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Rentoft, Matilda
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Publications (10 of 13) Show all publications
Rentoft, M., Svensson, D., Sjödin, A., Olason, P. I., Sjöström, O., Nylander, C., . . . Johansson, E. (2019). A geographically matched control population efficiently limits the number of candidate disease-causing variants in an unbiased whole-genome analysis. PLoS ONE, 14(3), Article ID e0213350.
Open this publication in new window or tab >>A geographically matched control population efficiently limits the number of candidate disease-causing variants in an unbiased whole-genome analysis
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2019 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 3, article id e0213350Article in journal (Refereed) Published
Abstract [en]

Whole-genome sequencing is a promising approach for human autosomal dominant disease studies. However, the vast number of genetic variants observed by this method constitutes a challenge when trying to identify the causal variants. This is often handled by restricting disease studies to the most damaging variants, e.g. those found in coding regions, and overlooking the remaining genetic variation. Such a biased approach explains in part why the genetic causes of many families with dominantly inherited diseases, in spite of being included in whole-genome sequencing studies, are left unsolved today. Here we explore the use of a geographically matched control population to minimize the number of candidate disease-causing variants without excluding variants based on assumptions on genomic position or functional predictions. To exemplify the benefit of the geographically matched control population we apply a typical disease variant filtering strategy in a family with an autosomal dominant form of colorectal cancer. With the use of the geographically matched control population we end up with 26 candidate variants genome wide. This is in contrast to the tens of thousands of candidates left when only making use of available public variant datasets. The effect of the local control population is dual, it (1) reduces the total number of candidate variants shared between affected individuals, and more importantly (2) increases the rate by which the number of candidate variants are reduced as additional affected family members are included in the filtering strategy. We demonstrate that the application of a geographically matched control population effectively limits the number of candidate disease-causing variants and may provide the means by which variants suitable for functional studies are identified genome wide.

Place, publisher, year, edition, pages
Public Library of Science, 2019
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-158021 (URN)10.1371/journal.pone.0213350 (DOI)000462465800028 ()30917156 (PubMedID)
Funder
Knut and Alice Wallenberg Foundation, 2011.0042
Available from: 2019-04-10 Created: 2019-04-10 Last updated: 2019-04-12Bibliographically approved
Rentoft, M., Lindell, K., Tran, P., Chabes, A. L., Buckland, R., Watt, D. L., . . . Chabes, A. (2016). Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance. Proceedings of the National Academy of Sciences of the United States of America, 113(17), 4723-4728
Open this publication in new window or tab >>Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance
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2016 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 17, p. 4723-4728Article in journal (Refereed) Published
Abstract [en]

Even small variations in dNTP concentrations decrease DNA replication fidelity, and this observation prompted us to analyze genomic cancer data for mutations in enzymes involved in dNTP metabolism. We found that sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1), a deoxyribonucleoside triphosphate triphosphohydrolase that decreases dNTP pools, is frequently mutated in colon cancers, that these mutations negatively affect SAMHD1 activity, and that severalSAMHD1mutations are found in tumors with defective mismatch repair. We show that minor changes in dNTP pools in combination with inactivated mismatch repair dramatically increase mutation rates. Determination of dNTP pools in mouse embryos revealed that inactivation of oneSAMHD1allele is sufficient to elevate dNTP pools. These observations suggest that heterozygous cancer-associatedSAMHD1mutations increase mutation rates in cancer cells.

National Category
Cell and Molecular Biology
Research subject
cellforskning
Identifiers
urn:nbn:se:umu:diva-119232 (URN)10.1073/pnas.1519128113 (DOI)000374748400052 ()27071091 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationSwedish Cancer SocietySwedish Research Council
Available from: 2016-04-14 Created: 2016-04-14 Last updated: 2018-06-07Bibliographically approved
Rentoft, M., Coates, P. J., Loljung, L., Wilms, T., Laurell, G. & Nylander, K. (2014). Expression of CXCL10 is associated with response to radiotherapy and overall survival in squamous cell carcinoma of the tongue. Tumor Biology, 35(5), 4191-4198
Open this publication in new window or tab >>Expression of CXCL10 is associated with response to radiotherapy and overall survival in squamous cell carcinoma of the tongue
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2014 (English)In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 35, no 5, p. 4191-4198Article in journal (Refereed) Published
Abstract [en]

