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Gunnarsson, Cecilia
Publications (10 of 23) Show all publications
Cordeddu, V., Yin, J. C., Gunnarsson, C., Virtanen, C., Drunat, S., Lepri, F., . . . Tartaglia, M. (2015). Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome. Human Mutation, 36(11), 1080-1087
Open this publication in new window or tab >>Activating Mutations Affecting the Dbl Homology Domain of SOS2 Cause Noonan Syndrome
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2015 (English)In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, no 11, p. 1080-1087Article in journal (Refereed) Published
Abstract [en]

The RASopathies constitute a family of autosomal-dominant disorders whose major features include facial dysmorphism, cardiac defects, reduced postnatal growth, variable cognitive deficits, ectodermal and skeletal anomalies, and susceptibility to certain malignancies. Noonan syndrome (NS), the commonest RASopathy, is genetically heterogeneous and caused by functional dysregulation of signal transducers and regulatory proteins with roles in the RAS/extracellular signal-regulated kinase (ERK) signal transduction pathway. Mutations in known disease genes account for approximately 80% of affected individuals. Here, we report that missense mutations altering Son of Sevenless, Drosophila, homolog 2 (SOS2), which encodes a RAS guanine nucleotide exchange factor, occur in a small percentage of subjects with NS. Four missense mutations were identified in five unrelated sporadic cases and families transmitting NS. Disease-causing mutations affected three conserved residues located in the Dbl homology (DH) domain, of which two are directly involved in the intramolecular binding network maintaining SOS2 in its autoinhibited conformation. All mutations were found to promote enhanced signaling from RAS to ERK. Similar to NS-causing SOS1 mutations, the phenotype associated with SOS2 defects is characterized by normal development and growth, as well as marked ectodermal involvement. Unlike SOS1 mutations, however, those in SOS2 are restricted to the DH domain.

Place, publisher, year, edition, pages
WILEY-BLACKWELL, 2015
Keywords
genotype-phenotype correlations; Noonan syndrome; RAS signaling; SOS2
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-122516 (URN)10.1002/humu.22834 (DOI)000362991400011 ()26173643 (PubMedID)
Note

Funding Agencies|National Institutes of Health [R01 HL071207, R01 HL0832732, U01 DE020060, R01 HG003988, U54 HG006997, U54 HG006504]; Telethon-Italy [GGP13107]; AIRC [IG 13360]; Ministry of Health [RF-2011-02349938]; Princess Margaret Cancer Foundation; Ontario Ministry of Health and Long Term Care; CIHR CGS-D

Available from: 2015-11-09 Created: 2015-11-06 Last updated: 2017-12-01
Gréen, A., Green, H., Rehnberg, M., Svensson, A., Gunnarsson, C. & Jonasson, J. (2015). Assessment of HaloPlex Amplification for Sequence Capture and Massively Parallel Sequencing of Arrhythmogenic Right Ventricular Cardiomyopathy-Associated Genes. Journal of Molecular Diagnostics, 17(1), 31-42
Open this publication in new window or tab >>Assessment of HaloPlex Amplification for Sequence Capture and Massively Parallel Sequencing of Arrhythmogenic Right Ventricular Cardiomyopathy-Associated Genes
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2015 (English)In: Journal of Molecular Diagnostics, ISSN 1525-1578, E-ISSN 1943-7811, Vol. 17, no 1, p. 31-42Article in journal (Refereed) Published
Abstract [en]

