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Falk, Elin
Alternative names
Publications (10 of 17) Show all publications
La Fleur, L., Falk-Sörqvist, E., Smeds, P., Berglund, A., Sundström, M., Mattsson, J. S., . . . Botling, J. (2019). Mutation patterns in a population-based non-small cell lung cancer cohort and prognostic impact of concomitant mutations in KRAS and TP53 or STK11. Lung Cancer, 130, 50-58
Open this publication in new window or tab >>Mutation patterns in a population-based non-small cell lung cancer cohort and prognostic impact of concomitant mutations in KRAS and TP53 or STK11
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2019 (English)In: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 130, p. 50-58Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: Non-small cell lung cancer (NSCLC) is a heterogeneous disease with unique combinations of somatic molecular alterations in individual patients, as well as significant differences in populations across the world with regard to mutation spectra and mutation frequencies. Here we aim to describe mutational patterns and linked clinical parameters in a population-based NSCLC cohort.

MATERIALS AND METHODS: Using targeted resequencing the mutational status of 82 genes was evaluated in a consecutive Swedish surgical NSCLC cohort, consisting of 352 patient samples from either fresh frozen or formalin fixed paraffin embedded (FFPE) tissues. The panel covers all exons of the 82 genes and utilizes reduced target fragment length and two-strand capture making it compatible with degraded FFPE samples.

RESULTS: We obtained a uniform sequencing coverage and mutation load across the fresh frozen and FFPE samples by adaption of sequencing depth and bioinformatic pipeline, thereby avoiding a technical bias between these two sample types. At large, the mutation frequencies resembled the frequencies seen in other western populations, except for a high frequency of KRAS hotspot mutations (43%) in adenocarcinoma patients. Worse overall survival was observed for adenocarcinoma patients with a mutation in either TP53, STK11 or SMARCA4. In the adenocarcinoma KRAS-mutated group poor survival appeared to be linked to concomitant TP53 or STK11 mutations, and not to KRAS mutation as a single aberration. Similar results were seen in the analysis of publicly available data from the cBioPortal. In squamous cell carcinoma a worse prognosis could be observed for patients with MLL2 mutations, while CSMD3 mutations were linked to a better prognosis.

CONCLUSION: Here we have evaluated the mutational status of a NSCLC cohort. We could not confirm any survival impact of isolated driver mutations. Instead, concurrent mutations in TP53 and STK11 were shown to confer poor survival in the KRAS-positive adenocarcinoma subgroup.

Keywords
KRAS, Mutation patterns, Non-small cell lung cancer, STK11, TP53, Targeted resequencing
National Category
Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-380587 (URN)10.1016/j.lungcan.2019.01.003 (DOI)000463276900008 ()30885352 (PubMedID)
Funder
Swedish Cancer Society, 2013/711Swedish Cancer Society, 2016/827
Available from: 2019-03-29 Created: 2019-03-29 Last updated: 2020-01-03Bibliographically approved
La Fleur, L., Falk-Sörqvist, E., Smeds, P., Sundström, M., Mattsson, J. S., Brandén, E., . . . Botling, J. (2017). Mutation Profiling by Targeted Next Generation Sequencing of an Unselected NSCLC Cohort. Journal of Thoracic Oncology, 12(1), S526-S527
Open this publication in new window or tab >>Mutation Profiling by Targeted Next Generation Sequencing of an Unselected NSCLC Cohort
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2017 (English)In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 12, no 1, p. S526-S527Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Elsevier, 2017
Keywords
Targeted resequencing, Consecutive cohort, NSCLC
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-377745 (URN)10.1016/j.jtho.2016.11.647 (DOI)000413055801149 ()
Available from: 2019-02-26 Created: 2019-02-26 Last updated: 2019-02-26Bibliographically approved
Mathot, L., Kundu, S., Ljungström, V., Svedlund, J., Moens, L., Adlerteg, T., . . . Sjöblom, T. (2017). Somatic Ephrin Receptor Mutations Are Associated with Metastasis in Primary Colorectal Cancer. Cancer Research, 77(7), 1730-1740
Open this publication in new window or tab >>Somatic Ephrin Receptor Mutations Are Associated with Metastasis in Primary Colorectal Cancer
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2017 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77, no 7, p. 1730-1740Article in journal (Refereed) Published
Abstract [en]

