Publications by authors named "Jon Jonasson"

181 Publications

The effect of sample age on the metabolic information extracted from formalin-fixed and paraffin embedded tissue samples using desorption electrospray ionization mass spectrometry imaging.

J Mass Spectrom Adv Clin Lab 2021 Nov 28;22:50-55. Epub 2021 Oct 28.

Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London SW7 2AZ, United Kingdom.

Metabolites, especially lipids, have been shown to be promising therapeutic targets. In conjugation with genes and proteins they can be used to identify phenotypes of disease and support the development of targeted treatments. The majority of clinically collected tissue samples are stored in formalin-fixed and paraffin embedded (FFPE) blocks due to their tissue conservation ability and indefinite storage capacity. For metabolic analysis, however, fresh frozen (FF) samples are currently preferred over FFPE samples due to concerns of metabolic information being lost when preparing the samples. With little or no sample preparation, desorption electrospray ionisation mass spectrometry imaging (DESI-MSI) allows for the study of spatial as well as spectral information. DESI-MSI analysis was performed on FFPE breast cancer tissue microarray samples from 213 patients collected between the years 1935-2013. Logistic regression (LR) models were built to classify samples based on age and FF samples were used for feature validation. LR models developed on the FFPE samples achieved an average classification accuracy of 96% when predicting their age with a 10-year grouping. Closer examination of the metabolic change over time revealed that the mean signal intensities for the lower mass range (100 - 500 m/z) linearly decrease over time, while the mean intensities for the higher mass range (500 - 900 m/z), remained relatively constant. In our samples, which span over 70 years, sample age has a weak yet quantifiable impact on metabolite content in FFPE samples, while the higher mass range is seemingly unaffected. FFPE samples thus provide an alternative avenue for metabolic analysis of lipids.
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http://dx.doi.org/10.1016/j.jmsacl.2021.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8662337PMC
November 2021

Sarcoidosis in Iceland: a nationwide study of epidemiology, clinical picture and environmental exposure.

ERJ Open Res 2021 Oct 13;7(4). Epub 2021 Dec 13.

Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

Background: This nationwide study aimed to elucidate the incidence and clinical characteristics of tissue-verified sarcoidosis in Iceland. A secondary aim was to analyse sex differences and identify possible environmental factors contributing to the pathological process.

Materials And Methods: This is a descriptive study covering 36 years (January 1, 1981 through December 31, 2016). Histopathological reports and electronic hospital discharge registries were reviewed in context for granulomas and/or sarcoidosis. National data were used for comparison regarding smoking habits and occupation, adjusted for age, sex and year of diagnosis. The data were stored in FileMaker and calculations were made by extracting data from this database to the statistical software package R.

Results: A total of 418 patients (54% females) were diagnosed with tissue-verified sarcoidosis. The incidence rate was 4.15/100 000/year, similar among females and males. The mean age at diagnosis was higher among females (53.0±14.2 years) than males (48.2±13.8 years). Fatigue was the most frequent single symptom (49.7%), but when all respiratory symptoms were grouped, they were the most frequent symptoms (60%). No significant difference was found between smoking status and sarcoidosis. Possible hazardous exposure in the workplace was reported by 19.4% of the cases.

Conclusion: The incidence of sarcoidosis in Iceland was higher than in an Asian population where the same inclusion criteria were applied. The clinical picture diverges partly from that in the Asian population but resembles that among other Caucasians. Fatigue and respiratory symptoms were predominant. The biphasic pattern of age at disease debut seen elsewhere among females was not evident in Iceland.
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http://dx.doi.org/10.1183/23120541.00550-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8666626PMC
October 2021

[Forty year old female with cough and chest pain].

Laeknabladid 2021 06;107(6):297-299

Faculty of Medicine, University of Iceland, Cardiothoracic Surgery, Landspitali University Hospital, Reykjavík, Iceland.

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http://dx.doi.org/10.17992/lbl.2021.06.641DOI Listing
June 2021

Reply to: Metformin use and keratinocyte carcinoma risk.

J Am Acad Dermatol 2021 10 27;85(4):e265. Epub 2021 May 27.

Faculty of Medicine, University of Iceland, Reykjavik, Iceland; Department of Pathology, Landspitali National-University Hospital, Reykjavik, Iceland.

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http://dx.doi.org/10.1016/j.jaad.2021.05.028DOI Listing
October 2021

A nationwide population-based prospective study of cirrhosis in Iceland.

JHEP Rep 2021 Jun 31;3(3):100282. Epub 2021 Mar 31.

Department of Internal Medicine, Division of Gastroenterology and Hepatology, Landspitali-National University Hospital of Iceland, Reykjavik, Iceland.

Background & Aims: The incidence of cirrhosis in Iceland has been the lowest in the world with only 3 cases per 100,000 inhabitants. Alcohol consumption has almost doubled in Iceland from 1980 to 2016. Obesity has also risen and hepatitis C virus has spread among people who inject drugs in Iceland. The aim of this study was to evaluate the effects of these risk factors on the incidence and aetiology of cirrhosis in Iceland.

Methods: The study included all patients diagnosed with cirrhosis for the first time during 2010-2015. Diagnosis was based on liver histology or 2 of 4 criteria: cirrhosis on imaging, ascites, varices, and/or elevated INR.

Results: Overall, 157 patients were diagnosed, 105 (67%) males, mean age 61 years. The overall incidence was 9.7 cases per 100,000 inhabitants annually. Alcohol was the only underlying cause in 48/157 (31%), non-alcoholic fatty liver disease (NAFLD) in 34/157(22%), and alcohol and hepatitis C together in 23/157(15%) were the most common causes. Only 6% of patients had an unknown cause of cirrhosis. Upon diagnosis, the median model for end-stage liver disease score was 11 (IQR 8-15), 53% were of Child-Pugh class A whereas 61 (39%) had ascites, 11% encephalopathy, and 8% variceal bleeding. In all, 25% of deaths were from HCC and 25% from liver failure.

