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Roos, Göran
Publications (10 of 110) Show all publications
Andersson-Evelönn, E., Landfors, M., Haider, Z., Köhn, L., Ljungberg, B., Roos, G. & Degerman, S. (2019). DNA methylation associates with survival in non-metastatic clear cell renal cell carcinoma. BMC Cancer, 19, Article ID 65.
Open this publication in new window or tab >>DNA methylation associates with survival in non-metastatic clear cell renal cell carcinoma
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2019 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 19, article id 65Article in journal (Refereed) Published
Abstract [en]

Background: Clear cell renal cell carcinoma (ccRCC) is the most common subtype among renal cancer and is associated with poor prognosis if metastasized. Up to one third of patients with local disease at diagnosis will develop metastasis after nephrectomy, and there is a need for new molecular markers to identify patients with high risk of tumor progression. In the present study, we performed genome-wide promoter DNA methylation analysis at diagnosis to identify DNA methylation profiles associated with risk for progress.

Method: Diagnostic tissue samples from 115 ccRCC patients were analysed by Illumina HumanMethylation450K arrays and methylation status of 155,931 promoter associated CpGs were related to genetic aberrations, gene expression and clinicopathological parameters.

Results: The ccRCC samples separated into two clusters (cluster A/B) based on genome-wide promoter methylation status. The samples in these clusters differed in tumor diameter (p < 0.001), TNM stage (p < 0.001), morphological grade (p < 0.001), and patients outcome (5 year cancer specific survival (pCSS5yr) p < 0.001 and cumulative incidence of progress (pCIP5yr) p < 0.001. An integrated genomic and epigenomic analysis in the ccRCCs, revealed significant correlations between the total number of genetic aberrations and total number of hypermethylated CpGs (R = 0.435, p < 0.001), and predicted mitotic age (R = 0.407, p < 0.001). We identified a promoter methylation classifier (PMC) panel consisting of 172 differently methylated CpGs accompanying progress of disease. Classifying non-metastatic patients using the PMC panel showed that PMC high tumors had a worse prognosis compared with the PMC low tumors (pCIP5yr 38% vs. 8%, p = 0.001), which was confirmed in non-metastatic ccRCCs in the publically available TCGA-KIRC dataset (pCIP5yr 39% vs. 16%, p < 0.001).

Conclusion: DNA methylation analysis at diagnosis in ccRCC has the potential to improve outcome-prediction in non-metastatic patients at diagnosis.

Place, publisher, year, edition, pages
BioMed Central, 2019
Keywords
Clear cell renal cell carcinoma, DNA methylation, Prognosis, Genetic
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-155957 (URN)10.1186/s12885-019-5291-3 (DOI)000455576500013 ()30642274 (PubMedID)
Funder
The Kempe FoundationsSwedish Cancer SocietyVästerbotten County Council
Available from: 2019-02-08 Created: 2019-02-08 Last updated: 2019-02-08Bibliographically approved
Norberg, A., Rosén, A., Raaschou-Jensen, K., Kjeldsen, L., Moilanen, J. S., Paulsson-Karisson, Y., . . . Hultdin, M. (2018). Novel variants in Nordic patients referred for genetic testing of telomere-related disorders. European Journal of Human Genetics, 26(6), 858-867
Open this publication in new window or tab >>Novel variants in Nordic patients referred for genetic testing of telomere-related disorders
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2018 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 26, no 6, p. 858-867Article in journal (Refereed) Published
Abstract [en]

