)10.1158/1538-7445.SABCS18-P2-08-57 (DOI)000478677001031 ()
Conference
San Antonio Breast Cancer Symposium, San Antonio, Texas, December 04-08, 2018
Available from: 2019-09-05 Created: 2019-09-05 Last updated: 2019-09-05Bibliographically approved
Walsh, N., Zhang, H., Hyland, P. L., Yang, Q., Mocci, E., Zhang, M., . . . Stolzenberg-Solomon, R. Z. (2019). Agnostic Pathway/Gene Set Analysis of Genome-Wide Association Data Identifies Associations for Pancreatic Cancer. Journal of the National Cancer Institute, 111(6), Article ID djy155.
Open this publication in new window or tab >>Agnostic Pathway/Gene Set Analysis of Genome-Wide Association Data Identifies Associations for Pancreatic Cancer
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2019 (English)In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 111, no 6, article id djy155Article in journal (Refereed) Published
Abstract [en]

Background: Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes.

Methods: We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided.

Results: We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P ≤ 1.3 × 10-5), the strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor (EGF) receptor transactivation by G protein-coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. We identified and validated rs876493 and three correlating SNPs (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets.

Conclusion: Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified.

Place, publisher, year, edition, pages
Oxford University Press, 2019
National Category
Clinical Medicine
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-154571 (URN)10.1093/jnci/djy155 (DOI)000474267400006 ()30541042 (PubMedID)
Funder
NIH (National Institute of Health), HHSN261200800001E
Available from: 2018-12-19 Created: 2018-12-19 Last updated: 2019-07-26Bibliographically approved
Nichols, H. B., Schoemaker, M. J., Cai, J., Xu, J., Wright, L. B., Brook, M. N., . . . Sandler, D. P. (2019). Breast Cancer Risk After Recent Childbirth: A Pooled Analysis of 15 Prospective Studies. Annals of Internal Medicine, 170(1), 22-30
Open this publication in new window or tab >>Breast Cancer Risk After Recent Childbirth: A Pooled Analysis of 15 Prospective Studies
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2019 (English)In: Annals of Internal Medicine, ISSN 0003-4819, E-ISSN 1539-3704, Vol. 170, no 1, p. 22-30Article in journal (Refereed) Published
Abstract [en]

Background: Parity is widely recognized as protective for breast cancer, but breast cancer risk may be increased shortly after childbirth. Whether this risk varies with breastfeeding, family history of breast cancer, or specific tumor subtype has rarely been evaluated.

Objective: To characterize breast cancer risk in relation to recent childbirth.

Design: Pooled analysis of individual-level data from 15 prospective cohort studies.

Setting: The international Premenopausal Breast Cancer Collaborative Group.

Participants: Women younger than 55 years.

Measurements: During 9.6 million person-years of follow-up, 18 826 incident cases of breast cancer were diagnosed. Hazard ratios (HRs) and 95% CIs for breast cancer were calculated using Cox proportional hazards regression.

Results: Compared with nulliparous women, parous women had an HR for breast cancer that peaked about 5 years after birth (HR, 1.80 [95% CI, 1.63 to 1.99]) before decreasing to 0.77 (CI, 0.67 to 0.88) after 34 years. The association crossed over from positive to negative about 24 years after birth. The overall pattern was driven by estrogen receptor (ER)-positive breast cancer; no crossover was seen for ER-negative cancer. Increases in breast cancer risk after childbirth were pronounced when combined with a family history of breast cancer and were greater for women who were older at first birth or who had more births. Breastfeeding did not modify overall risk patterns.

Limitations: Breast cancer diagnoses during pregnancy were not uniformly distinguishable from early postpartum diagnoses. Data on human epidermal growth factor receptor 2 (HER2) oncogene overexpression were limited.

Conclusion: Compared with nulliparous women, parous women have an increased risk for breast cancer for more than 20 years after childbirth. Health care providers should consider recent childbirth a risk factor for breast cancer in young women.

Primary Funding Source: The Avon Foundation, the National Institute of Environmental Health Sciences, Breast Cancer Now and the UK National Health Service, and the Institute of Cancer Research.

