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CASP8 SNP D302H (rs1045485) is associated with worse survival in MYCN-amplified neuroblastoma patients.

Rihani A, De Wilde B, Zeka F, Laureys G, Francotte N, Tonini GP, Coco S, Versteeg R, Noguera R, Schulte JH, Eggert A, Stallings RL, Speleman F, Vandesompele J, Van Maerken T - PLoS ONE (2014)

Bottom Line: Neuroblastoma is a pediatric cancer that exhibits a wide clinical spectrum ranging from spontaneous regression in low-risk patients to fatal disease in high-risk patients.SNPs in the TP53 pathway are of special importance, as several studies have reported associations between TP53 pathway SNPs and cancer.A missense SNP in exon 10 of the CASP8 gene SNP D302H was associated with worse overall and event-free survival in patients with MYCN-amplified neuroblastoma tumors.

View Article: PubMed Central - PubMed

Affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium.

ABSTRACT

Background: Neuroblastoma is a pediatric cancer that exhibits a wide clinical spectrum ranging from spontaneous regression in low-risk patients to fatal disease in high-risk patients. The identification of single nucleotide polymorphisms (SNPs) may help explain the heterogeneity of neuroblastoma and assist in identifying patients at higher risk for poor survival. SNPs in the TP53 pathway are of special importance, as several studies have reported associations between TP53 pathway SNPs and cancer. Of note, less than 2% of neuroblastoma tumors have a TP53 mutation at diagnosis.

Patients and methods: We selected 21 of the most frequently studied SNPs in the TP53 pathway and evaluated their association with outcome in 500 neuroblastoma patients using TaqMan allelic discrimination assays.

Results and conclusion: We investigated the impact of 21 SNPs on overall survival, event-free survival, age at diagnosis, MYCN status, and stage of the disease in 500 neuroblastoma patients. A missense SNP in exon 10 of the CASP8 gene SNP D302H was associated with worse overall and event-free survival in patients with MYCN-amplified neuroblastoma tumors.

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Overall and event-free survival of NB patients by CASP8 SNP D302H.Comparison of Kaplan-Meier survival curves between different genotypes of CASP8 SNP D302H. Overall survival of MYCN-amplified NB patients (A), event-free survival of MYCN-amplified NB patients (B). Raw P-values were calculated by the log rank test. q-values are adjusted p-values after Benjamini-Hochberg multiple testing correction.
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pone-0114696-g001: Overall and event-free survival of NB patients by CASP8 SNP D302H.Comparison of Kaplan-Meier survival curves between different genotypes of CASP8 SNP D302H. Overall survival of MYCN-amplified NB patients (A), event-free survival of MYCN-amplified NB patients (B). Raw P-values were calculated by the log rank test. q-values are adjusted p-values after Benjamini-Hochberg multiple testing correction.

Mentions: We used whole genome amplified DNA from tumors of 500 NB patients to genotype 21 SNPs in fifteen TP53 pathway genes (Table 1) using hydrolysis probe based qPCR genotyping assays for 17 SNPs, and Sanger sequencing for four MDM2 SNPs (285, 309, 344, and 354). The clinical features of the patients are shown in Table 2. The study population consisted mostly of European patients from Caucasian origin. We first validated the approach by genotyping the SNPs on whole genome amplified and non-amplified DNA from 31 NB cell lines, and results showed that all SNPs were genotyped correctly (Table S2 in S1 File). In patients, CASP8 SNP D302H was the only SNP that showed an association with worse overall (OS) (p = 0.0006; multiple testing corrected p-value, q-value = 0.049) and event-free survival (EFS) (p = 0.0002; multiple testing corrected p-value, q-value = 0.042) in NB patients with MYCN amplification (Fig. 1, Table 3). The stratified survival analyses of all the other SNPs are shown in table S3 in S1 File. To confirm that there is no difference in the SNP status between the tumor and the germline of the patients, we collected 41 representative blood samples from the patients in our cohort and genotyped them using the same TaqMan assay for the CASP8 SNP D302H. Our results show that all the 41 patients have exactly the same SNP status in their blood as in their tumor (data not shown). This additional analysis makes it highly unlikely that different SNP status exists in the tumor compared to the blood of the patients. We performed also multivariate Cox proportional hazard analysis and investigated the effect of CASP8 SNP D302H on the survival of neuroblastoma patients taking into account the different clinical covariates (stage of the disease, MYCN status, and the age at diagnosis). Our results show that CASP8 SNP D302H is an independent prognostic factor (Table S4 and S5 in S1 File)


CASP8 SNP D302H (rs1045485) is associated with worse survival in MYCN-amplified neuroblastoma patients.