The genetic basis of arrhythmogenic right ventricular cardiomyopathy (ARVC) is complex. Mutations in genes encoding components of the cardiac desmosomes have been implicated as being causally related to ARVC. Next-generation sequencing allows parallel sequencing and duplication/deletion analysis of many genes simultaneously, which is appropriate for screening of mutations in disorders with heterogeneous genetic backgrounds. We designed and validated a next-generation sequencing test panel for ARVC using HaloPlex. We used SureDesign to prepare a HaloPlex enrichment system for sequencing of DES, DSC2, DSG2, DSP, JUP, PKP2, RYR2, TGFB3, TMEM43, and TIN from patients with ARVC using a MiSeq instrument. Performance characteristics were determined by comparison with Sanger, as the gold standard, and TruSeq Custom Amplicon sequencing of DSC2, DSG2, DSP, JUP, and PKP2. All the samples were successfully sequenced after HaloPlex capture, with greater than99% of targeted nucleotides covered by greater than20x. The sequences were of high quality, although one problematic area due to a presumptive context-specific sequencing error causing motif Located in exon 1 of the DSP gene was detected. The mutations found by Sanger sequencing were also found using the HaloPlex technique. Depending on the bioinformatics pipeline, sensitivity varied from 99.3% to 100%, and specificity varied from 99.90/0 to 100%. Three variant positions found by Sanger and HaloPlex sequencing were missed by TruSeq Custom Amplicon owing to Loss of coverage.

Place, publisher, year, edition, pages
Elsevier, 2015
National Category
Basic Medicine Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:liu:diva-113731 (URN)10.1016/j.jmoldx.2014.09.006 (DOI)000347143100006 ()25445213 (PubMedID)
Available from: 2015-01-30 Created: 2015-01-29 Last updated: 2018-01-11
Shabo, I., Midtbö, K. M., Andersson, H., Åkerlund, E., Olsson, H., Wegman, P., . . . Lindström, A. (2015). Macrophage traits in cancer cells are induced by macrophage-cancer cell fusion and cannot be explained by cellular interaction. BMC Cancer, 15(1), 922
Open this publication in new window or tab >>Macrophage traits in cancer cells are induced by macrophage-cancer cell fusion and cannot be explained by cellular interaction
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2015 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 15, no 1, p. 922-Article in journal (Refereed) Published
Abstract [en]

Background: Cell fusion is a natural process in normal development and tissue regeneration. Fusion between cancer cells and macrophages generates metastatic hybrids with genetic and phenotypic characteristics from both maternal cells. However, there are no clinical markers for detecting cell fusion in clinical context. Macrophage-specific antigen CD163 expression in tumor cells is reported in breast and colorectal cancers and proposed being caused by macrophages-cancer cell fusion in tumor stroma. The purpose of this study is to examine the cell fusion process as a biological explanation for macrophage phenotype in breast. Methods: Monocytes, harvested from male blood donor, were activated to M2 macrophages and co-cultured in ThinCert transwell system with GFP-labeled MCF-7 cancer cells. MCF7/macrophage hybrids were generated by spontaneous cell fusion, isolated by fluorescence-activated cell sorting and confirmed by fluorescence microscopy, short tandem repeats analysis and flow cytometry. CD163 expression was evaluated in breast tumor samples material from 127 women by immunohistochemistry. Results: MCF-7/macrophage hybrids were generated spontaneously at average rate of 2 % and showed phenotypic and genetic traits from both maternal cells. CD163 expression in MCF-7 cells could not be induced by paracrine interaction with M2-activated macrophages. CD163 positive cancer cells in tumor sections grew in clonal collection and a cutoff point greater than25 % of positive cancer cells was significantly correlated to disease free and overall survival. Conclusions: In conclusion, macrophage traits in breast cancer might be caused by cell fusion rather than explained by paracrine cellular interaction. These data provide new insights into the role of cell fusion in breast cancer and contributes to the development of clinical markers to identify cell fusion.

Place, publisher, year, edition, pages
BIOMED CENTRAL LTD, 2015
Keywords
Cell fusion; Macrophages; Paracrine cellular interaction; Tumor markers
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-123328 (URN)10.1186/s12885-015-1935-0 (DOI)000365276000001 ()26585897 (PubMedID)
Note

Funding Agencies|County Council of Ostergotland (Sweden); National Organization of Breast Cancer Associations (Sweden); Bengt Ihre Foundation (Swedish Surgical Society)

Available from: 2015-12-14 Created: 2015-12-11 Last updated: 2018-01-10
Olsson, H., Jansson, A., Holmlund, B. & Gunnarsson, C. (2013). Methods for evaluating HER2 status in breast cancer: comparison of IHC, FISH, and real-time PCR analysis of formalin-fixed paraffin-embedded tissue. Pathology and Laboratory Medicine International, 5, 31-37
Open this publication in new window or tab >>Methods for evaluating HER2 status in breast cancer: comparison of IHC, FISH, and real-time PCR analysis of formalin-fixed paraffin-embedded tissue
2013 (English)In: Pathology and Laboratory Medicine International, ISSN 1179-2698, Vol. 5, p. 31-37Article in journal (Refereed) Published
Abstract [en]