Five-year survival for patients with oral cancer has been disappointingly stable during the last decades, creating a demand for new biomarkers and treatment targets. Lately, much focus has been set on immunomodulation as a possible treatment or an adjuvant increasing sensitivity to conventional treatments. The objective of this study was to evaluate the prognostic importance of response to radiotherapy in tongue carcinoma patients as well as the expression of the CXC-chemokines in correlation to radiation response in the same group of tumours. Thirty-eight patients with tongue carcinoma that had received radiotherapy followed by surgery were included. The prognostic impact of pathological response to radiotherapy, N-status, T-stage, age and gender was evaluated using Cox's regression models, Kaplan-Meier survival curves and chi-square test. The expression of 23 CXC-chemokine ligands and their receptors were evaluated in all patients using microarray and qPCR and correlated with response to treatment using logistic regression. Pathological response to radiotherapy was independently associated to overall survival with a 2-year survival probability of 81% for patients showing a complete pathological response, while patients with a non-complete response only had a probability of 42% to survive for 2 years (p = 0.016). The expression of one CXC-chemokine, CXCL10, was significantly associated with response to radiotherapy and the group of patients with the highest CXCL10 expression responded, especially poorly (p = 0.01). CXCL10 is a potential marker for response to radiotherapy and overall survival in patients with squamous cell carcinoma of the tongue.

Keywords
p63, prognosis, tongue carcinoma
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-92407 (URN)10.1007/s13277-013-1549-6 (DOI)000335759800029 ()24395654 (PubMedID)
Available from: 2014-08-26 Created: 2014-08-26 Last updated: 2018-06-13Bibliographically approved
Danielsson, K., Boldrup, L., Rentoft, M., Coates, P., Ebrahimi, M., Nylander, E., . . . Nylander, K. (2013). Autoantibodies and decreased expression of the transcription factor ELF-3 together with increased chemokine pathways support an autoimmune phenotype and altered differentiation in lichen planus located in oral mucosa. Journal of the European Academy of Dermatology and Venereology, 27(11), 1410-1416
Open this publication in new window or tab >>Autoantibodies and decreased expression of the transcription factor ELF-3 together with increased chemokine pathways support an autoimmune phenotype and altered differentiation in lichen planus located in oral mucosa
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2013 (English)In: Journal of the European Academy of Dermatology and Venereology, ISSN 0926-9959, E-ISSN 1468-3083, Vol. 27, no 11, p. 1410-1416Article in journal (Refereed) Published
Abstract [en]

