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Sundström, Magnus
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Publications (10 of 30) Show all publications
Aasebo, K., Dragomir, A., Sundström, M., Mezheyeuski, A., Edqvist, P.-H. D., Eide, G. E., . . . Sorbye, H. (2020). CDX2: A Prognostic Marker in Metastatic Colorectal Cancer Defining a Better BRAF Mutated and a Worse KRAS Mutated Subgroup. Frontiers in Oncology, 10, Article ID 8.
Open this publication in new window or tab >>CDX2: A Prognostic Marker in Metastatic Colorectal Cancer Defining a Better BRAF Mutated and a Worse KRAS Mutated Subgroup
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2020 (English)In: Frontiers in Oncology, ISSN 2234-943X, E-ISSN 2234-943X, Vol. 10, article id 8Article in journal (Refereed) Published
Abstract [en]

Background: Survival of metastatic colorectal cancer (mCRC) patients has improved, but mainly for trial patients. New predictive and prognostic biomarkers validated in the general mCRC population are needed. Caudal-type homeobox 2 (CDX2) is an intestine-specific transcription factor with potential prognostic and predictive effect, but the importance in mCRC has not been fully investigated. Methods: Immunohistochemistry analysis of CDX2 was performed in a Scandinavian population-based cohort of mCRC (n = 796). Frequency, clinical and tumor characteristics, response rate, progression-free survival, and overall survival (OS) were estimated. Results: Loss of CDX2 expression was found in 87 (19%) of 452 stained cases, in 53% if BRAF mutated (BRAFmut) and in 9% if KRAS mutated (KRASmut). CDX2 loss was associated with microsatellite instability, BRAFmut, and poor differentiation and inversely associated with KRASmut. Patients with CDX2 loss received less first-line (53 vs. 64%, p = 0.050) and second-line (23 vs. 39%, p = 0.006) chemotherapy and secondary surgery (1 vs. 9%, p = 0.019). Median progression-free survival and OS for patients given first-line combination chemotherapy was 4 and 10 months if CDX2 loss vs. 9 and 24 months if CDX2 expressed (p = 0.001, p < 0.001). Immediate progression on first-line combination chemotherapy was seen in 35% of patients with CDX2 loss vs. 10% if CDX2 expressed (p = 0.003). Median OS in patients with BRAFmut or KRASmut and CDX2 expressed in tumor (both 21 months) was comparable to wild-type patients (27 months). However, if CDX2 loss, median OS was only 8 and 11 months in BRAFmut and KRASmut cases, respectively, and 10 months in double wild-type patients. In multivariate analysis, CDX2 loss (hazard ratio: 1.50, p = 0.027) and BRAFmut (hazard ratio: 1.62, p = 0.012) were independent poor prognostic markers for OS. Conclusion: In a population-based cohort of mCRC patients, CDX2 loss is an independent poor prognostic marker. Expression of CDX2 defines a new subgroup of BRAFmut cases with a much better prognosis. Loss of CDX2 defines a small group of KRASmut cases with a worse prognosis. Patients with CDX2 loss receive less palliative chemotherapy with less benefit and rarely reach secondary surgery.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2020
Keywords
caudal type homeobox transcription factor, CDX2, colorectal cancer, metastatic disease, stage 4 colorectal cancer, prognosis, population based
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-407365 (URN)10.3389/fonc.2020.00008 (DOI)000517487200001 ()32117703 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2020-04-29 Created: 2020-04-29 Last updated: 2020-04-29Bibliographically approved
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 Clinical Laboratory Medicine
Research subject
Pathology
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: 2020-01-08Bibliographically 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: 2020-01-03Bibliographically 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
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
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
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