The human epidermal growth factor receptor 2 gene (HER2) is amplified in approximately 15%–20% of all breast cancers. This results in overexpression of the HER2 protein, which is associated with worse clinical outcomes in breast cancer patients. Several studies have shown that trastuzumab, a monoclonal antibody that interferes with the HER2/neu receptor, can improve overall survival in patients with HER2-positive breast cancer. Immunohistochemistry (IHC), combined with different methods for in situ hybridization, is currently used for routine assessment of HER2 status. The aim of the present study was to determine whether real-time polymerase chain reaction (PCR) can serve as a supplementary method for evaluation of HER2 status in primary breast cancer. For this purpose, 145 formalin-fixed paraffin-embedded primary breast cancer samples were tested by real-time PCR amplification of HER2, using amyloid precursor protein as a reference. The results were compared with HER2 status determined by fluorescence in situ hybridization (FISH) and IHC. The specificity, sensitivity, and reproducibility of real-time PCR were evaluated, and a comparison of formalin-fixed and fresh-frozen samples was performed. This showed concordance of 93% between real-time PCR and FISH, and 86% between real-time PCR and IHC. Therefore, we suggest that real-time PCR can be a useful supplementary method for assessment of HER2 status.

Place, publisher, year, edition, pages
Dove Medical Press, 2013
Keywords
17q, breast cancer, HER2, real-time PCR
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-105270 (URN)10.2147/PLMI.S44976 (DOI)
Available from: 2014-03-14 Created: 2014-03-14 Last updated: 2017-12-05Bibliographically approved
Sivik, T., Gunnarsson, C., Fornander, T., Nordenskjöld, B., Skoog, L., Stål, O. & Jansson, A. (2012). 17β-hydroxysteroid dehydrogenase type 14 is a predictive marker for tamoxifen response in oestrogen receptor positive breast cancer. PLoS ONE, 7(7), e40568
Open this publication in new window or tab >>17β-hydroxysteroid dehydrogenase type 14 is a predictive marker for tamoxifen response in oestrogen receptor positive breast cancer
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, p. e40568-Article in journal (Refereed) Published
Abstract [en]

Introduction: 17β-hydroxysteroid dehydrogenases (17βHSDs) are important enzymes regulating the pool of bioactive steroids in the breast. The current study was undertaken in order to evaluate implications of 17βHSD14 in breast cancer, measuring 17βHSD14 protein expression in breast tumours.

Methods: An antibody targeting the 17βHSD14 antigen was generated and validated using HSD17B14-transfected cells and a peptide-neutralising assay. Tissue microarrays with tumours from 912 post-menopausal women diagnosed with lymph node-negative breast cancer, and randomised to adjuvant tamoxifen or no endocrine treatment, were analysed for 17βHSD14 protein expression with immunohistochemistry.

Results: Results were obtained from 847 tumours. Patients with oestrogen positive tumours with high 17βHSD14 expression had fewer local recurrences when treated with tamoxifen (HR 0.38; 95% C.I. 0.19–0.77, p = 0.007) compared to patients with lower tumoural 17βHSD14 expression, for whom tamoxifen did not reduce the number of local recurrences (HR 1.19; 95% C.I. 0.54–2.59; p = 0.66). No prognostic importance of 17βHSD14 was seen for systemically untreated patients.

Conclusions: Using a highly specific validated antibody for immunohistochemical analysis of a large number of breast tumours, we have shown that tumoural expression levels of 17βHSD14 can predict the outcome of adjuvant tamoxifen treatment in terms of local recurrence-free survival in patients with lymph node-negative ER+ breast cancer. The results need be verified to confirm any clinical relevance.