Background  The pathogenesis of oral lichen planus (OLP), a chronic inflammatory disease, is not fully understood. It is known that OLP has autoimmune features, and it is suggested to be an autoimmune disease. ELF-3 is involved in differentiation of keratinocytes and deregulated in different tumours and inflammatory diseases. CXCR-3 and its ligands CXCL-10 and CXCL-11 are increased in autoimmune diseases and linked to Th-1 immune response. Objectives  To analyse and compare expression of ELF-3, CXCR-3, CXCL-10 and CXCL-11 in OLP lesions and controls in whole and microdissected epithelium. Methods  Tissue biopsies from 20 patients clinically and histologically diagnosed with OLP and 20 healthy controls were studied using whole tissues or microdissected epithelium. By the use of qRT-PCR, mRNA levels of ELF-3, CXCR-3, CXCL-10 and CXCL-11 were studied. Western blot was used for analysis of ELF-3 protein expression. Sera from 19 OLP patients and 20 controls were analysed with ELISA in search for autoantibodies. Results  The upregulation of CXCR-3, CXCL-10 and CXCL-11 found in OLP is similar to previous findings showing an autoimmune phenotype in lichen planus (LP) and lichen sclerosus. Decreased expression of the differentiation-related transcription factor ELF-3 was also seen in OLP lesions, and we further demonstrate presence of circulating autoantibodies against the ELF-3 protein in sera from 3 of 19 (16%) LP patients tested. Conclusions  On the basis of these findings, we confirm that OLP shows features of an autoimmune disease and suggest deregulated differentiation of keratinocytes to be one of the causes of the disease phenotype.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2013
National Category
Basic Medicine Dermatology and Venereal Diseases
Identifiers
urn:nbn:se:umu:diva-55418 (URN)10.1111/jdv.12027 (DOI)000325747200011 ()23134363 (PubMedID)
Available from: 2012-05-15 Created: 2012-05-14 Last updated: 2018-06-08Bibliographically approved
Matilda, R. (2012). The use of formalin fixed paraffin embedded tissue and global gene expression profiling for increased understanding of squamous cell carcinoma of the tongue. (Doctoral dissertation). Umeå: Umeå Universitet
Open this publication in new window or tab >>The use of formalin fixed paraffin embedded tissue and global gene expression profiling for increased understanding of squamous cell carcinoma of the tongue
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Head and neck cancer is the 6th most common malignancy worldwide, with tumours of the tongue being one of the most prevalent sites. Despite advances in surgery and radiotherapy, the five-year survival has not changed during the last decades and remains at approximately 50%. Identification of novel biomarkers for more personalized treatment is important for increasing survival in these patients. One of the most commonly used methods in the search for new biomarkers is microarray analysis. A substantial limitation with this technique is the requirement for fresh frozen samples from which high quality RNA can be extracted. This becomes particularly problematic when attempting to discover differences associated with individual sub-types or rare cancers. Recent developments, including the DASL microarray platform, have provided the possibility of analysing RNA of poorer quality from formalin fixed paraffin embedded (FFPE) samples. FFPE is the standard way of preserving tissue from patients and millions of samples are stored around the world. In this thesis we have evaluated the use of FFPE samples and global gene expression profiling for increasing basic knowledge in a subgroup of oral cancer patients with tumours of the tongue.

As confirmation of microarray results using qPCR is of outmost importance for conclusive data evaluation, we first aimed at finding a housekeeping gene stably expressed across malignant and non-malignant FFPE oral tissue. TUBA6, which belongs to the tubulin family was detected as being the most stable out of eight possible genes and was thus used for qPCR normalization throughout the following studies.

We have performed three separate microarray experiments. Initially only a focused DASL array covering 502 cancer related genes was available and we used it to analyze a smaller cohort of patients and controls (n=36). A similar cohort (n=29) was also analyzed for expression of 836 micoRNAs. In 2009 a whole genome DASL array was launched, covering over 20,000 genes, and all tongue tumour samples available between 1997 and 2010 (n=87) were analysed using this array.

Similar to other research groups we observed very high replicate reproducibility using both DASL arrays. When using the microRNA array and the whole genome DASL array an effect of sample quality on the detected expression level of individual genes was noticed. While the expression of some genes severely decreased with a decrease in sample quality others were not changed. This will impair normalization, leading to a residual non-biological variation within the data. Based on our findings we have presented some recommendations for minimizing the effect of sample quality and maximizing the level of biologically relevant information obtained from these experiments, e.g. ensuring that samples in groups to be compared are of the same quality range. For the microRNA data we also introduced an additional normalization step to the standard normalizations. We could show that lists of differentially expressed genes generated when taking these precautions were enriched for genes involved in cancer related processes and contained for tongue carcinoma previously identified changes. A number of differentially expressed genes, novel for tongue carcinoma, were also confirmed in high quality fresh frozen samples, including BCL2A1 (apoptosis), CXCL10 (immune response), SLC2A6 (energy transport) and miR-424 (angiogenesis).

