Maris, J. M. et al. Chromosome 6p22 locus associated with clinically aggressive neuroblastoma. N. Engl. J. Med. 358, 2585-2593

Division of Oncology and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104-4318, USA.
New England Journal of Medicine (Impact Factor: 55.87). 07/2008; 358(24):2585-93. DOI: 10.1056/NEJMoa0708698
Source: PubMed


Neuroblastoma is a malignant condition of the developing sympathetic nervous system that most commonly affects young children and is often lethal. Its cause is not known.
We performed a genomewide association study by first genotyping blood DNA samples from 1032 patients with neuroblastoma and 2043 control subjects of European descent using the Illumina HumanHap550 BeadChip. Samples from three independent groups of patients with neuroblastoma (a total of 720 patients) and 2128 control subjects were then genotyped to replicate significant associations.
We observed a significant association between neuroblastoma and the common minor alleles of three consecutive single-nucleotide polymorphisms (SNPs) at chromosome band 6p22 and containing the predicted genes FLJ22536 and FLJ44180 (P=1.71x10(-9) to 7.01x10(-10); allelic odds ratio, 1.39 to 1.40). Homozygosity for the at-risk G allele of the most significantly associated SNP, rs6939340, resulted in an increased likelihood of the development of neuroblastoma (odds ratio, 1.97; 95% confidence interval, 1.58 to 2.45). Subsequent genotyping of the three 6p22 SNPs in three independent case series confirmed our observation of an association (P=9.33x10(-15) at rs6939340 for joint analysis). Patients with neuroblastoma who were homozygous for the risk alleles at 6p22 were more likely to have metastatic (stage 4) disease (P=0.02), amplification of the MYCN oncogene in the tumor cells (P=0.006), and disease relapse (P=0.01).
A common genetic variation at chromosome band 6p22 is associated with susceptibility to neuroblastoma.

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    • "For evaluation of NET genotype, patients from A3961 and A3973 who had been included in a previous largescale neuroblastoma genome-wide association project were included [24] [25]. Patients were treated according to protocol therapy, as previously described [22] [23]. "
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    ABSTRACT: Purpose. (123)I-metaiodobenzylguanidine (MIBG) is used for the diagnostic evaluation of neuroblastoma. We evaluated the relationship between norepinephrine transporter (NET) expression and clinical MIBG uptake. Methods. Quantitative reverse transcription PCR (N = 82) and immunohistochemistry (IHC; N = 61) were performed for neuroblastoma NET mRNA and protein expression and correlated with MIBG avidity on diagnostic scans. The correlation of NET expression with clinical features was also performed. Results. Median NET mRNA expression level for the 19 MIBG avid patients was 12.9% (range 1.6-73.7%) versus 5.9% (range 0.6-110.0%) for the 8 nonavid patients (P = 0.31). Median percent NET protein expression was 50% (range 0-100%) in MIBG avid patients compared to 10% (range 0-80%) in nonavid patients (P = 0.027). MYCN amplified tumors had lower NET protein expression compared to nonamplified tumors (10% versus 50%; P = 0.0002). Conclusions. NET protein expression in neuroblastoma correlates with MIBG avidity. MYCN amplified tumors have lower NET protein expression.
    Full-text · Article · Sep 2012
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    • "The RALYL high expression in the normal adrenal, kidney and brain (Shyamsundar et al., 2005). Furthermore, RALYL expression down-regulated correlates with mental disorder (Lee et al., 2007), Parkinson's disease (Moran et al., 2006), brain cancer (Maris et al., 2008), adrenal cancer (Giordano et al., 2009) and kidney cancer (Higgins et al., 2003). However, there was not published report on the relationships between the expression of RALYL and "
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    ABSTRACT: The molecular mechanisms involved in the progression of clear cell renal cell carcinomas (ccRCCs) are still unclear. The aim of this study was to analyse the relationships between expression of RALYL and clinical characteristics. In 41 paired samples of ccRCCs and adjacent normal tissues, we used real-time qPCR to evaluate the expression of RALYL mRNA. RALYL protein levels were determined in 146 samples of ccRCC and 37 adjacent normal tissues by immunohistochemistry. Statistical analysis was used to explore the relationships between expression of RALYL and the clinical characteristics (gender, age, tumor size, T stage, N stage, M stage, survival times and survival outcome) in ccRCC. In addition, these patients were follow-up period 64 months (range: 4~116months) to investigate the influence on prognosis. We found significantly differences between ccRCC tissues and normal tissues (p<0.001, paired-sample t test) in mRNA levels of RALYL. Immunohistochemistry analyses in 146 ccRCC samples and 37 adjacent normal tissues showed significantly lower RALYL protein levels in ccRCC samples (χ2-test, p<0.001), inversely correlating with tumour size (p=0.024), T stage (0.005), N stage (p<0.001) as well as M stage (p=0.019), but not age (p=0.357) and gender (p=0.348) . Kaplan-Meier survival analysis demonstrated that people with lower level of RALYL expression had a poorer survival rate than those with a higher level of RALYL expression, significantly different by the log-rank test (p=0.011). Cox regression analysis indicated that RALYL expression (p=0.039), N stage (p=0.008) and distant metastasis (p<0.001) were independent prognosis factors for the overall survival of ccRCC patients. We demonstrated that the expression of RALYL was significantly low in ccRCC and correlated with a poor prognosis in a large number of clinical samples. Our findings showed that RALYL may be a potential therapeutic target as well as a poor prognostic factor.
    Preview · Article · Jul 2012 · Asian Pacific journal of cancer prevention: APJCP
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    • "The use of high-density SNP genotyping arrays in GWAS has proven to be a powerful tool in identifying genetic determinants of complex disease. The first report that identified common genetic variants predisposing to neuroblastoma came from a GWAS using blood samples from nearly 2000 neuroblastoma patients and more than 4000 healthy control subjects of European descent (Maris et al., 2008). In this study, over half a million SNPs were genotyped and 3 common SNPs within the FLJ22536 and FLJ44180 genes at chromosome 6p22.3 "

    Full-text · Chapter · Feb 2012
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