Place, publisher, year, edition, pages
Plos ONE, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-80247 (URN)10.1371/journal.pone.0040568 (DOI)
Available from: 2012-08-23 Created: 2012-08-23 Last updated: 2017-12-07
Gati, I., Danielsson, O., Gunnarsson, C., Vrethem, M., Häggqvist, B., Fredriksson, B.-A. & Landtblom, A.-M. (2012). Letter: Bent Spine Syndrome: A Phenotype of Dysferlinopathy or a Symptomatic DYSF Gene Mutation Carrier [Letter to the editor]. European Neurology, 67(5), 300-302
Open this publication in new window or tab >>Letter: Bent Spine Syndrome: A Phenotype of Dysferlinopathy or a Symptomatic DYSF Gene Mutation Carrier
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2012 (English)In: European Neurology, ISSN 0014-3022, E-ISSN 1421-9913, Vol. 67, no 5, p. 300-302Article in journal, Letter (Other academic) Published
Abstract [en]

n/a

Place, publisher, year, edition, pages
Karger, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-77740 (URN)10.1159/000336265 (DOI)000303444900009 ()
Available from: 2012-05-28 Created: 2012-05-28 Last updated: 2017-12-07
Aneq Åström, M., Fluur, C., Rehnberg, M., Söderkvist, P., Engvall, J., Nylander, E. & Gunnarsson, C. (2012). Novel plakophilin2 mutation. Three generation family with arrhythmogenic right ventricular cardiomyopathy. Scandinavian Cardiovascular Journal, 46(2), 72-75
Open this publication in new window or tab >>Novel plakophilin2 mutation. Three generation family with arrhythmogenic right ventricular cardiomyopathy
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2012 (English)In: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 46, no 2, p. 72-75Article in journal (Refereed) Published
Abstract [en]

Objectives: The autosomal dominant form of arrhythmogenic right ventricular cardiomyopathy (ARVC)has been linked to mutations in desmosomal proteins. Different studies have shown that amutation in plakophilin-2 (PKP 2) is a frequent genetic cause for ARVC. We describe a newmutation in the PKP2 gene, the genotype-phenotype variation in this mutation and its clinicalconsequences.

Design: Individuals in a three generation family were investigated after the sudden cardiac death of a young male. Clinical evaluation, electrocardiography, echocardiography, magnetic resonance imaging, endomyocardial biopsy and genetic testing were performed.

Results: A novel heterozygote mutation, a c.368G>A transition, located in exon 3 of the PKP2 gene was found (p.Trp123X). The phenotype was characterized by arrhythmia at an early age in some individuals, with mild abnormalities on imaging. However a relative carrying this mutation, with positive findings on endomyocardial biopsy had an otherwise normal phenotype, for 16 years, whereas a relative fulfilling the modified Task Force Criteria for ARVC turned out to be a non-carrier.

Conclusions: This shows the variable penetrance and phenotypic expression in ARVC and highlights the need of genetic testing as well as a thorough phenotype examination as a part of the investigations in ARVC pedigrees.

Place, publisher, year, edition, pages
Informa Healthcare, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-70402 (URN)10.3109/14017431.2011.636068 (DOI)000301496200002 ()
Note
Funding agencies|FORSS||Medical Research Council of Southeast Sweden| 12043 |Swedish Heart-Lung foundation| 20070864 |Available from: 2011-09-06 Created: 2011-09-06 Last updated: 2017-12-08Bibliographically approved
Rehnberg, M., Jonasson, J. & Gunnarsson, C. (2011). Letter: Novel L1CAM Splice Site Mutation in a Young Male With L1 Syndrome [Letter to the editor]. American Journal of Medical Genetics. Part A, 155A(2), 439-441
Open this publication in new window or tab >>Letter: Novel L1CAM Splice Site Mutation in a Young Male With L1 Syndrome
2011 (English)In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 155A, no 2, p. 439-441Article in journal, Letter (Other academic) Published
Abstract [en]

n/a

Place, publisher, year, edition, pages
John Wiley andamp; Sons, Ltd, 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-66152 (URN)10.1002/ajmg.a.33803 (DOI)000287153700031 ()
Available from: 2011-03-04 Created: 2011-03-04 Last updated: 2017-12-11Bibliographically approved
Gunnarsson, C. & Foyn Bruhn, C. (2010). Molecular Characterization and Clinical Features of a Patient With an Interstitial Deletion of 3p25.3-p26.1. AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 152A(12), 3110-3114
Open this publication in new window or tab >>Molecular Characterization and Clinical Features of a Patient With an Interstitial Deletion of 3p25.3-p26.1
2010 (English)In: AMERICAN JOURNAL OF MEDICAL GENETICS PART A, ISSN 1552-4825, Vol. 152A, no 12, p. 3110-3114Article in journal (Refereed) Published
Abstract [en]