Telomere-related disorders are a clinically and genetically heterogeneous group of disorders characterized by premature telomere shortening and proliferative failure of a variety of tissues. This study reports the spectrum of telomere-related gene variants and telomere length in Nordic patients referred for genetic testing due to suspected telomere-related disorder. We performed Sanger sequencing of the genes TERT, TERC, DKC1, and TINF2 on 135 unrelated index patients and measured telomere length by qPCR on DNA from peripheral blood leukocytes. We identified pathogenic or likely pathogenic variants in 10 index patients, all of which had short telomeres compared to age-matched healthy controls. Six of the 10 variants were novel; three in TERC (n.69_74dupAGGCGC, n.122_125delGCGG, and n.407_408delinsAA) and three in TERT (p.(D684G), p.(R774*), and p.(*1133Wext*39)). The high proportion of novel variants identified in our study highlights the need for solid interpretation of new variants that may be detected. Measurement of telomere length is a useful approach for evaluating pathogenicity of genetic variants associated with telomere-related disorders.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-149013 (URN)10.1038/s41431-018-0112-8 (DOI)000433424200010 ()29483670 (PubMedID)2-s2.0-85042538231 (Scopus ID)
Available from: 2018-06-15 Created: 2018-06-15 Last updated: 2018-06-15Bibliographically approved
Kostjukovits, S., Degerman, S., Pekkinen, M., Klemetti, P., Landfors, M., Roos, G., . . . Makitie, O. (2017). Decreased telomere length in children with cartilage-hair hypoplasia. Journal of Medical Genetics, 54(5), 365-370
Open this publication in new window or tab >>Decreased telomere length in children with cartilage-hair hypoplasia
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2017 (English)In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 54, no 5, p. 365-370Article in journal (Refereed) Published
Abstract [en]

Background Cartilage-hair hypoplasia (CHH) is an autosomal recessive chondrodysplasia caused by RMRP (RNA component of mitochondrial RNA processing endoribonuclease) gene mutations. Manifestations include short stature, variable immunodeficiency, anaemia and increased risk of malignancies, all of which have been described also in telomere biology disorders. RMRP interacts with the telomerase RT (TERT) subunit, but the influence of RMRP mutations on telomere length is unknown. We measured relative telomere length (RTL) in patients with CHH, their first-degree relatives and healthy controls and correlated RTL with clinical and laboratory features. Methods The study cohort included 48 patients with CHH with homozygous (n=36) or compound heterozygous RMRP mutations (median age 38.2 years, range 6.0-70.8 years), 86 relatives (74 with a heterozygous RMRP mutation) and 94 unrelated healthy controls. We extracted DNA from peripheral blood, sequenced the RMRP gene and measured RTL by qPCR. Results Compared with age-matched and sex-matched healthy controls, median RTL was significantly shorter in patients with CHH (n=40 pairs, 1.05 vs 1.21, p=0.017), but not in mutation carriers (n=48 pairs, 1.16 vs 1.10, p=0.224). RTL correlated significantly with age in RMRP mutation carriers (r=-0.482, p < 0.001) and non-carriers (r=-0.498, p<0.001), but not in patients (r=-0.236, p=0.107). In particular children (< 18 years) with CHH had shorter telomeres than controls (median RTL 1.12 vs 1.26, p=0.008). In patients with CHH, RTL showed no correlation with genotype, clinical or laboratory characteristics. Conclusions Telomere length was decreased in children with CHH. We found no correlation between RTL and clinical or laboratory parameters.

Place, publisher, year, edition, pages
BMJ PUBLISHING GROUP, 2017
National Category
Medical Genetics Clinical Laboratory Medicine
Identifiers
urn:nbn:se:umu:diva-136203 (URN)10.1136/jmedgenet-2016-104279 (DOI)000400022200009 ()27986801 (PubMedID)
Available from: 2017-07-03 Created: 2017-07-03 Last updated: 2018-06-09Bibliographically approved
Svenson, U., Roos, G. & Wikström, P. (2017). Long leukocyte telomere length in prostate cancer patients at diagnosis is associated with poor metastasis-free and cancer-specific survival. Tumor Biology, 39(2)
Open this publication in new window or tab >>Long leukocyte telomere length in prostate cancer patients at diagnosis is associated with poor metastasis-free and cancer-specific survival
2017 (English)In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 39, no 2Article in journal (Refereed) Published
Abstract [en]