Place, publisher, year, edition, pages
American College of Physicians, 2019
National Category
Surgery
Identifiers
urn:nbn:se:umu:diva-154575 (URN)10.7326/M18-1323 (DOI)000454685300008 ()30534999 (PubMedID)
Funder
NIH (National Institute of Health), UM1 CA176726NIH (National Institute of Health), UM1 CA186107NIH (National Institute of Health), UM1 CA164974NIH (National Institute of Health), R01 CA058420NIH (National Institute of Health), R01 CA092447NIH (National Institute of Health), P50 CA168504Swedish Research CouncilSwedish Cancer SocietyRegion SkåneVästerbotten County Council
Available from: 2018-12-19 Created: 2018-12-19 Last updated: 2019-09-05Bibliographically approved
Honda, K., Katzke, V. A., Hüsing, A., Okaya, S., Shoji, H., Onidani, K., . . . Kaaks, R. (2019). CA19-9 and apolipoprotein-A2 isoforms as detection markers for pancreatic cancer: a prospective evaluation. International Journal of Cancer, 144(8), 1877-1887
Open this publication in new window or tab >>CA19-9 and apolipoprotein-A2 isoforms as detection markers for pancreatic cancer: a prospective evaluation
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2019 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 144, no 8, p. 1877-1887Article in journal (Refereed) Published
Abstract [en]

Recently, we identified unique processing patterns of apolipoprotein A2 (ApoA2) in patients with pancreatic cancer. Our study provides a first prospective evaluation of an ApoA2 isoform ("ApoA2-ATQ/AT"), alone and in combination with carbohydrate antigen 19-9 (CA19-9), as an early detection biomarker for pancreatic cancer. We performed ELISA measurements of CA19-9 and ApoA2-ATQ/AT in 156 patients with pancreatic cancer and 217 matched controls within the European EPIC cohort, using plasma samples collected up to 60 months prior to diagnosis. The detection discrimination statistics were calculated for risk scores by strata of lag-time. For CA19-9, in univariate marker analyses, C-statistics to distinguish future pancreatic cancer patients from cancer-free individuals were 0.80 for plasma taken ≤6 months before diagnosis, and 0.71 for >6-18 months; for ApoA2-ATQ/AT, C-statistics were 0.62, and 0.65, respectively. Joint models based on ApoA2-ATQ/AT plus CA19-9 significantly improved discrimination within >6-18 months (C = 0.74 vs. 0.71 for CA19-9 alone, p = 0.022) and ≤ 18 months (C = 0.75 vs. 0.74, p = 0.022). At 98% specificity, and for lag times of ≤6, >6-18 or ≤ 18 months, sensitivities were 57%, 36% and 43% for CA19-9 combined with ApoA2-ATQ/AT, respectively, vs. 50%, 29% and 36% for CA19-9 alone. Compared to CA19-9 alone, the combination of CA19-9 and ApoA2-ATQ/AT may improve detection of pancreatic cancer up to 18 months prior to diagnosis under usual care, and may provide a useful first measure for pancreatic cancer detection prior to imaging.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2019
Keywords
CA19-9, apolipoprotein A2, early detection, isoforms, pancreatic cancer, prospective study
National Category
Surgery
Identifiers
urn:nbn:se:umu:diva-154581 (URN)10.1002/ijc.31900 (DOI)000458824300010 ()30259989 (PubMedID)
Available from: 2018-12-19 Created: 2018-12-19 Last updated: 2019-04-05Bibliographically approved
Nilchian, A., Johansson, J., Ghalali, A., Travica Asanin, S., Santiago, A., Rosencrantz, O., . . . Fuxe, J. (2019). CXADR-Mediated Formation of an AKT Inhibitory Signalosome at Tight Junctions Controls Epithelial-Mesenchymal Plasticity in Breast Cancer.. Cancer Research, 79(1), 47-60
Open this publication in new window or tab >>CXADR-Mediated Formation of an AKT Inhibitory Signalosome at Tight Junctions Controls Epithelial-Mesenchymal Plasticity in Breast Cancer.
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2019 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 79, no 1, p. 47-60Article in journal (Refereed) Published
Abstract [en]