In conclusion microarrays can be used to analyze FFPE samples but should be performed with care. Standard normalization methods will not remove the variation introduced by samples being of different quality, leading to spurious results. Taking a few precautions, however, led to the identification of differentially expressed genes relevant in tumour development and maintenance. The recommendations we make can facilitate design of future studies using FFPE samples. The genes we identified as being differentially expressed in tumour tissue now need to be further evaluated for their potential as biomarkers in tongue carcinoma.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2012. p. 45
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1495
Keywords
SCCHN, tongue, microarray, DASL, FFPE, archival, mRNA, miRNA
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Pathology
Identifiers
urn:nbn:se:umu:diva-54005 (URN)978-91-7459-413-3 (ISBN)
Public defence
2012-05-04, Betula, byggnad 6M, Norrlands Universitetsjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2012-04-13 Created: 2012-04-11 Last updated: 2018-06-08Bibliographically approved
Rentoft, M., Coates, P. J., Laurell, G. & Nylander, K. (2012). Transcriptional profiling of formalin fixed paraffin embedded tissue: pitfalls and recommendations for identifying biologically relevant changes. PLoS ONE, 7(4), e35276
Open this publication in new window or tab >>Transcriptional profiling of formalin fixed paraffin embedded tissue: pitfalls and recommendations for identifying biologically relevant changes
2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 4, p. e35276-Article in journal (Refereed) Published
Abstract [en]

Expression profiling techniques have been used to study the biology of many types of cancer but have been limited to some extent by the requirement for collection of fresh tissue. In contrast, formalin fixed paraffin embedded (FFPE) samples are widely available and represent a vast resource of potential material. The techniques used to handle the degraded and modified RNA from these samples are relatively new and all the pitfalls and limitations of this material for whole genome expression profiling are not yet clarified. Here, we analyzed 70 FFPE tongue carcinoma samples and 17 controls using the whole genome DASL array covering nearly 21000 genes. We identified that sample age is related to quality of extracted RNA and that sample quality influences apparent expression levels in a non-random manner related to gene probe sequence, leading to spurious results. However, by removing sub-standard samples and analysing only those 28 cancers and 15 controls that had similar quality we were able to generate a list of 934 genes significantly altered in tongue cancer compared to control samples of tongue. This list contained previously identified changes and was enriched for genes involved in many cancer-related processes such as tissue remodelling, inflammation, differentiation and apoptosis. Four novel genes of potential importance in tongue cancer development and maintenance, SH3BGL2, SLC2A6, SLC16A3 and CXCL10, were independently confirmed, validating our data. Hence, gene expression profiling can be performed usefully on archival material if appropriate quality assurance steps are taken to ensure sample consistency and we present some recommendations for the use of FFPE material based on our findings.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-57314 (URN)10.1371/journal.pone.0035276 (DOI)000305347400040 ()22530001 (PubMedID)
Available from: 2012-07-11 Created: 2012-07-11 Last updated: 2018-06-08Bibliographically approved
Rentoft, M., Fahlén, J., Coates, P., Laurell, G., Sjöström, B., Rydén, P. & Nylander, K. (2011). miRNA analysis of formalin-fixed squamous cell carcinomas of the tongue is affected by age of the samples. International Journal of Oncology, 38(1), 61-69
Open this publication in new window or tab >>miRNA analysis of formalin-fixed squamous cell carcinomas of the tongue is affected by age of the samples
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2011 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 38, no 1, p. 61-69Article in journal (Refereed) Published
Abstract [en]

Global miRNA expression arrays were used for analysis of 836 miRNAs in formalin-fixed paraffin-embedded samples from 21 tongue cancer patients and 8 controls. Samples had been stored for one to eleven years. Results separated tumour samples from controls, however, the largest variation was correlated to sample storage time, detectable already after one year. With the use of a linear regression model we could adjust for the storage-dependent effect, leading to the identification of 54 differentially expressed miRNAs in tongue cancer, compared to 16 when using standard normalization, including up-regulation of a novel miRNA, miR-424.

