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Loss of histone H3 lysine 36 trimethylation is associated with an increased risk of renal cell carcinoma-specific death.

Ho TH, Kapur P, Joseph RW, Serie DJ, Eckel-Passow JE, Tong P, Wang J, Castle EP, Stanton ML, Cheville JC, Jonasch E, Brugarolas J, Parker AS - Mod. Pathol. (2015)

Bottom Line: However, few data exist regarding the impact of loss of H3K36me3 on outcomes.In The Cancer Genome Atlas cohort, SETD2 DNA alterations or mRNA expression was not associated with overall survival (P>0.05).This association remains significant after stratifying for the SSIGN score, particularly among those patients with low-risk tumors.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ, USA.

ABSTRACT
Sequencing of clear cell renal cell carcinomas identified loss-of-function mutations of SETD2, a gene that encodes a nonredundant methytransferase responsible for histone H3 lysine 36 trimethylation (H3K36me3), and H3K36me3 is progressively deregulated in metastases. However, few data exist regarding the impact of loss of H3K36me3 on outcomes. We assessed the association of SETD2 DNA alterations and mRNA expression with overall survival using The Cancer Genome Atlas clear cell renal carcinoma data (N=411). Additionally, we assessed the association of H3K36 loss of methylation with renal cell carcinoma-specific survival and progression-free survival using an independent cohort at Mayo Clinic (N=1454). Overall survival, renal cell carcinoma-specific survival and progression-free survival were estimated using Kaplan-Meier method, and differences in survival across groups was compared using Cox regression models, adjusted for age and the Mayo SSIGN (stage, size, grade, and necrosis) score. In The Cancer Genome Atlas cohort, SETD2 DNA alterations or mRNA expression was not associated with overall survival (P>0.05). In the Mayo cohort, patients with H3K36me3-negative tumors were two times more likely to experience renal cell carcinoma-specific death than patients with H3K36me3-positive tumors (hazard ratio, 2.23; 95% confidence interval, 1.77-2.81); P<0.0001. After stratifying for the SSIGN score, H3K36me3-negative tumors in the low-risk SSIGN group had a worse renal cell carcinoma-specific survival (hazard ratio, 2.18; 95% confidence interval, 1.09-4.36); P=0.03. Although SETD2 DNA and mRNA alterations are not associated with overall survival, we provide evidence that deregulation of the H3K36me3 axis is associated with a higher risk of renal cell carcinoma-specific death. This association remains significant after stratifying for the SSIGN score, particularly among those patients with low-risk tumors.

No MeSH data available.


Related in: MedlinePlus

Kaplan-Meier Survival Plots for SETD2 DNA and RNA in The CancerGenome Atlas Kidney Renal Clear Cell Carcinoma Dataset. A, Analysis ofSETD2 copy number and mutations. B, Analysis ofSETD2 messenger RNA dichotomized as high or low expressionbased on median RNA-Sequencing by Expectation-Maximization value. 2 samples weremissing were missing overall survival.
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Figure 1: Kaplan-Meier Survival Plots for SETD2 DNA and RNA in The CancerGenome Atlas Kidney Renal Clear Cell Carcinoma Dataset. A, Analysis ofSETD2 copy number and mutations. B, Analysis ofSETD2 messenger RNA dichotomized as high or low expressionbased on median RNA-Sequencing by Expectation-Maximization value. 2 samples weremissing were missing overall survival.

Mentions: The impact of SETD2 DNA copy number loss or mRNAexpression on overall survival is unknown. 3p loss of heterozygosity occurs ingreater than 90% of clear cell renal cell carcinoma cases, and aloss-of-function SETD2 mutation in the remaining allele wouldlead to biallelic inactivation of SETD2. We assessed the impactof SETD2 copy number loss alone, concurrentSETD2 copy number loss and SETD2 mutation,and no SETD2 copy number loss or mutations on overall survival(Figure 1A, Supplementary Figure S1). We didnot observe an association (overall log-rank testP=0.25) between overall survival andSETD2 copy number alterations (hazard ratio=0.66,95% confidence interval=0.37–1.18) or concurrent copynumber loss with SETD2 mutation (hazard ratio=0.9,95% confidence interval=0.44–1.82). To determine ifoverall survival was associated with SETD2 mRNA expression, wedichotomized mRNA (high or low) expression at the median RNA-Sequencing byExpectation Maximization value (Figure 1B).As with SETD2 copy number alterations, we did not observe anassociation between high SETD2 mRNA expression and overallsurvival (low SETD2 expression hazard ratio[95% confidence interval], 1.28[0.91–1.80] (P=.16, log-ranktest).


