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Sundström, Magnus
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Publications (10 of 28) Show all publications
Aasebö, K. Ö., Dragomir, A., Sundström, M., Mezheyeuski, A., Edqvist, P.-H. D., Eide, G. E., . . . Sorbye, H. (2019). Consequences of a high incidence of microsatellite instability and BRAF-mutated tumors: A population-based cohort of metastatic colorectal cancer patients. Cancer Medicine, 8(7), 3623-3635
Open this publication in new window or tab >>Consequences of a high incidence of microsatellite instability and BRAF-mutated tumors: A population-based cohort of metastatic colorectal cancer patients
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2019 (English)In: Cancer Medicine, ISSN 2045-7634, E-ISSN 2045-7634, Vol. 8, no 7, p. 3623-3635Article in journal (Refereed) Published
Abstract [en]

Background: Immunotherapy for patients with microsatellite-instable (MSI-H) tumors or BRAF-inhibitors combination treatment for BRAF-mutated (mutBRAF) tumors in metastatic colorectal cancer (mCRC) is promising, but the frequency of these molecular changes in trial patients are low. Unselected population-based studies of these molecular changes are warranted.

Methods: A population-based cohort of 798 mCRC patients in Scandinavia was studied. Patient and molecular tumor characteristics, overall survival (OS) and progression-free survival (PFS) were estimated.

Results: Here, 40/583 (7%) tumor samples were MSI-H and 120/591 (20%) were mutBRAF; 87% of MSI-H tumors were mutBRAF (non-Lynch). Elderly (>75 years) had more often MSI-H (10% vs 6%) and MSI-H/mutBRAF (9% vs 4%) tumors. Response rate (5% vs 44%), PFS (4 vs 8 months), and OS (9 vs 18 months) after first-line chemotherapy was all significantly lower in patients with MSI-H compared to patients with microsatellite stable tumors. MSI-H and mutBRAF were both independent poor prognostic predictors for OS (P = 0.049, P < 0.001) and PFS (P = 0.045, P = 0.005) after first-line chemotherapy. Patients with MSI-H tumors received less second-line chemotherapy (15% vs 37%, P = 0.005).

Conclusions: In unselected mCRC patients, MSI-H and mutBRAF cases were more common than previously reported. Patients with MSI-H tumors had worse survival, less benefit from chemotherapy, and they differed considerably from recent third-line immunotherapy trial patients as they were older and most had mutBRAF tumor (non-Lynch).

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
colorectal neoplasm, microsatellite instability, proto-oncogene proteins, B-raf, prognosis, neoplasm metastasis, KRAS protein
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-391954 (URN)10.1002/cam4.2205 (DOI)000477017100030 ()31070306 (PubMedID)
Funder
Erik, Karin och Gösta Selanders FoundationSwedish Cancer Society
Available from: 2019-08-27 Created: 2019-08-27 Last updated: 2019-08-27Bibliographically approved
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: 2019-08-20Bibliographically approved
Davanian, H., Balasiddaiah, A., Heymann, R., Sundström, M., Redenström, P., Silfverberg, M., . . . Chen, M. (2017). Ameloblastoma RNA profiling uncovers a distinct non-coding RNA signature. OncoTarget, 8(3), 4530-4542
Open this publication in new window or tab >>Ameloblastoma RNA profiling uncovers a distinct non-coding RNA signature
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 3, p. 4530-4542Article in journal (Refereed) Published
Abstract [en]

Ameloblastoma of the jaws remains the top difficult to treat odontogenic tumour and has a high recurrence rate. New evidence suggests that non-coding RNAs (ncRNAs) play a critical role in tumourgenesis and prognosis of cancer. However, ameloblastoma ncRNA expression data is lacking. Here we present the first report of ameloblastoma ncRNA signatures. A total of 95 ameloblastoma cases and a global array transcriptome technology covering > 285.000 full-length transcripts were used in this two-step analysis. The analysis first identified in a test cohort 31 upregulated ameloblastoma-associated ncRNAs accompanied by signalling pathways of cancer, spliceosome, mRNA surveillance and Wnt. Further validation in an independent cohort points out the long non-coding (lncRNAs) and small nucleolar RNA (snoRNAs): LINC340, SNORD116-25, SNORA11, SNORA21, SNORA47 and SNORA65 as a distinct ncRNA signature of ameloblastoma. Importantly, the presence of these ncRNAs was independent of BRAFV600E and SMO-L412F mutations, histology type or tumour location, but was positively correlated with the tumour size. Taken together, this study shows a systematic investigation of ncRNA expression of ameloblastoma, and illuminates new diagnostic and therapeutic targets for this invasive odontogenic tumour.