Conclusion: A major increase in incidence of cirrhosis has occurred in Iceland associated with increases in alcohol consumption, obesity, and hepatitis C. In a high proportion NAFLD was the aetiology and very few had unknown cause of cirrhosis. The highest death rate was from HCC.

Lay Summary: In a nationwide population-based study from Iceland, including all patients diagnosed with cirrhosis of the liver over a period of 5 years, we found the incidence of new cases had increased 3-fold compared with a previous study 20 years ago. The increase is attributable to increased alcohol consumption, an epidemic of diabetes and obesity, and infection with the hepatitis C virus. Furthermore, we found that with thorough investigations, a specific cause for cirrhosis could be found in 94% of patients. Patients with cirrhosis frequently die of liver cancer and other complications related to their liver disease.
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http://dx.doi.org/10.1016/j.jhepr.2021.100282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141932PMC
June 2021

Technical in-depth comparison of two massive parallel DNA-sequencing methods for formalin-fixed paraffin-embedded tissue from victims of sudden cardiac death.

Forensic Sci Int Genet 2021 07 26;53:102522. Epub 2021 Apr 26.

Department of Laboratory Medicine, Örebro University Hospital, Sweden; Faculty of Medicine and Health, Örebro University, Örebro Sweden.

Sudden cardiac death (SCD) is a tragic and traumatic event. SCD is often associated with hereditary genetic disease and in such cases, sequencing of stored formalin fixed paraffin embedded (FFPE) tissue is often crucial in trying to find a causal genetic variant. This study was designed to compare two massive parallel sequencing assays for differences in sensitivity and precision regarding variants related to SCD in FFPE material. From eight cases of SCD where DNA from blood had been sequenced using HaloPlex, corresponding FFPE samples were collected six years later. DNA from FFPE samples were amplified using HaloPlex HS, sequenced on MiSeq, representing the first method, as well as amplified using modified Twist and sequenced on NextSeq, representing the second method. Molecular barcodes were included to distinguish artefacts from true variants. In both approaches, read coverage, uniformity and variant detection were compared using genomic DNA isolated from blood and corresponding FFPE tissue, respectively. In terms of coverage uniformity, Twist performed better than HaloPlex HS for FFPE samples. Despite higher overall coverage, amplicon-based HaloPlex technologies, both for blood and FFPE tissue, suffered from design and/or performance issues resulting in genes lacking complete coverage. Although Twist had considerably lower overall mean coverage, high uniformity resulted in equal or higher fraction of genes covered at ≥ 20X. By comparing variants found in the matched samples in a pre-defined cardiodiagnostic gene panel, HaloPlex HS for FFPE material resulted in high sensitivity, 98.0% (range 96.6-100%), and high precision, 99.9% (range 99.5-100%) for moderately fragmented samples, but suffered from reduced sensitivity (range 74.2-91.1%) in more severely fragmented samples due to lack of coverage. Twist had high sensitivity, 97.8% (range 96.8-98.7%) and high precision, 99.9% (range 99.3-100%) in all analyzed samples, including the severely fragmented samples.
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http://dx.doi.org/10.1016/j.fsigen.2021.102522DOI Listing
July 2021

Statins are associated with increased risk of squamous cell carcinoma of the skin: a whole-population study from Iceland.

Arch Dermatol Res 2021 Mar 27. Epub 2021 Mar 27.

Faculty of Medicine, University of Iceland, Saemundargata 2, 101, Reykjavík, Iceland.

Statins have been associated with an increased risk of keratinocyte carcinoma but data are limited and conflicting. Statins are hypothesized to contribute to KC through immunomodulation. A whole-population case-control study of the Icelandic population was conducted using the Icelandic Cancer Registry and Icelandic Prescription Medicine Register. These are high-quality registers which include all cancer diagnoses, as well as every prescription in the country. Cases included all first-time histologically confirmed diagnoses of (BCC), in situ squamous cell carcinoma (SCCis) and invasive SCC between 2003 and 2017. Each case was paired with 10 age- and sex-matched controls. Multivariate conditional logistic regression analysis was performed. Four thousand seven hundred patients with BCC, 1167 patients with SCCis and 1013 patients with invasive SCC were identified and paired with 47,292, 11,961 and 10,367 controls, respectively. Overall statin use was associated with an increased risk of invasive SCC and SCCis but not BCC (adjusted OR [95% CI]: 1.29 [1.11-1.50]; 1.43 [1.24-1.64]; 1.03 [0.95-1.12], respectively). Subgroup analysis demonstrated that statins were significantly associated with invasive SCC and SCCis in patients over 60, but not in those under 60. Atorvastatin was only associated with an increased risk of SCCis; whereas, simvastatin was associated with an increased risk of both invasive SCC and SCCis. This whole-population study of Iceland demonstrates that statin exposure is associated with increased risk of SCC, but not BCC, in a low UV environment. The reasons are unclear, but our results may suggest that individuals receiving atorvastatin and simvastatin have differing levels of baseline keratinocyte cancer risk or that properties of a statin other than 'statin intensity' affect association with SCC.
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http://dx.doi.org/10.1007/s00403-021-02227-wDOI Listing
March 2021

Metformin is associated with decreased risk of basal cell carcinoma: A whole-population case-control study from Iceland.

J Am Acad Dermatol 2021 Jul 19;85(1):56-61. Epub 2021 Feb 19.

Faculty of Medicine, University of Iceland, Reykjavik, Iceland; Department of Pathology, Landspitali National-University Hospital, Reykjavik, Iceland.

Background: Metformin has anticarcinogenic properties and is also known to inhibit the sonic hedgehog pathway, but population-based studies analyzing the potential protective effect for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are needed.

Objectives: To delineate the association between metformin use and invasive SCC, SCC in situ (SCCis), and BCC.