Tight junctions (TJ) act as hubs for intracellular signaling pathways controlling epithelial cell fate and function. Deregulation of TJ is a hallmark of epithelial-mesenchymal transition (EMT), which contributes to carcinoma progression and metastasis. However, the signaling mechanisms linking TJ to the induction of EMT are not understood. Here we identify a TJ-based signalosome, which controls AKT signaling and EMT in breast cancer. The coxsackie- and adenovirus receptor (CXADR), a TJ protein with an essential yet uncharacterized role in organogenesis and tissue homeostasis, was identified as a key component of the signalosome. CXADR regulated the stability and function of the phosphatases and AKT inhibitors PTEN and PHLPP2. Loss of CXADR led to hyper-activation of AKT and sensitized cells to TGF-β1-induced EMT. Conversely, restoration of CXADR stabilized PHLPP2 and PTEN, inhibited AKT, and promoted epithelial differentiation. Loss of CXADR in luminal A breast cancer correlated with loss of PHLPP2 and PTEN and poor prognosis. These results show that CXADR promotes the formation of an AKT-inhibitory signalosome at TJ and regulates epithelial-mesenchymal plasticity in breast cancer cells. Moreover, loss of CXADR might be used as a prognostic marker in luminal breast cancer.

Place, publisher, year, edition, pages
American Association for Cancer Research, 2019
National Category
Basic Medicine Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-154580 (URN)10.1158/0008-5472.CAN-18-1742 (DOI)000454833400006 ()30385615 (PubMedID)
Funder
Swedish Research Council, 2017-03056Swedish Research Council, 2018-3114Swedish Cancer Society, CAN 2015/773
Available from: 2018-12-19 Created: 2018-12-19 Last updated: 2019-01-25Bibliographically approved
Maggino, L., Schmidt, A., Kaeding, A., Westermark, S., Sund, M. & Gaujoux, S. (2019). Cystic Pancreatic Neuroendocrine Neoplasms: A Multicenter International Cohort Study. Paper presented at 16th Annual ENETS Conference, 6-8 March 2019, Barcelona, Spain. Neuroendocrinology, 108(Suppl. 1), 245-245
Open this publication in new window or tab >>Cystic Pancreatic Neuroendocrine Neoplasms: A Multicenter International Cohort Study
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2019 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 108, no Suppl. 1, p. 245-245Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Introduction: Natural history of cystic pancreatic neuroendocrine neoplasms (cPanNENs) is unknown, and their clinical management remains unclear. An observational strategy for asymptomatic cPanNENs ≤2cm has been proposed by recent guidelines, but evidence is scarce and limited to single-institutional series.

Aim(s): Analyze a large international cohort of cPanNENs.

Materials and methods: All resected cPanNENs (1995-2017) from 16 institutions worldwide were included. Solid lesions (>50% solid component), functional tumors and MEN-1 patients were excluded. Malignancy was defined as G3 grading, lymph node (LN) involvement, metastasis and/or recurrence.

Results: Overall, 263 resected cPanNENs were included, among which 177 (63.5%) were preoperatively >2cm. A preoperative diagnosis of cPanNEN was established in 162 cases (61.6%) and was more frequent when patients underwent endoscopic ultrasound (EUS, OR 3.01, 95%CI 1.66-5.44) and nuclear medicine investigations (OR 3.97, 95%CI 1.93-8.18), and for those managed in high-volume institutions (OR 3.48, 95%CI 1.88-6.45). Forty-one cPanNENs (15.6%) were malignant. Suspicion of LN involvement on imaging, age >65 years, preoperative size >2cm and pancreatic duct dilation were independently associated with malignancy in the whole cohort. In asymptomatic patients, older age and a preoperative size >2cm remained independently associated with malignancy. Notably, malignancy occurred in only 1/61 asymptomatic patients with a preoperative size ≤2cm.

Conclusion: The diagnostic accuracy of cPanNENs is increased by the use of EUS and nuclear medicine investigations and is higher in high-volume institutions. A preoperative size >2cm is independently associated with malignancy, so that a wait-and-see policy for sporadic asymptomatic cPanNENs≤ 2cm seems justified.

Place, publisher, year, edition, pages
S. Karger, 2019
Keywords
cystic pancreatic neuroendocrine tumors, surgery
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-157793 (URN)10.1159/000498996 (DOI)000460981800246 ()
Conference
16th Annual ENETS Conference, 6-8 March 2019, Barcelona, Spain
Available from: 2019-04-02 Created: 2019-04-02 Last updated: 2019-04-02Bibliographically approved
Javed, M. A., Beyer, G., Le, N., Vinci, A., Wong, H., Palmer, D., . . . Krug, S. (2019). Impact of intensified chemotherapy in metastatic pancreatic ductal adenocarcinoma (PDAC) in clinical routine in Europe. Pancreatology (Print), 19(1), 97-104
Open this publication in new window or tab >>Impact of intensified chemotherapy in metastatic pancreatic ductal adenocarcinoma (PDAC) in clinical routine in Europe
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2019 (English)In: Pancreatology (Print), ISSN 1424-3903, E-ISSN 1424-3911, Vol. 19, no 1, p. 97-104Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis. Gemcitabine is the standard chemotherapy for patients with metastatic pancreatic adenocarcinoma (MPA). Randomized clinical trials evaluating intensified chemotherapies including FOLFIRINOX and nab-paclitaxel plus gemcitabine (NAB+GEM) have shown improvement in survival. Here, we have evaluated the efficacy of intensified chemotherapy versus gemcitabine monotherapy in real-life settings across Europe.