Place, publisher, year, edition, pages
Spandidos Publ. Ltd, 2011
Keywords
miRNA, FFPE, tongue carcinoma, storage, normalization
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-38654 (URN)10.3892/ijo_00000824 (DOI)000286293000008 ()21109926 (PubMedID)
Available from: 2010-12-20 Created: 2010-12-20 Last updated: 2018-06-08Bibliographically approved
Rentoft, M., Johnsson, E., Laurell, G., Coates, P. J. & Nylander, K. (2011). RNA expression profiling of archival tongue carcinoma samples. Paper presented at 16th World Congress on Advances in Oncology and 14th International Symposium on Molecular Medicine October 6-8, 2011 Hotel Rodos Palace, Rhodes Island, Greece. , 28
Open this publication in new window or tab >>RNA expression profiling of archival tongue carcinoma samples
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2011 (English)Conference paper, Published paper (Refereed)
Series
International Journal of Molecular Medicine, ISSN 1107-3756 ; Vol. 28 Suppl. 1
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-49274 (URN)000295422700059 ()
Conference
16th World Congress on Advances in Oncology and 14th International Symposium on Molecular Medicine October 6-8, 2011 Hotel Rodos Palace, Rhodes Island, Greece
Available from: 2011-11-09 Created: 2011-11-04 Last updated: 2018-06-08Bibliographically approved
Rentoft, M., Laurell, G., Coates, P. J., Sjöström, B. & Nylander, K. (2010). Comments on "Transcriptional profiling of oral squamous cell carcinoma using formalin-fixed paraffin-embedded samples" by Saleh et al., Oral Oncol 46 (2010) 379-386.. Oral Oncology, 46(12), 891-892
Open this publication in new window or tab >>Comments on "Transcriptional profiling of oral squamous cell carcinoma using formalin-fixed paraffin-embedded samples" by Saleh et al., Oral Oncol 46 (2010) 379-386.
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2010 (English)In: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 46, no 12, p. 891-892Article in journal (Other academic) Published
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-36092 (URN)10.1016/j.oraloncology.2010.05.007 (DOI)000284403000011 ()20656546 (PubMedID)
Available from: 2010-09-16 Created: 2010-09-16 Last updated: 2018-06-08Bibliographically approved
Fahlén, J., Rentoft, M. & Rydén, P. (2010). MicroRNA-microarray data analysis in the precence of FFPE storage time effects.
Open this publication in new window or tab >>MicroRNA-microarray data analysis in the precence of FFPE storage time effects
2010 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: The standard method for preserving patient samples for diagnostic purposes is fixation in formalin followed by embedding in paraffin (FFPE). The use of FFPE blocks makes it possible to include a large number of patients in the experimental studies since millions of FFPE blocks are stored around the world. However, FFPE storage can cause degradation and modifi­cations of nucleic acids. In order to draw reliable biological conclusions it is therefore important to know what effect FFPE-storage have on the tissues and to have procedures that normalize this effect. In this paper, we study the effect that FFPE-storage has on microRNA-microarray data from tongue-cancer patients and propose a novel procedure for normalizing the bias intro­duced by FFPE-storage.

Results: MicroRNA-microarray data from 21 tongue-cancer patients and 8 control patients were used. The samples were stored in FFPE blocks and had been in storage for up to 11 years. The data contained a large amount of biological relevant variation, yet the largest variation was due to the samples storage times. The storage effect was shown to be significant and some results suggested that it may be causal. Moreover, the microRNAs were unequally affected by storage and this could partially be explained by sequence characteristics. The novel normaliza­tion procedure was shown to have a large impact in the analysis ability to identify differentially expressed microRNAs between young and old cancer patients as well as between cancer and control patients. The p-values for the top microRNAs candidates were much lower for the pro­posed novel normalization compared to a standard normalization procedure which suggested that the novel normalization made the analysis more efficient.

Conclusions: MicroRNA-microarray data can be seriously affected by FFPE-storage and the introduced variation cannot be removed by standard normalizations. The proposed normaliza­tion removes the bias introduced by FFPE-storage and gives higher sensitivity than the standard normalization.

Keywords
microRNA, microarray, FFPE, storage time effects, normalization
National Category
Probability Theory and Statistics
Research subject
Statistics
Identifiers
urn:nbn:se:umu:diva-33355 (URN)
Available from: 2010-04-22 Created: 2010-04-22 Last updated: 2018-06-08
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