Distal chromosome 3p deletions (3p- syndrome) are associated with various developmental defects. The majority of cases have a terminal deletion of the short arm of chromosome 3 with loss of either the maternal or the paternal copy. A girl with an interstitial molecularly characterized 1.6 Mb deletion in cytoband 3p25.3-26.1 of the paternal chromosome 3 is presented. To our knowledge, she possesses the smallest deletion that has ever been reported for a patient with a clinical phenotype in accordance with the 3p- syndrome. The boundaries of the deletion lies within nearly all previously reported terminal deletions causing this syndrome. Selected genes that are present in the hemizygous state and which might be important for the phenotype of this patient as regards the congenital heart defect, autistic behavior and mental retardation (CAV3, OXTR, and SRGAP3/MEGAP, respectively) are discussed in context of the clinical features.

Place, publisher, year, edition, pages
John Wiley and Sons, Ltd, 2010
Keywords
3p deletion syndrome, interstitial deletion, SNP array
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-64244 (URN)10.1002/ajmg.a.33353 (DOI)000285251800026 ()
Available from: 2011-01-17 Created: 2011-01-17 Last updated: 2011-01-17
Gunnarsson, C., Graffmann, B. & Jonasson, J. (2009). Chromosome r(10)(p15.3q26.12) in a newborn child: case report.. Molecular Cytogenetics, 2, 25
Open this publication in new window or tab >>Chromosome r(10)(p15.3q26.12) in a newborn child: case report.
2009 (English)In: Molecular Cytogenetics, ISSN 1755-8166, Vol. 2, p. 25-Article in journal (Refereed) Published
Abstract [en]

ABSTRACT: BACKGROUND: Ring chromosome 10 is a rare cytogenetic finding. Of the less than 10 reported cases we have found in the literature, none was characterized using high-resolution microarray analysis. Ring chromosomes are frequently unstable due to sister chromatid exchanges and mitotic failures. When mosaicism is present, the interpretation of genotype-phenotype correlations becomes extremely difficult. RESULTS: We report on a newborn girl with growth retardation, microcephaly, congenital heart defects, dysmorphic features and psychomotor retardation. Karyotyping revealed a non-mosaic apparently stable ring chromosome 10 replacing one of the normal homologues in all analyzed metaphases. High-resolution oligonucleotide microarray analysis showed a de novo approximately 12.5 Mb terminal deletion 10q26.12 -> qter and a corresponding 285 kb terminal deletion of 10pter -> p15.3. CONCLUSION: This case demonstrates that an increased nuchal translucency thickness detected by early ultrasonography should preferably lead to not only QF-PCR for the diagnosis of Down syndrome but also karyotyping. In the future, microarray analysis, which needs further evaluation, might become the method of choice. The clinical phenotype of our patient was in agreement with that of patients with a terminal 10q deletion. For the purpose of genotype-phenotype analysis, there seems to be no need for a "ring syndrome" concept.

Place, publisher, year, edition, pages
BioMed Central, 2009
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-53074 (URN)10.1186/1755-8166-2-25 (DOI)000208460900024 ()19968867 (PubMedID)
Note

Original Publication: Cecilia Gunnarsson, Barbara Graffmann, Jo and Jonasson, Chromosome r(10)(p15.3q26.12) in a newborn child: case report., 2009, Molecular Cytogenetics, (2), 25. http://dx.doi.org/10.1186/1755-8166-2-25 Licensee: BioMed Central http://www.biomedcentral.com/

Available from: 2010-01-15 Created: 2010-01-15 Last updated: 2017-01-19
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