Rihani A, De Wilde B, Zeka F, Laureys G, Francotte N, Tonini GP, Coco S, Versteeg R, Noguera R, Schulte JH, Eggert A, Stallings RL, Speleman F, Vandesompele J, Van Maerken T - PLoS ONE (2014)

Overall and event-free survival of NB patients by CASP8 SNP D302H.Comparison of Kaplan-Meier survival curves between different genotypes of CASP8 SNP D302H. Overall survival of MYCN-amplified NB patients (A), event-free survival of MYCN-amplified NB patients (B). Raw P-values were calculated by the log rank test. q-values are adjusted p-values after Benjamini-Hochberg multiple testing correction.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4263607&req=5

pone-0114696-g001: Overall and event-free survival of NB patients by CASP8 SNP D302H.Comparison of Kaplan-Meier survival curves between different genotypes of CASP8 SNP D302H. Overall survival of MYCN-amplified NB patients (A), event-free survival of MYCN-amplified NB patients (B). Raw P-values were calculated by the log rank test. q-values are adjusted p-values after Benjamini-Hochberg multiple testing correction.
Mentions: We used whole genome amplified DNA from tumors of 500 NB patients to genotype 21 SNPs in fifteen TP53 pathway genes (Table 1) using hydrolysis probe based qPCR genotyping assays for 17 SNPs, and Sanger sequencing for four MDM2 SNPs (285, 309, 344, and 354). The clinical features of the patients are shown in Table 2. The study population consisted mostly of European patients from Caucasian origin. We first validated the approach by genotyping the SNPs on whole genome amplified and non-amplified DNA from 31 NB cell lines, and results showed that all SNPs were genotyped correctly (Table S2 in S1 File). In patients, CASP8 SNP D302H was the only SNP that showed an association with worse overall (OS) (p = 0.0006; multiple testing corrected p-value, q-value = 0.049) and event-free survival (EFS) (p = 0.0002; multiple testing corrected p-value, q-value = 0.042) in NB patients with MYCN amplification (Fig. 1, Table 3). The stratified survival analyses of all the other SNPs are shown in table S3 in S1 File. To confirm that there is no difference in the SNP status between the tumor and the germline of the patients, we collected 41 representative blood samples from the patients in our cohort and genotyped them using the same TaqMan assay for the CASP8 SNP D302H. Our results show that all the 41 patients have exactly the same SNP status in their blood as in their tumor (data not shown). This additional analysis makes it highly unlikely that different SNP status exists in the tumor compared to the blood of the patients. We performed also multivariate Cox proportional hazard analysis and investigated the effect of CASP8 SNP D302H on the survival of neuroblastoma patients taking into account the different clinical covariates (stage of the disease, MYCN status, and the age at diagnosis). Our results show that CASP8 SNP D302H is an independent prognostic factor (Table S4 and S5 in S1 File)

Bottom Line: Neuroblastoma is a pediatric cancer that exhibits a wide clinical spectrum ranging from spontaneous regression in low-risk patients to fatal disease in high-risk patients.SNPs in the TP53 pathway are of special importance, as several studies have reported associations between TP53 pathway SNPs and cancer.A missense SNP in exon 10 of the CASP8 gene SNP D302H was associated with worse overall and event-free survival in patients with MYCN-amplified neuroblastoma tumors.

View Article: PubMed Central - PubMed

Affiliation: Center for Medical Genetics, Ghent University, Ghent, Belgium.

ABSTRACT

Background: Neuroblastoma is a pediatric cancer that exhibits a wide clinical spectrum ranging from spontaneous regression in low-risk patients to fatal disease in high-risk patients. The identification of single nucleotide polymorphisms (SNPs) may help explain the heterogeneity of neuroblastoma and assist in identifying patients at higher risk for poor survival. SNPs in the TP53 pathway are of special importance, as several studies have reported associations between TP53 pathway SNPs and cancer. Of note, less than 2% of neuroblastoma tumors have a TP53 mutation at diagnosis.

Patients and methods: We selected 21 of the most frequently studied SNPs in the TP53 pathway and evaluated their association with outcome in 500 neuroblastoma patients using TaqMan allelic discrimination assays.

Results and conclusion: We investigated the impact of 21 SNPs on overall survival, event-free survival, age at diagnosis, MYCN status, and stage of the disease in 500 neuroblastoma patients. A missense SNP in exon 10 of the CASP8 gene SNP D302H was associated with worse overall and event-free survival in patients with MYCN-amplified neuroblastoma tumors.

Show MeSH
Related in: MedlinePlus