Previous studies have suggested that leukocyte telomere length is associated with risk of developing prostate cancer. Investigations of leukocyte telomere length as a prognostic factor in prostate cancer are, however, lacking. In this study, leukocyte telomere length was investigated both as a risk marker, comparing control subjects and patient risk groups (based on serum levels of prostate-specific antigen, tumor differentiation, and tumor stage), and as a prognostic marker for metastasis-free and cancer-specific survival. Relative telomere length was measured by a well-established quantitative polymerase chain reaction method in 415 consecutively sampled individuals. Statistical evaluation included 162 control subjects without cancer development during follow-up and 110 untreated patients with newly diagnosed localized prostate cancer at the time of blood draw. Leukocyte telomere length did not differ significantly between control subjects and patients, or between patient risk groups. Interestingly, however, and in line with our previous results in breast and kidney cancer patients, relative telomere length at diagnosis was an independent prognostic factor. Patients with long leukocyte telomeres (>= median) had a significantly worse prostate cancer-specific and metastasisfree survival compared to patients with short telomere length. In contrast, for patients who died of other causes than prostate cancer, long relative telomere length was not coupled to shorter survival time. To our knowledge, these results are novel and give further strength to our hypothesis that leukocyte telomere length might be used as a prognostic marker in malignancy.

Place, publisher, year, edition, pages
SAGE PUBLICATIONS LTD, 2017
Keywords
Telomere length, peripheral leukocytes, prostate cancer, metastasis, survival
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-133550 (URN)10.1177/1010428317692236 (DOI)000397167300029 ()
Available from: 2017-04-12 Created: 2017-04-12 Last updated: 2018-06-09Bibliographically approved
Andersson, U., Degerman, S., Dahlin, A., Brannstrom, T., Roos, G. & Melin, B. S. (2017). TELOMERE LENGTH, ALLERGIES AND RISK OF GLIOMA. Paper presented at 5th Quadrennial Meeting of the World-Federation-of-Neuro-Oncology-Societies (WFNOS), MAY 04-07, 2017, Zurich, SWITZERLAND. Neuro-Oncology, 19(Supplement: 3), 23-23, Article ID Meeting Abstract: P01.03.
Open this publication in new window or tab >>TELOMERE LENGTH, ALLERGIES AND RISK OF GLIOMA
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2017 (English)In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 19, no Supplement: 3, p. 23-23, article id Meeting Abstract: P01.03Article in journal, Meeting abstract (Refereed) Published
Place, publisher, year, edition, pages
OXFORD UNIV PRESS INC, 2017
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-136984 (URN)000402732900081 ()
Conference
5th Quadrennial Meeting of the World-Federation-of-Neuro-Oncology-Societies (WFNOS), MAY 04-07, 2017, Zurich, SWITZERLAND
Available from: 2017-06-30 Created: 2017-06-30 Last updated: 2018-06-09Bibliographically approved
Borssén, M., Haider, Z., Landfors, M., Norén-Nyström, U., Schmiegelow, K., Åsberg, A. E., . . . Degerman, S. (2016). DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T-Cell Acute Lymphoblastic Leukemia. Pediatric Blood & Cancer, 63(7), 1185-1192
Open this publication in new window or tab >>DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T-Cell Acute Lymphoblastic Leukemia
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2016 (English)In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 63, no 7, p. 1185-1192Article in journal (Refereed) Published
Abstract [en]