METHODS: A retrospective multi-center study including 1056 MPA patients, between 2012 and 2015, from nine centers in UK, Germany, Italy, Hungary and the Swedish registry was performed. Follow-up was at least 12 months. Cox proportional Harzards regression was used for uni- and multivariable evaluation of prognostic factors.

RESULTS: Of 1056 MPA patients, 1030 (98.7%) were assessable for survival analysis. Gemcitabine monotherapy was the most commonly used regimen (41.3%), compared to FOLFIRINOX (n = 204, 19.3%), NAB+GEM (n = 81, 7.7%) and other gemcitabine- or 5-FU-based regimens (n = 335, 31.7%). The median overall survival (OS) was: FOLFIRINOX 9.9 months (95%CI 8.4-12.6), NAB+GEM 7.9 months (95%CI 6.2-10.0), other combinations 8.5 months (95%CI 7.7-9.3) and gemcitabine monotherapy 4.9 months (95%CI 4.4-5.6). Compared to gemcitabine monotherapy, any combination of chemotherapeutics improved the survival with no significant difference between the intensified regimens. Multivariable analysis showed an association between treatment center, male gender, inoperability at diagnosis and performance status (ECOG 1-3) with poor prognosis.

CONCLUSION: Gemcitabine monotherapy was predominantly used in 2012-2015. Intensified chemotherapy improved OS in comparison to gemcitabine monotherapy. In real-life settings, the OS rates of different treatment approaches are lower than shown in randomized phase III trials.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Intensified chemotherapy, Multicenter study, Pancreatic cancer
National Category
Surgery Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-154578 (URN)10.1016/j.pan.2018.10.003 (DOI)000456089400015 ()30529068 (PubMedID)
Available from: 2018-12-19 Created: 2018-12-19 Last updated: 2019-02-26Bibliographically approved
Gasull, M., Pumarega, J., Kiviranta, H., Rantakokko, P., Raaschou-Nielsen, O., Bergdahl, I. A., . . . Porta, M. (2019). Methodological issues in a prospective study on plasma concentrations of persistent organic pollutants and pancreatic cancer risk within the EPIC cohort. Environmental Research, 169, 417-433
Open this publication in new window or tab >>Methodological issues in a prospective study on plasma concentrations of persistent organic pollutants and pancreatic cancer risk within the EPIC cohort
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2019 (English)In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 169, p. 417-433Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The use of biomarkers of environmental exposure to explore new risk factors for pancreatic cancer presents clinical, logistic, and methodological challenges that are also relevant in research on other complex diseases.

OBJECTIVES: First, to summarize the main design features of a prospective case-control study -nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort- on plasma concentrations of persistent organic pollutants (POPs) and pancreatic cancer risk. And second, to assess the main methodological challenges posed by associations among characteristics and habits of study participants, fasting status, time from blood draw to cancer diagnosis, disease progression bias, basis of cancer diagnosis, and plasma concentrations of lipids and POPs. Results from etiologic analyses on POPs and pancreatic cancer risk, and other analyses, will be reported in future articles.

METHODS: Study subjects were 1533 participants (513 cases and 1020 controls matched by study centre, sex, age at blood collection, date and time of blood collection, and fasting status) enrolled between 1992 and 2000. Plasma concentrations of 22 POPs were measured by gas chromatography - triple quadrupole mass spectrometry (GC-MS/MS). To estimate the magnitude of the associations we calculated multivariate-adjusted odds ratios by unconditional logistic regression, and adjusted geometric means by General Linear Regression Models.