The contribution of somatic mutations to metastasis of colorectal cancers is currently unknown. To find mutations involved in the colorectal cancer metastatic process, we performed deep mutational analysis of 676 genes in 107 stages II to IV primary colorectal cancer, of which half had metastasized. The mutation prevalence in the ephrin (EPH) family of tyrosine kinase receptors was 10-fold higher in primary tumors of metastatic colorectal than in nonmetastatic cases and preferentially occurred in stage III and IV tumors. Mutational analyses in situ confirmed expression of mutant EPH receptors. To enable functional studies of EPHB1 mutations, we demonstrated that DLD-1 colorectal cancer cells expressing EPHB1 form aggregates upon coculture with ephrin B1 expressing cells. When mutations in the fibronectin type III and kinase domains of EPHB1 were compared with wild-type EPHB1 in DLD-1 colorectal cancer cells, they decreased ephrin B1-induced compartmentalization. These observations provide a mechanistic link between EPHB receptor mutations and metastasis in colorectal cancer.

National Category
Clinical Laboratory Medicine Cancer and Oncology
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-319146 (URN)10.1158/0008-5472.CAN-16-1921 (DOI)000398262400019 ()28108514 (PubMedID)
Funder
Swedish Cancer Society, 2006/2154EU, European Research Council, 601939Swedish Foundation for Strategic Research , F06-0050VinnovaSwedish Cancer Society, 2012/834Swedish Cancer Society, 2007/775
Available from: 2017-03-31 Created: 2017-03-31 Last updated: 2020-04-17Bibliographically approved
McGinn, S., Bauer, D., Brefort, T., Dong, L., El-Sagheer, A., Elsharawy, A., . . . Gut, I. G. (2016). New technologies for DNA analysis: a review of the READNA Project. New Biotechnology, 33(3), 311-330
Open this publication in new window or tab >>New technologies for DNA analysis: a review of the READNA Project
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2016 (English)In: New Biotechnology, ISSN 1871-6784, E-ISSN 1876-4347, Vol. 33, no 3, p. 311-330Article, review/survey (Refereed) Published
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Computerized Image Processing
Identifiers
urn:nbn:se:uu:diva-279724 (URN)10.1016/j.nbt.2015.10.003 (DOI)000373545600001 ()26514324 (PubMedID)
Funder
EU, European Research Council, HEALTH-F4-2008-201418
Available from: 2015-10-26 Created: 2016-03-03 Last updated: 2017-11-30Bibliographically approved
Moens, L. N. N., Falk-Sörqvist, E., La Fleur, L., Mattsson, J., Bergfors, M., Sundström, M., . . . Botling, J. (2015). Clinical Validation of HaloPlex Targeted Resequencing in Formalin-Fixed, Paraffin-Embedded (FFPE) Cancer Biopsies. Paper presented at Annual Meeting of the Association-for-Molecular-Pathology (AMP), NOV 05-07, 2015, Austin, TX. Journal of Molecular Diagnostics, 17(6), 822-822
Open this publication in new window or tab >>Clinical Validation of HaloPlex Targeted Resequencing in Formalin-Fixed, Paraffin-Embedded (FFPE) Cancer Biopsies
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2015 (English)In: Journal of Molecular Diagnostics, ISSN 1525-1578, E-ISSN 1943-7811, Vol. 17, no 6, p. 822-822Article in journal, Meeting abstract (Other academic) Published
National Category
General Practice Other Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-274832 (URN)000363830000299 ()
Conference
Annual Meeting of the Association-for-Molecular-Pathology (AMP), NOV 05-07, 2015, Austin, TX
Available from: 2016-01-26 Created: 2016-01-26 Last updated: 2018-02-01Bibliographically approved
Mansouri, L., Sutton, L.-A., Ljungström, V., Bondza, S., Arngården, L., Bhoi, S., . . . Rosenquist Brandell, R. (2015). Functional loss of IκBε leads to NF-κB deregulation in aggressive chronic lymphocytic leukemia. Journal of Experimental Medicine, 212(6), 833-843
Open this publication in new window or tab >>Functional loss of IκBε leads to NF-κB deregulation in aggressive chronic lymphocytic leukemia
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2015 (English)In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 212, no 6, p. 833-843Article in journal (Refereed) Published
Abstract [en]