Background. Despite increased knowledge about genetic aberrations in pediatric T-cell acute lymphoblastic leukemia (T-ALL), no clinically feasible treatment-stratifying marker exists at diagnosis. Instead patients are enrolled in intensive induction therapies with substantial side effects. In modern protocols, therapy response is monitored by minimal residual disease (MRD) analysis and used for postinduction risk group stratification. DNA methylation profiling is a candidate for subtype discrimination at diagnosis and we investigated its role as a prognostic marker in pediatric T-ALL. Procedure. Sixty-five diagnostic T-ALL samples from Nordic pediatric patients treated according to the Nordic Society of Pediatric Hematology and Oncology ALL 2008 (NOPHO ALL 2008) protocol were analyzed by HumMeth450K genome wide DNA methylation arrays. Methylation status was analyzed in relation to clinical data and early T-cell precursor (ETP) phenotype. Results. Two distinct CpG island methylator phenotype (CIMP) groups were identified. Patients with a CIMP-negative profile had an inferior response to treatment compared to CIMP-positive patients (3-year cumulative incidence of relapse (CIR3y) rate: 29% vs. 6%, P = 0.01). Most importantly, CIMP classification at diagnosis allowed subgrouping of high-risk T-ALL patients (MRD >= 0.1% at day 29) into two groups with significant differences in outcome (CIR3y rates: CIMP negative 50% vs. CIMP positive 12%; P = 0.02). These groups did not differ regarding ETP phenotype, but the CIMP-negative group was younger (P = 0.02) and had higher white blood cell count at diagnosis (P = 0.004) compared with the CIMP-positive group. Conclusions. CIMP classification at diagnosis in combination with MRD during induction therapy is a strong candidate for further risk classification and could confer important information in treatment decision making.

Keywords
childhood leukemia, DNA methylation, MRD, prognosis, T-ALL, WBC
National Category
Cancer and Oncology Hematology Pediatrics
Identifiers
urn:nbn:se:umu:diva-124837 (URN)10.1002/pbc.25958 (DOI)000380105400008 ()26928953 (PubMedID)
Available from: 2016-10-03 Created: 2016-08-26 Last updated: 2019-05-10Bibliographically approved
Evelönn, E. A., Degerman, S., Köhn, L., Landfors, M., Ljungberg, B. & Roos, G. (2016). DNA methylation status defines clinicopathological parameters including survival for patients with clear cell renal cell carcinoma (ccRCC). Tumor Biology, 37(8), 10219-10228
Open this publication in new window or tab >>DNA methylation status defines clinicopathological parameters including survival for patients with clear cell renal cell carcinoma (ccRCC)
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2016 (English)In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 37, no 8, p. 10219-10228Article in journal (Refereed) Published
Abstract [en]

Epigenetic alterations in the methylome have been associated with tumor development and progression in renal cell carcinoma (RCC). In this study, 45 tumor samples, 12 tumor-free kidney cortex tissues, and 24 peripheral blood samples from patients with clear cell RCC (ccRCC) were analyzed by genome-wide promoter-directed methylation arrays and related to clinicopathological parameters. Unsupervised hierarchical clustering separated the tumors into two distinct methylation groups (clusters A and B), where cluster B had higher average methylation and increased number of hypermethylated CpG sites (CpGs). Furthermore, tumors in cluster B had, compared with cluster A, a larger tumor diameter (p = 0.033), a higher morphologic grade (p < 0.001), a higher tumor-node-metastasis (TNM) stage (p < 0.001), and a worse prognosis (p = 0.005). Higher TNM stage was correlated to an increase in average methylation level (p = 0.003) and number of hypermethylated CpGs (p = 0.003), whereas a number of hypomethylated CpGs were mainly unchanged. However, the predicted age of the tumors based on methylation profile did not correlate with TNM stage, morphological grade, or methylation cluster. Differently methylated (DM) genes (n = 840) in ccRCC samples compared with tumor-free kidney cortex samples were predominantly hypermethylated and a high proportion were identified as polycomb target genes. The DM genes were overrepresented by transcription factors, ligands, and receptors, indicating functional alterations of significance for ccRCC progression. To conclude, increased number of hypermethylated genes was associated with increased TNM stage of the tumors. DNA methylation classification of ccRCC tumor samples at diagnosis can serve as a clinically applicable prognostic marker in ccRCC.

Keywords
Clear cell renal cell carcinoma, DNA methylation, Survival, Predicted age, Polycomb target genes
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-126325 (URN)10.1007/s13277-016-4893-5 (DOI)000382672900022 ()26831665 (PubMedID)
Available from: 2016-10-27 Created: 2016-10-03 Last updated: 2018-06-09Bibliographically approved
Machiela, M. J., Lan, Q., Slager, S. L., Vermeulen, R. C. H., Teras, L. R., Camp, N. J., . . . Rothman, N. (2016). Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes. Human Molecular Genetics, 25(8), 1663-1676
Open this publication in new window or tab >>Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes
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2016 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 25, no 8, p. 1663-1676Article in journal (Refereed) Published
Abstract [en]

Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82, P-value = 8.5 x 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51, P-value = 4.0 x 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk.