Loss of histone H3 lysine 36 trimethylation is associated with an increased risk of renal cell carcinoma-specific death.

Ho TH, Kapur P, Joseph RW, Serie DJ, Eckel-Passow JE, Tong P, Wang J, Castle EP, Stanton ML, Cheville JC, Jonasch E, Brugarolas J, Parker AS - Mod. Pathol. (2015)

Kaplan-Meier Survival Plots for SETD2 DNA and RNA in The CancerGenome Atlas Kidney Renal Clear Cell Carcinoma Dataset. A, Analysis ofSETD2 copy number and mutations. B, Analysis ofSETD2 messenger RNA dichotomized as high or low expressionbased on median RNA-Sequencing by Expectation-Maximization value. 2 samples weremissing were missing overall survival.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4697879&req=5

Figure 1: Kaplan-Meier Survival Plots for SETD2 DNA and RNA in The CancerGenome Atlas Kidney Renal Clear Cell Carcinoma Dataset. A, Analysis ofSETD2 copy number and mutations. B, Analysis ofSETD2 messenger RNA dichotomized as high or low expressionbased on median RNA-Sequencing by Expectation-Maximization value. 2 samples weremissing were missing overall survival.
Mentions: The impact of SETD2 DNA copy number loss or mRNAexpression on overall survival is unknown. 3p loss of heterozygosity occurs ingreater than 90% of clear cell renal cell carcinoma cases, and aloss-of-function SETD2 mutation in the remaining allele wouldlead to biallelic inactivation of SETD2. We assessed the impactof SETD2 copy number loss alone, concurrentSETD2 copy number loss and SETD2 mutation,and no SETD2 copy number loss or mutations on overall survival(Figure 1A, Supplementary Figure S1). We didnot observe an association (overall log-rank testP=0.25) between overall survival andSETD2 copy number alterations (hazard ratio=0.66,95% confidence interval=0.37–1.18) or concurrent copynumber loss with SETD2 mutation (hazard ratio=0.9,95% confidence interval=0.44–1.82). To determine ifoverall survival was associated with SETD2 mRNA expression, wedichotomized mRNA (high or low) expression at the median RNA-Sequencing byExpectation Maximization value (Figure 1B).As with SETD2 copy number alterations, we did not observe anassociation between high SETD2 mRNA expression and overallsurvival (low SETD2 expression hazard ratio[95% confidence interval], 1.28[0.91–1.80] (P=.16, log-ranktest).

Bottom Line: However, few data exist regarding the impact of loss of H3K36me3 on outcomes.In The Cancer Genome Atlas cohort, SETD2 DNA alterations or mRNA expression was not associated with overall survival (P>0.05).This association remains significant after stratifying for the SSIGN score, particularly among those patients with low-risk tumors.

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ, USA.

ABSTRACT
Sequencing of clear cell renal cell carcinomas identified loss-of-function mutations of SETD2, a gene that encodes a nonredundant methytransferase responsible for histone H3 lysine 36 trimethylation (H3K36me3), and H3K36me3 is progressively deregulated in metastases. However, few data exist regarding the impact of loss of H3K36me3 on outcomes. We assessed the association of SETD2 DNA alterations and mRNA expression with overall survival using The Cancer Genome Atlas clear cell renal carcinoma data (N=411). Additionally, we assessed the association of H3K36 loss of methylation with renal cell carcinoma-specific survival and progression-free survival using an independent cohort at Mayo Clinic (N=1454). Overall survival, renal cell carcinoma-specific survival and progression-free survival were estimated using Kaplan-Meier method, and differences in survival across groups was compared using Cox regression models, adjusted for age and the Mayo SSIGN (stage, size, grade, and necrosis) score. In The Cancer Genome Atlas cohort, SETD2 DNA alterations or mRNA expression was not associated with overall survival (P>0.05). In the Mayo cohort, patients with H3K36me3-negative tumors were two times more likely to experience renal cell carcinoma-specific death than patients with H3K36me3-positive tumors (hazard ratio, 2.23; 95% confidence interval, 1.77-2.81); P<0.0001. After stratifying for the SSIGN score, H3K36me3-negative tumors in the low-risk SSIGN group had a worse renal cell carcinoma-specific survival (hazard ratio, 2.18; 95% confidence interval, 1.09-4.36); P=0.03. Although SETD2 DNA and mRNA alterations are not associated with overall survival, we provide evidence that deregulation of the H3K36me3 axis is associated with a higher risk of renal cell carcinoma-specific death. This association remains significant after stratifying for the SSIGN score, particularly among those patients with low-risk tumors.

No MeSH data available.


Related in: MedlinePlus