Keywords
ameloblastoma, biomarkers, transcriptome, ncRNA, gene expression analysis
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-317696 (URN)10.18632/oncotarget.13891 (DOI)000393228400064 ()27965463 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2017-03-17 Created: 2017-03-17 Last updated: 2018-01-13Bibliographically approved
Ghanipour, L., Jirström, K., Sundström, M., Glimelius, B., Påhlman, L. & Birgisson, H. (2017). Associations of defect mismatch repair genes with prognosis and heredity in sporadic colorectal cancer. European Journal of Surgical Oncology, 43(2), 311-321
Open this publication in new window or tab >>Associations of defect mismatch repair genes with prognosis and heredity in sporadic colorectal cancer
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2017 (English)In: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 43, no 2, p. 311-321Article in journal (Refereed) Published
Abstract [en]

Background: Microsatellite instability arises due to defect mismatch repair (MMR) and occurs in 10-20% of sporadic colorectal cancer. The purpose was to investigate correlations between defect MMR, prognosis and heredity for colorectal cancer in first-degree relatives.

Material and methods: Tumour tissues from 320 patients consecutively operated for colorectal cancer were analysed for immunohistochemical expression of MLH1, MSH2 and MSH6 on tissue microarrays. Information on KRAS and BRAF mutation status was available for selected cases.

Results: Forty-seven (15%) tumours displayed MSI. No correlation was seen between patients exhibiting MSI in the tumour and heredity (p= 1.000). Patients with proximal colon cancer and MSI had an improved cancer-specific survival (p= 0.006) and prolonged time to recurrence (p= 0.040). In a multivariate analysis including MSI status, gender, CEA, vascular and neural invasion, patients with MSS and proximal colon cancer had an impaired cancer-specific survival compared with patients with MSI (HR, 3.87; CI, 1.36-11.01). The same prognostic information was potentially also in distal colon cancer; no recurrences seen in the 8 patients with stages II and III distal colon cancer and MSI, but the difference was not statistically significant.  Conclusion:No correlation between MSI and heredity was seen. Patients with MSI tumours had improved survival.

 

Keywords
colorectal cancer, MSI, heredity, prognosis
National Category
Cancer and Oncology Surgery
Identifiers
urn:nbn:se:uu:diva-224695 (URN)10.1016/j.ejso.2016.10.013 (DOI)000394072300011 ()27836416 (PubMedID)
Available from: 2014-05-19 Created: 2014-05-19 Last updated: 2017-04-25Bibliographically approved
Isaksson, J., Willen, L., La Fleur, L., Mindus, S., Sundström, M., Branden, E., . . . Botling, J. (2017). Establishing Reflex NGS Testing in NSCLC in a Regional Network of County Hospitals in Central Sweden. Journal of Thoracic Oncology, 12(1), S499-S500
Open this publication in new window or tab >>Establishing Reflex NGS Testing in NSCLC in a Regional Network of County Hospitals in Central Sweden
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2017 (English)In: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 12, no 1, p. S499-S500Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Elsevier, 2017
Keywords
FFPE, next generation sequencing, NSCLC
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-377744 (URN)10.1016/j.jtho.2016.11.605 (DOI)000413055801108 ()
Available from: 2019-02-26 Created: 2019-02-26 Last updated: 2019-02-26Bibliographically 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
Casar-Borota, O., Oystese, K. A., Sundström, M., Melchior, L. & Popovic, V. (2016). A high-throughput analysis of the IDH1(R132H) protein expression in pituitary adenomas. Pituitary, 19(4), 407-414
Open this publication in new window or tab >>A high-throughput analysis of the IDH1(R132H) protein expression in pituitary adenomas
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2016 (English)In: Pituitary, ISSN 1386-341X, E-ISSN 1573-7403, Vol. 19, no 4, p. 407-414Article in journal (Refereed) Published
Abstract [en]