RESULTS: There were differences among countries in subjects' characteristics (as age, gender, smoking, lipid and POP concentrations), and in study characteristics (as time from blood collection to index date, year of last follow-up, length of follow-up, basis of cancer diagnosis, and fasting status). Adjusting for centre and time of blood collection, no factors were significantly associated with fasting status. Plasma concentrations of lipids were related to age, body mass index, fasting, country, and smoking. We detected and quantified 16 of the 22 POPs in more than 90% of individuals. All 22 POPs were detected in some participants, and the smallest number of POPs detected in one person was 15 (median, 19) with few differences by country. The highest concentrations were found for p,p'-DDE, PCBs 153 and 180 (median concentration: 3371, 1023, and 810 pg/mL, respectively). We assessed the possible occurrence of disease progression bias (DPB) in eight situations defined by lipid and POP measurements, on one hand, and by four factors: interval from blood draw to index date, tumour subsite, tumour stage, and grade of differentiation, on the other. In seven of the eight situations results supported the absence of DPB.

CONCLUSIONS: The coexistence of differences across study centres in some design features and participant characteristics is of relevance to other multicentre studies. Relationships among subjects' characteristics and among such characteristics and design features may play important roles in the forthcoming analyses on the association between plasma concentrations of POPs and pancreatic cancer risk.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Biomarkers, methods, Disease progression bias, Environmental epidemiology, Lipids, Pancreatic cancer, Persistent organic pollutants
National Category
Surgery
Identifiers
urn:nbn:se:umu:diva-154577 (URN)10.1016/j.envres.2018.11.027 (DOI)000458592200045 ()30529143 (PubMedID)
Available from: 2018-12-19 Created: 2018-12-19 Last updated: 2019-04-15Bibliographically approved
Borgmästars, E., de Weerd, H. A., Lubovac-Pilav, Z. & Sund, M. (2019). miRFA: an automated pipeline for microRNA functional analysis with correlation support from TCGA and TCPA expression data in pancreatic cancer. BMC Bioinformatics, 20, Article ID 393.
Open this publication in new window or tab >>miRFA: an automated pipeline for microRNA functional analysis with correlation support from TCGA and TCPA expression data in pancreatic cancer
2019 (English)In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 20, article id 393Article in journal (Refereed) Published
Abstract [en]

Background: MicroRNAs (miRNAs) are small RNAs that regulate gene expression at a post-transcriptional level and are emerging as potentially important biomarkers for various disease states, including pancreatic cancer. In silico-based functional analysis of miRNAs usually consists of miRNA target prediction and functional enrichment analysis of miRNA targets. Since miRNA target prediction methods generate a large number of false positive target genes, further validation to narrow down interesting candidate miRNA targets is needed. One commonly used method correlates miRNA and mRNA expression to assess the regulatory effect of a particular miRNA.

The aim of this study was to build a bioinformatics pipeline in R for miRNA functional analysis including correlation analyses between miRNA expression levels and its targets on mRNA and protein expression levels available from the cancer genome atlas (TCGA) and the cancer proteome atlas (TCPA). TCGA-derived expression data of specific mature miRNA isoforms from pancreatic cancer tissue was used.

Results: Fifteen circulating miRNAs with significantly altered expression levels detected in pancreatic cancer patients were queried separately in the pipeline. The pipeline generated predicted miRNA target genes, enriched gene ontology (GO) terms and Kyoto encyclopedia of genes and genomes (KEGG) pathways. Predicted miRNA targets were evaluated by correlation analyses between each miRNA and its predicted targets. MiRNA functional analysis in combination with Kaplan-Meier survival analysis suggest that hsa-miR-885-5p could act as a tumor suppressor and should be validated as a potential prognostic biomarker in pancreatic cancer.

Conclusions: Our miRNA functional analysis (miRFA) pipeline can serve as a valuable tool in biomarker discovery involving mature miRNAs associated with pancreatic cancer and could be developed to cover additional cancer types. Results for all mature miRNAs in TCGA pancreatic adenocarcinoma dataset can be studied and downloaded through a shiny web application at https://emmbor.shinyapps.io/mirfa/.

Place, publisher, year, edition, pages
BioMed Central, 2019
Keywords
miRNA functional analysis, miRNA target prediction, Functional enrichment, Mature miRNA, TCGA, TCPA, Pancreatic cancer
National Category
Bioinformatics and Systems Biology
Identifiers
urn:nbn:se:umu:diva-161899 (URN)10.1186/s12859-019-2974-3 (DOI)000475761100001 ()31311505 (PubMedID)2-s2.0-85069159500 (Scopus ID)
Available from: 2019-08-07 Created: 2019-08-07 Last updated: 2019-08-07Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-7516-9543

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