Methods: A population-based case-control study design was employed using all 6880 patients diagnosed in Iceland between 2003-2017 with first-time BCC, SCCis, or invasive SCC, and 69,620 population controls. Multivariate odds ratios (ORs) were calculated using conditional logistic regression.

Results: Metformin was associated with a lower risk of developing BCC (OR, 0.71; 95% confidence interval [CI], 0.61-0.83), even at low doses. No increased risk of developing SCC was observed. SCCis risk was mildly elevated in the 501-1500 daily dose unit category (OR, 1.40; 95% CI, 1.00-1.96).

Limitations: This study was retrospective in nature with the inability to adjust for ultraviolet exposure, Fitzpatrick skin type, and comorbidities.

Conclusion: Metformin is associated with decreased risk of BCC development, even at low doses. Metformin might have potential as a chemoprotective agent for patients at high risk of BCC, although this will need confirmation in future studies.
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http://dx.doi.org/10.1016/j.jaad.2021.02.042DOI Listing
July 2021

Loss-of-Function Variants in the Tumor-Suppressor Gene Confer Increased Cancer Risk.

Cancer Res 2021 04 18;81(8):1954-1964. Epub 2021 Feb 18.

deCODE Genetics/Amgen, Reykjavik, Iceland.

The success of genome-wide association studies (GWAS) in identifying common, low-penetrance variant-cancer associations for the past decade is undisputed. However, discovering additional high-penetrance cancer mutations in unknown cancer predisposing genes requires detection of variant-cancer association of ultra-rare coding variants. Consequently, large-scale next-generation sequence data with associated phenotype information are needed. Here, we used genotype data on 166,281 Icelanders, of which, 49,708 were whole-genome sequenced and 408,595 individuals from the UK Biobank, of which, 41,147 were whole-exome sequenced, to test for association between loss-of-function burden in autosomal genes and basal cell carcinoma (BCC), the most common cancer in Caucasians. A total of 25,205 BCC cases and 683,058 controls were tested. Rare germline loss-of-function variants in conferred substantial risks of BCC (OR, 8.0; = 1.9 × 10), with a quarter of carriers getting BCC before age 70 and over half in their lifetime. Furthermore, common variants at the locus were associated with BCC, suggesting as a new, high-impact BCC predisposition gene. A follow-up investigation of 24 cancers and three benign tumor types showed that loss-of-function variants are associated with high risk of cervical cancer (OR, 12.7, = 1.6 × 10) and low age at diagnosis. Our findings, using power-increasing methods with high-quality rare variant genotypes, highlight future prospects for new discoveries on carcinogenesis. SIGNIFICANCE: This study identifies the tumor-suppressor gene as a high-impact BCC predisposition gene and indicates that inactivation of by germline sequence variants may also lead to increased risk of cervical cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3065DOI Listing
April 2021

Hereditary Hypertrophic Cardiomyopathy in Children and Young Adults-The Value of Reevaluating and Expanding Gene Panel Analyses.

Genes (Basel) 2020 12 8;11(12). Epub 2020 Dec 8.

Department of Clinical Genetics, and Department of Biomedical and Clinical Sciences, Linköping University, 581 83 Linköping, Sweden.

Introduction: Sudden cardiac death (SCD) and early onset cardiomyopathy (CM) in the young will always lead to suspicion of an underlying genetic disorder. Incited by the rapid advances in genetic testing for disease we have revisited families, which previously tested "gene-negative" for familial predominantly pediatric CM, in hopes of finding a causative gene variant.

Methods: 10 different families with non-syndromic pediatric CM or hypertrophic cardiomyopathy (HCM) with severe disease progression and/or heredity for HCM/CM related SCD with "gene-negative" results were included. The index patient underwent genetic testing with a recently updated gene panel for CM and SCD. In case of failure to detect a pathogenic variant in a relevant gene, the index patient and both parents underwent clinical (i.e., partial) exome sequencing (trio-exome) in order to catch pathogenic variants linked to the disease in genes that were not included in the CM panel.

Results: The mean age at clinical presentation of the 10 index cases was 12.5 years (boys 13.4 years, = 8; girls 9 years, = 2) and the family history burden was 33 HCM/CM cases including 9 HCM-related SCD and one heart transplantation. In 5 (50%) families we identified a genetic variant classified as pathogenic or likely pathogenic, in accordance with the American College of Medical Genetics and Genomics (ACMG) criteria, in ( = 2), , , and , respectively, and genetic variants of unknown significance (VUS) segregating with the disease in an additional 3 (30%) families, in , , and , respectively.

Conclusion: Our results show the importance of renewed thorough clinical assessment and the necessity to challenge previous genetic test results with more comprehensive updated gene panels or exome sequencing if the initial test failed to identify a causative gene for early onset CM or SCD in children. In pediatric cardiomyopathy cases when the gene panel still fails to detect a causative variant, a trio exome sequencing strategy might resolve some unexplained cases, especially if a multisystemic condition is clinically missed.
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http://dx.doi.org/10.3390/genes11121472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764692PMC
December 2020

Increased risk of inflammatory bowel disease among patients treated with rituximab in Iceland from 2001 to 2018.

Scand J Gastroenterol 2021 Jan 5;56(1):46-52. Epub 2020 Dec 5.

Faculty of Medicine, University of Iceland, Reykjavík, Iceland.

Objective: Immune-mediated diseases are on the rise after the introduction of powerful immunomodulating drugs. The objective of this study was to determine the population-based incidence rate of inflammatory bowel disease (IBD) among patients treated with the monoclonal antibody rituximab in Iceland and compare it to the baseline incidence rate of IBD in the general population.

Methods: We identified all patients treated with rituximab in Iceland from 2001 to 2018 through a central medicine database. IBD cases were indexed from medical records and ICD-10 codes and further confirmed by colonoscopy- and pathology reports. An experienced pathologist compared the pathology of IBD cases with matched controls of IBD patients.