Inactivating mutations of isocitrate dehydrogenase (IDH) 1 and 2, mitochondrial enzymes participating in the Krebs tricarboxylic acid cycle play a role in the tumorigenesis of gliomas and also less frequently in acute myeloid leukemia and other malignancies. Inhibitors of mutant IDH1 and IDH2 may potentially be effective in the treatment of the IDH mutation driven tumors. Mutations in the succinate dehydrogenase, the other enzyme complex participating in the Krebs cycle and electron transfer of oxidative phosphorylation occur in the paragangliomas, gastrointestinal stromal tumors, and occasionally in the pituitary adenomas. We aimed to determine whether the IDH1(R132H) mutation, the most frequent IDH mutation in human malignancies, occurs in pituitary adenomas. We performed immunohistochemical analysis by using a monoclonal anti-IDH1(R132H) antibody on the tissue microarrays containing specimens from the pituitary adenomas of different hormonal types from 246 patients. In positive samples, the status of the IDH1 gene was further examined by molecular genetic analyses. In all but one patient, there was no expression of mutated IDH1(R132H) protein in the tumor cells by immunohistochemistry. Only one patient with a recurring clinically non-functioning gonadotroph adenoma demonstrated IDH1(R132H)-immunostaining in both the primary tumor and the recurrence. However, no mutation in the IDH1 gene was detected using different molecular genetic analyses. IDH1(R132H) mutation occurs only exceptionally in pituitary adenomas and does not play a role in their pathogenesis. Patients with pituitary adenomas do not seem to be candidates for treatment with the inhibitors of mutant IDH1.

Keywords
Pituitary adenoma, Isocitrate dehydrogenase, IDH1(R132H), Immunohistochemistry, Tissue microarrays
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-300440 (URN)10.1007/s11102-016-0720-7 (DOI)000379350000009 ()27097804 (PubMedID)
Available from: 2016-08-09 Created: 2016-08-09 Last updated: 2017-11-28Bibliographically approved
Segerman, A., Niklasson, M., Haglund, C., Bergström, T., Jarvius, M., Xie, Y., . . . Westermark, B. (2016). Clonal Variation in Drug and Radiation Response among Glioma-Initiating Cells Is Linked to Proneural-Mesenchymal Transition. Cell reports, 17(11), 2994-3009
Open this publication in new window or tab >>Clonal Variation in Drug and Radiation Response among Glioma-Initiating Cells Is Linked to Proneural-Mesenchymal Transition
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2016 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 17, no 11, p. 2994-3009Article in journal (Refereed) Published
Abstract [en]

Intratumoral heterogeneity is a hallmark of glioblastoma multiforme and thought to negatively affect treatment efficacy. Here, we establish libraries of glioma-initiating cell (GIC) clones from patient samples and find extensive molecular and phenotypic variability among clones, including a range of responses to radiation and drugs. This widespread variability was observed as a continuumof multitherapy resistance phenotypes linked to a proneural-mesenchymal shift in the transcriptome. Multitherapy resistance was associated with a semi-stable cell state that was characterized by an altered DNA methylation pattern at promoter regions of mesenchymal master regulators and enhancers. The gradient of cell states within the GIC compartment constitutes a distinct form of heterogeneity. Our findings may open an avenue toward the development of new therapeutic rationales designed to reverse resistant cell states.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-314416 (URN)10.1016/j.celrep.2016.11.056 (DOI)000390894700019 ()
Funder
Knut and Alice Wallenberg Foundation, 2013.0280Swedish Cancer Society, 150670
Available from: 2017-02-08 Created: 2017-02-02 Last updated: 2017-11-29Bibliographically approved
Padhan, N., Nordling, T. E. M., Sundström, M., Åkerud, P., Birgisson, H., Nygren, P., . . . Claesson-Welsh, L. (2016). High sensitivity isoelectric focusing to establish a signaling biomarker for the diagnosis of human colorectal cancer. BMC Cancer, 16, Article ID 683.
Open this publication in new window or tab >>High sensitivity isoelectric focusing to establish a signaling biomarker for the diagnosis of human colorectal cancer
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2016 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 16, article id 683Article in journal (Refereed) Published
Abstract [en]

Background: The progression of colorectal cancer (CRC) involves recurrent amplifications/mutations in the epidermal growth factor receptor (EGFR) and downstream signal transducers of the Ras pathway, KRAS and BRAF. Whether genetic events predicted to result in increased and constitutive signaling indeed lead to enhanced biological activity is often unclear and, due to technical challenges, unexplored. Here, we investigated proliferative signaling in CRC using a highly sensitive method for protein detection. The aim of the study was to determine whether multiple changes in proliferative signaling in CRC could be combined and exploited as a "complex biomarker" for diagnostic purposes. Methods: We used robotized capillary isoelectric focusing as well as conventional immunoblotting for the comprehensive analysis of epidermal growth factor receptor signaling pathways converging on extracellular regulated kinase 1/2 (ERK1/2), AKT, phospholipase C gamma 1 (PLC gamma 1) and c-SRC in normal mucosa compared with CRC stage II and IV. Computational analyses were used to test different activity patterns for the analyzed signal transducers. Results: Signaling pathways implicated in cell proliferation were differently dysregulated in CRC and, unexpectedly, several were downregulated in disease. Thus, levels of activated ERK1 (pERK1), but not pERK2, decreased in stage II and IV while total ERK1/2 expression remained unaffected. In addition, c-SRC expression was lower in CRC compared with normal tissues and phosphorylation on the activating residue Y418 was not detected. In contrast, PLC gamma 1 and AKT expression levels were elevated in disease. Immunoblotting of the different signal transducers, run in parallel to capillary isoelectric focusing, showed higher variability and lower sensitivity and resolution. Computational analyses showed that, while individual signaling changes lacked predictive power, using the combination of changes in three signaling components to create a "complex biomarker" allowed with very high accuracy, the correct diagnosis of tissues as either normal or cancerous. Conclusions: We present techniques that allow rapid and sensitive determination of cancer signaling that can be used to differentiate colorectal cancer from normal tissue.