NF-κB is constitutively activated in chronic lymphocytic leukemia (CLL); however, the implicated molecular mechanisms remain largely unknown. Thus, we performed targeted deep sequencing of 18 core complex genes within the NF-κB pathway in a discovery and validation CLL cohort totaling 315 cases. The most frequently mutated gene was NFKBIE (21/315 cases; 7%), which encodes IκBε, a negative regulator of NF-κB in normal B cells. Strikingly, 13 of these cases carried an identical 4-bp frameshift deletion, resulting in a truncated protein. Screening of an additional 377 CLL cases revealed that NFKBIE aberrations predominated in poor-prognostic patients and were associated with inferior outcome. Minor subclones and/or clonal evolution were also observed, thus potentially linking this recurrent event to disease progression. Compared with wild-type patients, NFKBIE-deleted cases showed reduced IκBε protein levels and decreased p65 inhibition, along with increased phosphorylation and nuclear translocation of p65. Considering the central role of B cell receptor (BcR) signaling in CLL pathobiology, it is notable that IκBε loss was enriched in aggressive cases with distinctive stereotyped BcR, likely contributing to their poor prognosis, and leading to an altered response to BcR inhibitors. Because NFKBIE deletions were observed in several other B cell lymphomas, our findings suggest a novel common mechanism of NF-κB deregulation during lymphomagenesis.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-279237 (URN)10.1084/jem.20142009 (DOI)000355569300001 ()25987724 (PubMedID)
Funder
Swedish National Infrastructure for Computing (SNIC), b2011080Swedish Cancer SocietySwedish Research CouncilNIH (National Institute of Health), CA81554; CA081554EU, European Research Council, 259796EU, FP7, Seventh Framework Programme, 306242
Available from: 2016-02-29 Created: 2016-02-29 Last updated: 2018-01-10Bibliographically approved
Moens, L. N. J., Falk-Sörqvist, E., Ljungström, V., Mattsson, J., Sundström, M., La Fleur, L., . . . Botling, J. (2015). HaloPlex Targeted Resequencing for Mutation Detection in Clinical Formalin-Fixed, Paraffin-Embedded Tumor Samples. Journal of Molecular Diagnostics, 17(6), 729-739
Open this publication in new window or tab >>HaloPlex Targeted Resequencing for Mutation Detection in Clinical Formalin-Fixed, Paraffin-Embedded Tumor Samples
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2015 (English)In: Journal of Molecular Diagnostics, ISSN 1525-1578, E-ISSN 1943-7811, Vol. 17, no 6, p. 729-739Article in journal (Refereed) Published
Abstract [en]

In recent years, the advent of massively parallel next-generation sequencing technologies has enabled substantial advances in the study of human diseases. Combined with targeted DNA enrichment methods, high sequence coverage can be obtained for different genes simultaneously at a reduced cost per sample, creating unique opportunities for clinical cancer diagnostics. However, the formalin-fixed, paraffin-embedded (FFPE) process of tissue samples, routinely used in pathology departments, results in DNA fragmentation and nucleotide modifications that introduce a number of technical challenges for downstream biomotecular analyses. We evaluated the HaloPlex target enrichment system for somatic mutation detection in 80 tissue fractions derived from 20 clinical cancer cases with paired tumor and normal tissue available in both FFPE and fresh-frozen format. Several modifications to the standard method were introduced, including a reduced target fragment Length and two strand capturing. We found that FFPE material can be used for HaloPlex-based target enrichment and next-generation sequencing, even when starting from small amounts of DNA. By specifically capturing both strands for each target fragment, we were able to reduce the number of false-positive errors caused by FFPE-induced artifacts and Lower the detection limit for somatic mutations. We believe that the HaloPlex method presented here will be broadly applicable as a tool for somatic mutation detection in clinical cancer settings.