Results: Lymphomas and related neoplasms were the most frequent indication for treatment with rituximab ( = 367) among the 651 patients included in the analysis. Following treatment, seven patients developed IBD: two cases of Crohn's disease, three with ulcerative colitis, and two with indeterminate IBD. The incidence rate of IBD among rituximab treated patients was 202 cases per 100,000 person-years. Comparing our data to IBD incidence in Iceland, rituximab treated patients have an age-adjusted hazard ratio of 6.6 for developing IBD. The risk did not correlate with dose or treatment duration. Prior diagnosis of an autoimmune illness did not increase the risk of IBD in rituximab treated patients.

Conclusions: Patients on rituximab have a sixfold increased risk of developing IBD compared to the general population. This risk was not affected by the indication for treatment and was not associated with concurrent immune-mediated diseases. Summary This population-based retrospective cohort study included all patients receiving treatment with rituximab between 2001 and 2018 in Iceland and identified a sixfold increased risk of developing IBD when compared to the general population.
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http://dx.doi.org/10.1080/00365521.2020.1854847DOI Listing
January 2021

Anti-tumor necrosis factor therapy is associated with increased in situ squamous cell carcinoma of the skin: A population-based case-control study.

J Am Acad Dermatol 2021 Jun 27;84(6):1760-1762. Epub 2020 Nov 27.

Faculty of Medicine, University of Iceland, Reykjavik, Iceland; Department of Pathology, Landspitali National-University Hospital, Reykjavik, Iceland.

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http://dx.doi.org/10.1016/j.jaad.2020.11.029DOI Listing
June 2021

[Hepatitisvirus E: A discussion on two Icelandic cases].

Laeknabladid 2020 11;106(11):512-515

Department of gastroenterology, Landspítali University Hospital Reykjavík, Iceland.

Hepatitis E is a viral disease that is usually transmitted through contaminated drinking water and most often causes a self-limiting infection that does not require specific treatment. It is common in India and has caused outbreaks in Asia, Africa and Mexico but has very rarely been diagnosed in Iceland. We describe two cases of hepatitis E diagnosed in Iceland in the last year.
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http://dx.doi.org/10.17992/lbl.2020.11.606DOI Listing
November 2020

A nationwide study on hepatocellular carcinoma.

Cancer Epidemiol 2020 12 14;69:101835. Epub 2020 Oct 14.

Department of Gastroenterology and Hepatology, Landspitali University Hospital, Hringbraut, 101, Reykjavik, Iceland; Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, 101, Reykjavik, Iceland. Electronic address:

Background & Aims: Population based studies on the epidemiology of HCC are scarce. We aimed to compare CG (cirrhotic HCC group) with NCG (non-cirrhotic HCC group), analyze incidence, etiology and survival among patients diagnosed in Iceland in a population-based cohort. A previous study from Iceland (1984-1998) showed an incidence of HCC of 1.1/100.000, mostly with NCG.

Methods: A nationwide, population based retrospective study. Information on patients with HCC during 1998-2017 was obtained and medical records viewed.

Results: Overall 152 patients with HCC were identified. The mean incidence was 1.7/100.000 and increased by 8% annually. Alcohol and hepatitis C combined was more common as a risk factor in CG than in the NCG (13 % vs. 2%, p = 0.03). Tumor size was larger in NCG (11 cm vs 5 cm, p < 0.01) and portal vein thrombosis less common (11 % vs. 30 %, p = 0.03). Overall, 44 % in NCG underwent surgical treatment vs. 23 % in CG (p = 0.02). The proportion of patients diagnosed by surveillance in 1998-2007 was 3% and 19 % in 2008-2017 (p = 0.03). The disease specific median survival for cirrhotic patients diagnosed by surveillance was 519 days and 86 days in other cirrhotic patients, hazard ratio 0.45 (p = 0.007, CI 0.25-0.81).

Conclusions: A major increase in the incidence of patients with HCC has occurred. The non-cirrhotic HCC presented with larger size tumors, lower proportion of portal vein thrombosis and were more likely to be surgical candidates, although not affecting prognosis. Diagnosis by surveillance in patients with cirrhosis has increased and the survival of those patients is better compared to others.
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http://dx.doi.org/10.1016/j.canep.2020.101835DOI Listing
December 2020

Salivary gland tumours in Iceland 1986-2015: a nationwide epidemiological analysis over a 30-year time period.

APMIS 2021 Feb 3;129(2):55-60. Epub 2020 Nov 3.

Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

Salivary gland tumours (SGT) are a vast and heterogenous group of neoplasms. There is a relative lack of comprehensive nationwide epidemiological studies on the subject. The aim of this nationwide analysis was to gain insight into epidemiological traits, such as site, incidence and histological subtypes of SGT in general. Patients diagnosed with a primary SGT between 1986 and 2015 were identified from The Icelandic Cancer Registry and registries from all pathology departments in Iceland. Information on age, sex, tumour location and histology was retrieved from pathology reports. A total of 687 patients were diagnosed with a SGT, 609 (89%) were benign and 78 (11%) malignant. 9% of parotid gland tumours, 22% of submandibular gland tumours and 26% of minor SGT were malignant. The most common malignant tumours were mucoepidermoid carcinoma, acinic cell carcinoma and adenoid cystic carcinoma. The incidence of benign SGT was 4.9 per 100 000 among men and 7.0 per 100 000 among women. The incidence of malignant tumours was 0.59 per 100 000 for men and 0.79 per 100 000 for women. The proportion of malignant SGT is lower than most often reported. Only 10% of parotid gland tumours, 20% of submandibular gland tumours and 25% of minor salivary gland tumours are malignant.
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http://dx.doi.org/10.1111/apm.13090DOI Listing
February 2021

Breast cancer survival in Nordic BRCA2 mutation carriers-unconventional association with oestrogen receptor status.

Br J Cancer 2020 11 17;123(11):1608-1615. Epub 2020 Sep 17.

