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DNA methylation as a prognostic marker in clear cell Renal Cell Carcinoma
Umeå University, Faculty of Medicine, Department of Medical Biosciences.
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cell carcinoma worldwide. Metastatic ccRCC is correlated to poor prognosis whereas non-metastatic disease has a 5-year survival rate up to 90%. Due to increased accessibility to different types of diagnostic imaging the frequency of metastatic ccRCC at diagnosis has decreased since the beginning of the 21st century. This has led to an earlier detection of primary tumors before patients present symptoms. However, 20-30% of the non-metastatic patients at diagnosis will progress and metastasize within five years of primary nephrectomy. Identifying patients at high risk of tumor progression at an early stage after diagnosis is of importance to improve outcome and survival. Currently, in Sweden, the Mayo scoring system is used to divide tumors into low, intermediate or high risk for tumor progression.

DNA methylation has been associated with tumor development and progression in different malignancies. In this thesis, Illumina Infinium HumanMeth27 BeadChip Arrays and Human Meth450K BeadChip Arrays have been used to evaluate the relationship between methylation and clinicopathological variables as well as ccRCC outcome in 45 and 115 patients.

Our studies identified an association between higher level of promoter-associated DNA methylation and clinicopathological variables in ccRCC. There was a significant stepwise increase of average methylation from tumor-free tissue, via non-metastatic tumors to metastatic disease. Cluster analysis divided patients into two distinct groups that differed in average methylation levels, TNM stage, Fuhrman nuclear grade, tumor size, survival and tumor progression. We also presented two prognostic classifiers for non-metastatic tumors; the promoter methylation classifier (PMC) panel and the triple classifier. The PMC panel divided tumors depending on the methylation level, PMC low or PMC high, with significantly worse prognosis in the PMC high group. This data was verified in an independent, publically available cohort. The triple classifier was created using a combination of clinicopathological variables, previously identified CpGs biomarkers and a novel cluster analysis approach (Directed Cluster Analysis). The triple classifier had a higher specificity compared to the clinically used Mayo scoring system and predicted tumor progression with higher accuracy at a fixed sensitivity.

The identification of two epigenetic classifiers that predicted outcome in non-metastatic ccRCC further establishes the role of DNA methylation as a prognostic marker. This knowledge can contribute to identification of patients with a high risk of tumor progression and can be of importance in the decision regarding adjuvant treatment post-nephrectomy.

Abstract [sv]

Populärvetenskaplig sammanfattning

Klarcellig njurcancer är den vanligaste form av njurcancer. I Sverige diagnostiseras ca 1 000 individer årligen med sjukdomen. Idag upptäcks ofta njurcancer när patienter undersöks med bilddiagnostik av buken av andra anledningar, exempelvis vid oklar buksmärta och vid trauma. Detta gör att tumörerna upptäcks innan de hunnit ge symtom och andelen patienter med spridd sjukdom vid diagnos är under 20%, jämfört med över 30% i början av milleniet.

Den enda botande behandling som finns för njurcancer är total eller partiell nefrektomi, vilket innebär att hela njuren eller delen av njuren med tumör opereras bort. Om sjukdomen upptäcks tidigt, innan den hunnit sprida sig till kringliggande organ, är prognosen god och 90% av patienterna lever minst fem år efter diagnos. Är sjukdomen spridd vid diagnos finns det idag behandlingar som förlänger överlevnadstiden, och ny immunbehandling som också kan bota sjukdomen.

Även om klarcellig njurcancer som är begränsad till njuren botas när tumören avlägsnas är det ungefär en tredjedel av dessa patienter som drabbas av en ny njurtumör eller spridning till andra organ inom fem år efter diagnos. Behovet av att identifiera dessa patienter är stort när de är i behov av tilläggsbehandling. Idag utgår klinikerna från hur tumören ser ut när de bestämmer hur patienterna ska följas efter kirurgi, vid karakteristika som talar för en hög risk för spridning följs patienterna tätare och under längre tid.

Genom att analysera hur ccRCC tumörer ser ut på cellnivå har skillnader i genuttryck och DNA-sekvenser kunna identifieras. Att utnyttja dessa skillnader är viktiga för att identifiera tumörer med ökad risk för spridning.

I min avhandling har vi analyserat DNA metylering i klarcellig njurcancer vid diagnos. DNA metylering är en epigenetisk förändring, en förändring på DNA nivå som inte påverkar DNA sekvensen men kan påverkar vilka gener som uttrycks i cellerna. Nivåerna av DNA metylering skiljer sig mellan olika prognostiska grupper ccRCC. De tumörer som vid diagnos redan spridit sig till kringliggande organ har en högre grad av metylering jämfört med de tumörer som växer endast i njuren. Vi har även kunnat visa på skillnader mellan de lokala tumörer som senare sprids. Detta gör att DNA metylering kan användas som prognostisk markör i ccRCC.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2020. , p. 50
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2066
Keywords [en]
Clear cell renal cell carcinoma, DNA methylation, Prognosis, Clinical outcome, Epigenetic classifiers
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-167591ISBN: 978-91-7855-166-8 (electronic)ISBN: 978-91-7855-165-1 (print)OAI: oai:DiVA.org:umu-167591DiVA, id: diva2:1390300
Public defence
2020-02-21, Stora Hörsalen, byggnad 5B, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2020-01-31 Created: 2020-01-31 Last updated: 2020-02-04Bibliographically approved
List of papers
1. DNA methylation status defines clinicopathological parameters including survival for patients with clear cell renal cell carcinoma (ccRCC)
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: 2020-01-31Bibliographically approved
2. DNA methylation associates with survival in non-metastatic clear cell renal cell carcinoma
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: 2020-01-31Bibliographically approved
3. Combining epigenetic and clinicopathological variables improves prognostic prediction in clear cell Renal Cell Carcinoma
Open this publication in new window or tab >>Combining epigenetic and clinicopathological variables improves prognostic prediction in clear cell Renal Cell Carcinoma
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(English)Manuscript (preprint) (Other academic)
Keywords
DNA methylation, cancer, cluster analysis, classification, clear cell renal cell carcinoma
National Category
Cancer and Oncology Probability Theory and Statistics
Identifiers
urn:nbn:se:umu:diva-167269 (URN)
Available from: 2020-01-14 Created: 2020-01-14 Last updated: 2020-01-31Bibliographically approved

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Andersson-Evelönn, Emma

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