National Category
Clinical Medicine Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-269252 (URN)10.1016/j.jmoldx.2015.06.009 (DOI)000363830000013 ()26354930 (PubMedID)
Available from: 2015-12-17 Created: 2015-12-15 Last updated: 2018-02-01Bibliographically approved
La Fleur, L., Moens, L., Falk-Sörqvist, E., Sundström, M., Mattsson, J. S. M., Koyi, H., . . . Botling, J. (2015). Mutation Profiling by Targeted Next-Generation Sequencing for Diagnostics and Patient Cohort Screening in FFPE NSCLC Samples. Journal of Thoracic Oncology, 10(9), S697-S697
Open this publication in new window or tab >>Mutation Profiling by Targeted Next-Generation Sequencing for Diagnostics and Patient Cohort Screening in FFPE NSCLC Samples
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2015 (English)In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 10, no 9, p. S697-S697Article in journal, Meeting abstract (Other academic) Published
Keywords
target enrichment, formalin-fixed paraffin embedded, next-generation sequencing, non-small cell lung cancer
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-298974 (URN)000370365103337 ()
Available from: 2016-07-13 Created: 2016-07-12 Last updated: 2018-06-08Bibliographically approved
Lundin, K. E., Hamasy, A., Backe, P. H., Moens, L. N., Falk-Sörqvist, E., Elgstoen, K. B., . . . Smith, C. I. (2015). Susceptibility to infections, without concomitant hyper-IgE, reported in 1976, is caused by hypomorphic mutation in the phosphoglucomutase 3 (PGM3) gene. Clinical Immunology, 161(2), 366-372
Open this publication in new window or tab >>Susceptibility to infections, without concomitant hyper-IgE, reported in 1976, is caused by hypomorphic mutation in the phosphoglucomutase 3 (PGM3) gene
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2015 (English)In: Clinical Immunology, ISSN 1521-6616, E-ISSN 1521-7035, Vol. 161, no 2, p. 366-372Article in journal (Refereed) Published
Abstract [en]

Phosphoglucomutase 3 (PGM3) is an enzyme converting N-acetyl-glucosamine-6-phosphate to N-acetylglucosamine-l-phosphate, a precursor important for glycosylation. Mutations in the PGM3 gene have recently been identified as the cause of novel primary immunodeficiency with a hyper-IgE like syndrome. Here we report the occurrence of a homozygous mutation in the PGM3 gene in a family with immunodeficient children, described already in 1976. DNA from two of the immunodeficient siblings was sequenced and shown to encode the same homozygous missense mutation, causing a destabilized protein with reduced enzymatic capacity. Affected individuals were highly prone to infections, but lack the developmental defects in the nervous and skeletal systems, reported in other families. Moreover, normal IgE levels were found. Thus, belonging to the expanding group of congenital glycosylation defects, PGM3 deficiency is characterized by immunodeficiency, with or without increased IgE levels, and with variable forms of developmental defects affecting other organ systems.

Keywords
Primary immunodeficiency, N-acetylglucosamine-phosphate mutase hyper-IgE syndrome, Congenital defects of glycosylation, CDG
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-270937 (URN)10.1016/j.clim.2015.10.002 (DOI)000365831600042 ()26482871 (PubMedID)
Funder
EU, FP7, Seventh Framework ProgrammeSwedish Research CouncilStockholm County Council
Available from: 2016-01-05 Created: 2016-01-05 Last updated: 2018-01-10Bibliographically approved
Moens, L. N., Falk-Sörqvist, E., Asplund, A. C., Bernatowska, E., Smith, C. I. & Nilsson, M. (2014). Diagnostics of Primary Immunodeficiency Diseases: A Sequencing Capture Approach. PLoS ONE, 9(12), e114901
Open this publication in new window or tab >>Diagnostics of Primary Immunodeficiency Diseases: A Sequencing Capture Approach
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 12, p. e114901-Article in journal (Refereed) Published
Abstract [en]

Primary Immunodeficiencies (PID) are genetically inherited disorders characterized by defects of the immune system, leading to increased susceptibility to infection. Due to the variety of clinical symptoms and the complexity of current diagnostic procedures, accurate diagnosis of PID is often difficult in daily clinical practice. Thanks to the advent of "next generation'' sequencing technologies and target enrichment methods, the development of multiplex diagnostic assays is now possible. In this study, we applied a selector-based target enrichment assay to detect disease-causing mutations in 179 known PID genes. The usefulness of this assay for molecular diagnosis of PID was investigated by sequencing DNA from 33 patients, 18 of which had at least one known causal mutation at the onset of the experiment. We were able to identify the disease causing mutations in 60% of the investigated patients, indicating that the majority of PID cases could be resolved using a targeted sequencing approach. Causal mutations identified in the unknown patient samples were located in STAT3, IGLL1, RNF168 and PGM3. Based on our results, we propose a stepwise approach for PID diagnostics, involving targeted resequencing, followed by whole transcriptome and/or whole genome sequencing if causative variants are not found in the targeted exons.

National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-242873 (URN)10.1371/journal.pone.0114901 (DOI)000347146700066 ()
Available from: 2015-02-03 Created: 2015-02-02 Last updated: 2018-01-11Bibliographically approved
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