Icelandic Cancer Registry, Icelandic Cancer Society, Reykjavik, Iceland.

Background: The natural history of breast cancer among BRCA2 carriers has not been clearly established. In a previous study from Iceland, positive ER status was a negative prognostic factor. We sought to identify factors that predicted survival after invasive breast cancer in an expanded cohort of BRCA2 carriers.

Methods: We studied 608 women with invasive breast cancer and a pathogenic BRCA2 mutation (variant) from four Nordic countries. Information on prognostic factors and treatment was retrieved from health records and by analysis of archived tissue specimens. Hazard ratios (HR) were estimated for breast cancer-specific survival using Cox regression.

Results: About 77% of cancers were ER-positive, with the highest proportion (83%) in patients under 40 years. ER-positive breast cancers were more likely to be node-positive (59%) than ER-negative cancers (34%) (P < 0.001). The survival analysis included 584 patients. Positive ER status was protective in the first 5 years from diagnosis (multivariate HR = 0.49; 95% CI 0.26-0.93, P = 0.03); thereafter, the effect was adverse (HR = 1.91; 95% CI 1.07-3.39, P = 0.03). The adverse effect of positive ER status was limited to women who did not undergo endocrine treatment (HR = 2.36; 95% CI 1.26-4.44, P = 0.01) and patients with intact ovaries (HR = 1.99; 95% CI 1.11-3.59, P = 0.02).

Conclusions: The adverse effect of a positive ER status in BRCA2 carriers with breast cancer may be contingent on exposure to ovarian hormones.
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http://dx.doi.org/10.1038/s41416-020-01056-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686356PMC
November 2020

Association between hydrochlorothiazide and the risk of in situ and invasive squamous cell skin carcinoma and basal cell carcinoma: A population-based case-control study.

J Am Acad Dermatol 2021 Mar 11;84(3):669-675. Epub 2020 Aug 11.

Faculty of Medicine, University of Iceland, Reykjavik, Iceland; Department of Pathology, Landspitali National-University Hospital, Reykjavik, Iceland.

Background: Population-based studies analyzing hydrochlorothiazide's (HCTZ's) effect on keratinocyte carcinoma, and particularly invasive squamous cell carcinoma (SCC), are lacking.

Objectives: To characterize the association between HCTZ use and invasive SCC, SCC in situ (SCCis), and basal cell carcinoma (BCC).

Methods: This population-based case-control study included all 6880 patients diagnosed with first-time BCC, SCCis, and invasive SCC between 2003 and 2017 in Iceland and 69,620 population controls. Conditional logistic regression analyses were used to calculate multivariate odds ratios (ORs) for keratinocyte carcinoma associated with HCTZ use.

Results: A cumulative HCTZ dose above 37,500 mg was associated with increased risk of invasive SCC (OR, 1.69; 95% confidence interval [CI], 1.04-2.74). Users of HCTZ also had an increased risk of SCCis (OR, 1.24; 95% CI, 1.01-1.52) and BCC (OR, 1.14; 95% CI, 1.02-1.29).

Limitations: Limitations include this study's retrospective nature with the resulting inability to adjust for ultraviolet exposure, Fitzpatrick skin type, and comorbidities.

Conclusions: High cumulative exposure to HCTZ is associated with the development of keratinocyte carcinoma and, most importantly, invasive SCC. Sun protective behaviors alone may not eliminate the carcinogenic potential of HCTZ.
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http://dx.doi.org/10.1016/j.jaad.2020.08.025DOI Listing
March 2021

GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer.

Nat Commun 2020 08 7;11(1):3981. Epub 2020 Aug 7.

Center for Statistical Genetics and Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.

Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. To better understand the genetic contribution to TSH levels, we conduct a GWAS meta-analysis at 22.4 million genetic markers in up to 119,715 individuals and identify 74 genome-wide significant loci for TSH, of which 28 are previously unreported. Functional experiments show that the thyroglobulin protein-altering variants P118L and G67S impact thyroglobulin secretion. Phenome-wide association analysis in the UK Biobank demonstrates the pleiotropic effects of TSH-associated variants and a polygenic score for higher TSH levels is associated with a reduced risk of thyroid cancer in the UK Biobank and three other independent studies. Two-sample Mendelian randomization using TSH index variants as instrumental variables suggests a protective effect of higher TSH levels (indicating lower thyroid function) on risk of thyroid cancer and goiter. Our findings highlight the pleiotropic effects of TSH-associated variants on thyroid function and growth of malignant and benign thyroid tumors.
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http://dx.doi.org/10.1038/s41467-020-17718-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414135PMC
August 2020

Ashwagandha as a cause for liver injury.

Liver Int 2020 08 11;40(8):2035-2036. Epub 2020 Jun 11.

Einstein Healthcare Network, Sidney Kimmel Medical College, Philadelphia, Pennsylvania, USA.

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http://dx.doi.org/10.1111/liv.14551DOI Listing
August 2020

Monozygotic twins with myocarditis and a novel likely pathogenic desmoplakin gene variant.

ESC Heart Fail 2020 06 17;7(3):1210-1216. Epub 2020 Apr 17.

Department of Clinical Genetics and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.