Place, publisher, year, edition, pages
Oxford University Press, 2016
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-121474 (URN)10.1093/hmg/ddw027 (DOI)000374231400016 ()27008888 (PubMedID)
Available from: 2016-06-20 Created: 2016-06-02 Last updated: 2018-06-07Bibliographically approved
Svenson, U., Öberg, Å., Stenling, R., Palmqvist, R. & Roos, G. (2016). Telomere length in peripheral leukocytes is associated with immune cell tumor infiltration and prognosis in colorectal cancer patients. Tumor Biology, 37(8), 10877-10882
Open this publication in new window or tab >>Telomere length in peripheral leukocytes is associated with immune cell tumor infiltration and prognosis in colorectal cancer patients
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2016 (English)In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 37, no 8, p. 10877-10882Article in journal (Refereed) Published
Abstract [en]

Telomeres are protective structures at the end of chromosomes, essential for chromosomal integrity. A large number of studies have investigated leukocyte telomere length as a possible risk marker for various cancers, colorectal cancer (CRC) included. In contrast, studies investigating leukocyte telomere length in relation to CRC survival are lacking. We previously reported that relative telomere length (RTL) of leukocytes collected at diagnosis predicted survival in patients with breast and kidney cancer. We suggested that these findings might reflect various immunological mechanisms, affected by the presence of a tumor. In the present study, leukocyte RTL was examined in relation to immune cell tumor infiltration and prognosis in 130 patients with CRC diagnosis. RTL was measured with a well-established qPCR method. We found that patients with the highest degree of lymphocyte tumor infiltration had shorter leukocyte RTL. Consistent with our previous findings, short RTL was a favorable prognostic marker in univariate survival analysis. In the current study, RTL did not remain as an independent predictor in multivariate survival analysis, when including metastatic status in the model. However, a non-significant trend towards a similar telomere-associated survival pattern was observed in patients with limited disease. In contrast, for patients who died of other causes than CRC, short RTL was associated with significantly shorter survival time. To our knowledge, this is the first study to investigate an association between leukocyte RTL, immune cell tumor infiltration, and cancer-specific survival in CRC patients. Larger studies are warranted to verify these findings.

Keywords
Telomere length, Peripheral leukocytes, Colorectal carcinoma, Immune cell infiltration
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-126330 (URN)10.1007/s13277-016-4987-0 (DOI)000382672900088 ()26883253 (PubMedID)
Available from: 2016-10-27 Created: 2016-10-03 Last updated: 2019-05-09Bibliographically approved
de Almeida, F. J. M., Kivijarvi, K., Roos, G. & Nylander, K. (2015). A case of disseminated histoplasmosis diagnosed after oral presentation in an old HIV-negative patient in Sweden. Gerodontology, 32(3), 234-236
Open this publication in new window or tab >>A case of disseminated histoplasmosis diagnosed after oral presentation in an old HIV-negative patient in Sweden
2015 (English)In: Gerodontology, ISSN 0734-0664, E-ISSN 1741-2358, Vol. 32, no 3, p. 234-236Article in journal (Refereed) Published
Abstract [en]

Histoplasmosis is an endemic disease in various regions such as North America and South-East Asia but remains rare in Europe. Disseminated histoplasmosis is unusual in HIV-negative patients. Here, we describe a case of disseminated histoplasmosis in an HIV-negative patient diagnosed after oral presentation.

Keywords
histoplasmosis, Sweden, Mouth
National Category
Dentistry Geriatrics
Identifiers
urn:nbn:se:umu:diva-108450 (URN)10.1111/ger.12150 (DOI)000360047400011 ()
Available from: 2015-09-29 Created: 2015-09-11 Last updated: 2018-06-07Bibliographically approved
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