Keywords
Colorectal cancer, Isoelectric focusing, Signal transduction, Proliferation, ERK, c-SRC
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-305935 (URN)10.1186/s12885-016-2725-z (DOI)000384194500001 ()27562229 (PubMedID)
Funder
Swedish Cancer Society, CAN2013/661Knut and Alice Wallenberg Foundation, KAW 2015.0275eSSENCE - An eScience Collaboration
Available from: 2016-11-14 Created: 2016-10-24 Last updated: 2017-11-29Bibliographically approved
Larsson, A. H., Lehn, S., Wangefjord, S., Karnevi, E., Kuteeva, E., Sundström, M., . . . Jirström, K. (2016). Significant association and synergistic adverse prognostic effect of podocalyxin-like protein and epidermal growth factor receptor expression in colorectal cancer. Journal of Translational Medicine, 14, Article ID 128.
Open this publication in new window or tab >>Significant association and synergistic adverse prognostic effect of podocalyxin-like protein and epidermal growth factor receptor expression in colorectal cancer
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2016 (English)In: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 14, article id 128Article in journal (Refereed) Published
Abstract [en]

Background: Podocalyxin-like 1 (PODXL) is an anti-adhesive transmembrane protein that has been demonstrated to be an independent factor of poor prognosis in colorectal cancer (CRC). The gene encoding PODXL is located to chromosome 7, which also harbours the gene for the epidermal growth factor receptor (EGFR). The aim of this study was to examine the associations between PODXL and EGFR expression in CRC in vitro and in vivo.

Methods: EGFR expression was analysed in tumours from three independent patient cohorts; cohort 1 (n = 533), cohort 2 (n = 259) and cohort 3 (n = 310), previously analysed for immunohistochemical PODXL expression and KRAS and BRAF mutations (cohort 1 and 3). Levels of EGFR and PODXL were determined by western blot in six different CRC cell lines.

Results: High expression of PODXL was significantly associated with high EGFR expression (p < 0.001) in all three cohorts, and with BRAF mutation (p < 0.001) in cohort 1 and 3. High EGFR expression correlated with BRAF mutation (p < 0.001) in cohort 1. High EGFR expression was associated with adverse clinicopathological factors and independently predicted a reduced 5-year overall survival (OS) in cohort 1 (HR 1.77; 95 % CI 1.27-2.46), cohort 2 (HR 1.58; 95 % CI 1.05-2.38) and cohort 3 (HR 1.83; 95 % CI 1.19-2.81). The highest risk of death within 5 years was observed in patients with tumours displaying high expression of both EGFR and PODXL in cohort 1 and 3 (HR 1.97; 95 % CI 1.18-3.28 and HR 3.56; 95 % CI 1.75-7.22, respectively). Western blot analysis showed a uniform expression of PODXL and EGFR in all six examined CRC cell lines.

Conclusions: The results from this study demonstrate that high expression of EGFR is an independent factor of poor prognosis in CRC. Moreover, strong links have been uncovered between expression of the recently proposed biomarker candidate PODXL with EGFR expression in CRC in vivo and in vitro, and with BRAF mutation in vivo. High expression of both PODXL and EGFR may also have a synergistic adverse effect on survival. These findings suggest a potential functional link in CRC between PODXL, EGFR and BRAF, all originating from chromosome 7, which may be highly relevant in the clinical setting and therefore merit future in-depth study.

Keywords
Podocalyxin-like, EGFR, BRAF, Colorectal cancer, Prognosis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-297267 (URN)10.1186/s12967-016-0882-0 (DOI)000375475400002 ()27160084 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationSwedish Cancer SocietyGunnar Nilsson Cancer Foundation
Available from: 2016-06-23 Created: 2016-06-22 Last updated: 2017-11-28Bibliographically approved
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