Myocarditis most often affects otherwise healthy athletes and is one of the leading causes of sudden death in children and young adults. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically determined heart muscle disorder with increased risk for paroxysmal ventricular arrhythmias and sudden cardiac death. The clinical picture of myocarditis and ARVC may overlap during the early stages of cardiomyopathy, which may lead to misdiagnosis. In the literature, we found several cases that presented with episodes of myocarditis and ended up with a diagnosis of arrhythmogenic cardiomyopathy, mostly of the left predominant type. The aim of this case presentation is to shed light upon a possible link between myocarditis, a desmoplakin (DSP) gene variant, and ARVC by describing a case of male monozygotic twins who presented with symptoms and signs of myocarditis at 17 and 18 years of age, respectively. One of them also had a recurrent episode of myocarditis. The twins and their family were extensively examined including electrocardiograms (ECG), biochemistry, multimodal cardiac imaging, myocardial biopsy, genetic analysis, repeated cardiac magnetic resonance (CMR) and echocardiography over time. Both twins presented with chest pain, ECG with slight ST-T elevation, and increased troponin T levels. CMR demonstrated an affected left ventricle with comprehensive inflammatory, subepicardial changes consistent with myocarditis. The right ventricle did not appear to have any abnormalities. Genotype analysis revealed a nonsense heterozygous variant in the desmoplakin (DSP) gene [NM_004415.2:c.2521_2522del (p.Gln841Aspfs*9)] that is considered likely pathogenic and presumably ARVC related. There was no previous family history of heart disease. There might be a common pathophysiology of ARVC, associated with desmosomal dysfunction, and myocarditis. In our case, both twins have an affected left ventricle without any right ventricular involvement, and they are carriers of a novel DSP variant that is likely associated with ARVC. The extensive inflammation of the LV that was apparent in the CMR may or may not be the primary event of ARVC. Nevertheless, our data suggest that irrespective of a possible link here to ARVC, genetic testing for arrhythmogenic cardiomyopathy might be advisable for patients with recurrent myocarditis associated with a family history of myocarditis.
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http://dx.doi.org/10.1002/ehf2.12658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261567PMC
June 2020

Genome-wide analyses disclose the distinctive HLA architecture and the pharmacogenetic landscape of the Somali population.

Sci Rep 2020 03 27;10(1):5652. Epub 2020 Mar 27.

Department of Clinical Chemistry, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.

African populations are underrepresented in medical genomics studies. For the Somali population, there is virtually no information on genomic markers with significance to precision medicine. Here, we analyzed nearly 900,000 genomic markers in samples collected from 95 unrelated individuals in the North Eastern Somalia. ADMIXTURE program for estimation of individual ancestries revealed a homogenous Somali population. Principal component analysis with PLINK software showed approximately 60% East African and 40% West Eurasian genes in the Somali population, with a close relation to the Cushitic and Semitic speaking Ethiopian populations. We report the unique features of human leukocyte antigens (HLA) in the Somali population, which seem to differentiate from all other neighboring regions compared. Current study identified high prevalence of the diabetes type 1 (T1D) predisposing HLA DR-DQ haplotypes in Somalia. This finding may explain the increased T1D risk observed among Somali children. In addition, ethnic Somalis were found to host the highest frequencies observed thus far for several pharmacogenetic variants, including UGT1A4*2. In conclusion, we report that the Somali population displays genetic traits of significance to health and disease. The Somali dataset is publicly available and will add more information to the few genomic datasets available for African populations.
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http://dx.doi.org/10.1038/s41598-020-62645-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101338PMC
March 2020

ECM1 secreted by HER2-overexpressing breast cancer cells promotes formation of a vascular niche accelerating cancer cell migration and invasion.

Lab Invest 2020 07 18;100(7):928-944. Epub 2020 Mar 18.

Department of Anatomy, Stem Cell Research Unit, Biomedical Center, Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.

The tumor microenvironment is increasingly recognized as key player in cancer progression. Investigating heterotypic interactions between cancer cells and their microenvironment is important for understanding how specific cell types support cancer. Forming the vasculature, endothelial cells (ECs) are a prominent cell type in the microenvironment of both normal and neoplastic breast gland. Here, we sought out to analyze epithelial-endothelial cross talk in the breast using isogenic non-tumorigenic vs. tumorigenic breast epithelial cell lines and primary ECs. The cellular model used here consists of D492, a breast epithelial cell line with stem cell properties, and two isogenic D492-derived EMT cell lines, D492M and D492HER2. D492M was generated by endothelial-induced EMT and is non-tumorigenic while D492HER2 is tumorigenic, expressing the ErbB2/HER2 oncogene. To investigate cellular cross talk, we used both conditioned medium (CM) and 2D/3D co-culture systems. Secretome analysis of D492 cell lines was performed using mass spectrometry and candidate knockdown (KD), and overexpression (OE) was done using siRNA and CRISPRi/CRISPRa technology. D492HER2 directly enhances endothelial network formation and activates a molecular axis in ECs promoting D492HER2 migration and invasion, suggesting an endothelial feedback response. Secretome analysis identified extracellular matrix protein 1 (ECM1) as potential angiogenic inducer in D492HER2. Confirming its involvement, KD of ECM1 reduced the ability of D492HER2-CM to increase endothelial network formation and induce the endothelial feedback, while recombinant ECM1 (rECM1) increased both. Interestingly, NOTCH1 and NOTCH3 expression was upregulated in ECs upon treatment with D492HER2-CM or rECM1 but not by CM from D492HER2 with ECM1 KD. Blocking endothelial NOTCH signaling inhibited the increase in network formation and the ability of ECs to promote D492HER2 migration and invasion. In summary, our data demonstrate that cancer-secreted ECM1 induces a NOTCH-mediated endothelial feedback promoting cancer progression by enhancing migration and invasion. Targeting this interaction may provide a novel possibility to improve cancer treatment.
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http://dx.doi.org/10.1038/s41374-020-0415-6DOI Listing
July 2020

Promoter Methylation Status in 1031 Primary Breast Cancers Predicts Favorable Outcomes Following Chemotherapy.

JNCI Cancer Spectr 2020 Apr 11;4(2):pkz100. Epub 2019 Dec 11.

Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

Background: Breast Cancer 1 gene () is known to be inactivated in breast tumors by promoter methylation. Tumor cells in patients carrying a germline mutation in are sensitive to cytotoxic drugs that cause DNA double strand breaks. However, very little is known on whether patients with promoter methylated tumors are similarly sensitive to cytotoxic drugs. In this study, we address this by making use of extensive follow-up data on patients treated with cyclophosphamide, methotrexate, and fluorouracil in Iceland between 1976 and 2007.

Methods: We analyzed promoter methylation by pyrosequencing DNA from tumor samples from 1031 patients with primary breast cancer. Of those, 965 were sporadic cases, 61 were , and five were germline mutation carriers. All cases were examined with respect to clinicopathological parameters and breast cancer-specific survival in patients treated with cytotoxic drugs. Information on chemotherapy treatment in noncarriers was available for 26 methylated tumors and 857 unmethylated tumors.

Results: was promoter methylated in 29 sporadic tumors or in 3.0% of cases (29 of 965), whereas none of the tumors derived from germline mutation carriers were promoter methylated. Important to note, patients with promoter methylation receiving chemotherapeutic drug treatment show highly improved breast cancer-specific survival compared with unmethylated controls (hazard ratio = 0.10, 95% confidence interval = 0.01 to 0.75, two-sided  = .02).

Conclusions: promoter methylation is predictive of improved disease outcome in patients receiving cyclophosphamide, methotrexate, and fluorouracil drug treatment. Our results support the use of markers indicative of "BRCAness" in sporadic breast cancers to identify patients that are likely to benefit from the use of DNA-damaging agents.
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http://dx.doi.org/10.1093/jncics/pkz100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7061679PMC
April 2020

Assessing thyroid cancer risk using polygenic risk scores.

Proc Natl Acad Sci U S A 2020 03 4;117(11):5997-6002. Epub 2020 Mar 4.

Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210;

Genome-wide association studies (GWASs) have identified at least 10 single-nucleotide polymorphisms (SNPs) associated with papillary thyroid cancer (PTC) risk. Most of these SNPs are common variants with small to moderate effect sizes. Here we assessed the combined genetic effects of these variants on PTC risk by using summarized GWAS results to build polygenic risk score (PRS) models in three PTC study groups from Ohio (1,544 patients and 1,593 controls), Iceland (723 patients and 129,556 controls), and the United Kingdom (534 patients and 407,945 controls). A PRS based on the 10 established PTC SNPs showed a stronger predictive power compared with the clinical factors model, with a minimum increase of area under the receiver-operating curve of 5.4 percentage points ( ≤ 1.0 × 10). Adding an extended PRS based on 592,475 common variants did not significantly improve the prediction power compared with the 10-SNP model, suggesting that most of the remaining undiscovered genetic risk in thyroid cancer is due to rare, moderate- to high-penetrance variants rather than to common low-penetrance variants. Based on the 10-SNP PRS, individuals in the top decile group of PRSs have a close to sevenfold greater risk (95% CI, 5.4-8.8) compared with the bottom decile group. In conclusion, PRSs based on a small number of common germline variants emphasize the importance of heritable low-penetrance markers in PTC.
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http://dx.doi.org/10.1073/pnas.1919976117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084156PMC
March 2020

Novel SMAD3 p.Arg386Thr genetic variant co-segregating with thoracic aortic aneurysm and dissection.

Mol Genet Genomic Med 2020 04 5;8(4):e1089. Epub 2020 Feb 5.

Department of Clinical Genetics and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.

Background: Pathogenic variants in the SMAD3 gene affecting the TGF-β/SMAD3 signaling pathway with aortic vessel involvement cause Loeys-Dietz syndrome 3, also known as aneurysms-osteoarthritis syndrome.

Methods: Description of clinical history of a family in Sweden using clinical data, DNA sequencing, bioinformatics, and pedigree analysis.

Results: We report a novel SMAD3 variant, initially classified as a genetic variant of uncertain clinical significance (VUS), and later found to be co-segregating with aortic dissection in the family. The index patient presented with a dissecting aneurysm of the aorta including the ascending, descending, and abdominal parts. Genotype analysis revealed a heterozygous missense SMAD3 variant: NM_005902.3(SMAD3): c.11576G > C (p.Arg386Thr). The same variant was also identified in a 30 years old formalin-fixed paraffin-embedded block of tissue from a second cousin, who died at 26 years of age from a dissecting aneurysm of the aorta.

Conclusion: A "variant of uncertain significance" according to the ACMG guidelines has always a scope for reappraisal. Genetic counselling to relatives, and the offering of surveillance service is important to families with aortic aneurysm disease. The report also highlight the potential use of FFPE analysis from deceased relatives to help in the interpretation of variants.
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http://dx.doi.org/10.1002/mgg3.1089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196476PMC
April 2020

Ashwagandha-induced liver injury: A case series from Iceland and the US Drug-Induced Liver Injury Network.

Liver Int 2020 04 11;40(4):825-829. Epub 2020 Feb 11.

Einstein Healthcare Network, Sidney Kimmel Medical College, Philadelphia, PA, USA.

Background & Aims: Ashwagandha (Withania somnifera) is widely used in Indian Ayurvedic medicine. Several dietary supplements containing ashwagandha are marketed in the US and Europe, but only one case of drug-induced liver injury (DILI) due to ashwagandha has been published. The aim of this case series was to describe the clinical phenotype of suspected ashwagandha-induced liver injury.

Methods: Five cases of liver injury attributed to ashwagandha-containing supplements were identified; three were collected in Iceland during 2017-2018 and two from the Drug-Induced Liver Injury Network (DILIN) in 2016. Other causes for liver injury were excluded. Causality was assessed using the DILIN structured expert opinion causality approach.

Results: Among the five patients, three were males; mean age was 43 years (range 21-62). All patients developed jaundice and symptoms such as nausea, lethargy, pruritus and abdominal discomfort after a latency of 2-12 weeks. Liver injury was cholestatic or mixed (R ratios 1.4-3.3). Pruritus and hyperbilirubinaemia were prolonged (5-20 weeks). No patient developed hepatic failure. Liver tests normalized within 1-5 months in four patients. One patient was lost to follow-up. One biopsy was performed, showing acute cholestatic hepatitis. Chemical analysis confirmed ashwagandha in available supplements; no other toxic compounds were identified. No patient was taking potentially hepatotoxic prescription medications, although four were consuming additional supplements, and in one case, rhodiola was a possible causative agent along with ashwagandha.

Conclusions: These cases illustrate the hepatotoxic potential of ashwagandha. Liver injury is typically cholestatic or mixed with severe jaundice and pruritus, but self-limited with liver tests normalizing in 1-5 months.
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http://dx.doi.org/10.1111/liv.14393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041491PMC
April 2020

[Primary sclerosing cholangitis in Iceland 1992-2012].

Laeknabladid 2019 09;105(9):371-376

Department of Internal Medicine, Division of Gastroenterology, Landspítali University Hospital, Reykjavík, Iceland.

Background: Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease affecting the intra- and/or extrahepatic biliary tree with inflammation and progressive stricture formation that can lead to cirrhosis, end stage liver failure and liver transplantation. Known risk factors include inflammatory bowel diseases (IBD), mainly ulcerative colitis (UC). Highest reported incidence in an adult population is 1.2-1.3/100.000 in Norway and Sweden, where 60-76% have IBD. The aim of this study was to investigate epidemiology of PSC in Iceland in the years 1992 to 2012 and the patients outcomes.

Methods: A search for the diagnosis "cholangitis" (ICD-10, K83.0) was performed in the database for hospital records in Landspítali (The National University Hospital of Iceland, LSH) and Akureyri Hospital from 1992 to 2012. We also looked through all ERCP and MRCP imaging done in LSH in the same period along with a text search in both the hospital records and the pathology database for liver biopsies. Data on these patients was collected until the end of 2016.

Results: A total of 42 patient got the diagnosis PSC within the period. Median age at diagnosis was 34 years, 67% were male and 90% adults (≥18 years old). Mean incidence per year was 0.69/100.000. Overall 88% of patients had IBD, thereof 89% UC. Seven patients have been diagnosed with cancer, four with cancer in the bile ducts and one in the gallbladder. Within the study period a total of five patients died (12%), 51 months (median) from diagnosis and three from cholangiocarcinoma, 51 months (median) from diagnosis. Three patients (7%) underwent liver transplantation, one required a transplant two times.

Conclusions: The incidence of PSC in Iceland turned out to be lower than in our neighbouring countries in Scandinavia. It is unclear if this is due to underdiagnosis or, more likely, that PSC is simply more uncommon in Iceland. Overall 7% underwent liver transplantation and 12% died within the study period, main cause of mortality being cholangiocarcinoma.
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http://dx.doi.org/10.17992/lbl.2019.09.245DOI Listing
September 2019

Epigenetic inactivation of the splicing RNA-binding protein CELF2 in human breast cancer.

Oncogene 2019 11 13;38(45):7106-7112. Epub 2019 Aug 13.

Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain.

Human tumors show altered patterns of protein isoforms that can be related to the dysregulation of messenger RNA alternative splicing also observed in transformed cells. Although somatic mutations in core spliceosome components and their associated factors have been described in some cases, almost nothing is known about the contribution of distorted epigenetic patterns to aberrant splicing. Herein, we show that the splicing RNA-binding protein CELF2 is targeted by promoter hypermethylation-associated transcriptional silencing in human cancer. Focusing on the context of breast cancer, we also demonstrate that CELF2 restoration has growth-inhibitory effects and that its epigenetic loss induces an aberrant downstream pattern of alternative splicing, affecting key genes in breast cancer biology such as the autophagy factor ULK1 and the apoptotic protein CARD10. Furthermore, the presence of CELF2 hypermethylation in the clinical setting is associated with shorter overall survival of the breast cancer patients carrying this epigenetic lesion.
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http://dx.doi.org/10.1038/s41388-019-0936-xDOI Listing
November 2019

CpG promoter hypo-methylation and up-regulation of microRNA-190b in hormone receptor-positive breast cancer.

Oncotarget 2019 Jul 23;10(45):4664-4678. Epub 2019 Jul 23.

Cancer Research Laboratory, Biomedical Center, Reykjavik, Iceland.

Estrogen receptor-positive breast cancer is subdivided into subtypes LuminalA and LuminalB, based on different expression patterns. MicroRNA-190b has been reported to be up-regulated in estrogen receptor-positive breast cancers. In this study we aimed to investigate the role of CpG promoter methylation in regulating miR-190b expression and its impact on clinical presentation and prognosis. DNA methylation analysis for the promotor of microRNA-190b was performed by pyrosequencing 549 primary breast tumors, of which 62 were carriers of the founder mutation, 71 proximal normal breast samples and 16 breast derived cell lines. MicroRNA-190b expression was analysed in 67 primary breast tumors, 14 paired normal breast samples and 16 breast derived cell lines. Tissue microarrays (TMAs) were available for ER ( = 436), PR ( 436), HER-2 ( = 258) and Ki67 ( 248). MiR-190b had reduced promoter methylation in estrogen receptor-positive breast cancers ( 1.02e-12, Median values: ER+ 24.3, ER- 38.26) and miR-190b's expression was up-regulated in a correlative manner ( 1.83e-06, Spearman's rho -0.62). Through breast cancer specific survival analysis, we demonstrated that LuminalA patients exhibiting miR-190b hypo-methylation had better survival than other patients ( = 0.034, HR = 0.29, 95% CI 0.09-0.91). We, furthermore, demonstrated that miR-190b hypo-methylation occurs less frequently in ER+ tumors from mutation carriers than in non-mutated individuals ( 0.038, = 4.32, 335). Our results suggest that upregulation of miR-190b may occur through loss of promoter DNA methylation during the development of estrogen-receptor (ER) positive breast cancers, and that miR-190b hypo-methylation leads to increased breast cancer specific survival within the LuminalA- subtype but not LuminalB.
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http://dx.doi.org/10.18632/oncotarget.27083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659800PMC
July 2019
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