Clinical significance of the reduced expression of G protein gamma 7 (GNG7) in oesophageal cancer

Ohta, Masayuki; Mimori, Koshi; Fukuyoshi, Yoko; Kita, Yoshiaki; Motoyama, Keiichi; Yamashita, Keishi; Ishii, Hideshi; Inoue, Hiroshi; Mori, Masaki

doi:10.1038/sj.bjc.6604124

Cited by 65 publications

(56 citation statements)

References 19 publications

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“…Interestingly, in patients with no TMEM127 mutation but with 2q11 LOH, TMEM127 mRNA levels were also decreased by 35%, thus showing that 2q11 LOH itself had a dosage effect. Such a correlation has already been reported for many other genes, such as 19p13 LOH and GNG7 expression in esophageal cancer (14) or 3p14 LOH and FHIT expression in breast cancer (15).…”

Section: Discussionmentioning

confidence: 74%

A novel TMEM127 mutation in a patient with familial bilateral pheochromocytoma

Burnichon¹,

Lepoutre-Lussey²,

Laffaire³

et al. 2011

European Journal of Endocrinology

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Objective: In this report, we describe a new patient with unexplained familial bilateral pheochromocytoma. Following the recent description of TMEM127 as a new pheochromocytoma susceptibility gene, the aim of this study was to test the hypothesis of a causative TMEM127 gene mutation in this patient. Design: Pheochromocytoma susceptibility genes were analyzed in germline DNA and losses of heterozygosity (LOH) assessed by BAC array comparative genomic hybridization in tumor DNA. SDHB expression and S6 kinase (S6K) phosphorylation were analyzed by immunohistochemistry. Genomewide expression microarray studies were performed, and vascular density was quantified after CD34 immunohistochemistry. Results: A first germline variant was identified in the SDHB gene (c.158GOA; p.Gly53Glu). However, a positive SDHB immunostaining in the tumor indicated that this SDHB variant was a non-functional polymorphism. A novel TMEM127 germline mutation (c.140COA, p.Ala47Asp) associated with a 2q11 LOH was found. Transcriptome and immunohistochemical analyses showed that TMEM127-related pheochromocytoma clusterized with NF1-related and RET-related tumors in a large series of pheochromocytomas and paragangliomas, exhibited a reduced TMEM127 mRNA expression and displayed a low vascularization. The phosphorylation of S6K observed in this tumor was suggestive of an activation of the MTOR pathway. Conclusions: Pathological and genomic data demonstrated that a TMEM127 gene mutation not previously described was causative of a new case of familial bilateral pheochromocytoma. This report highlights the importance of supplementary analyses on tumor tissue to provide an accurate pheochromocytoma/paraganglioma genetic testing result to affected patients.

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Section: Discussionmentioning

confidence: 74%

A novel TMEM127 mutation in a patient with familial bilateral pheochromocytoma

Burnichon¹,

Lepoutre-Lussey²,

Laffaire³

et al. 2011

European Journal of Endocrinology

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“…MiRNA expression profiles have been frequently reported to be correlated with the etiology, classification, progression, and prognosis of multiple human cancers including esophageal cancer (8, 13-17). However, whether genetic variants of miRNA-related genes have an influence on esophageal cancer risk has largely remained unknown.…”

Section: Introductionmentioning

confidence: 99%

Genetic Variations in MicroRNA-Related Genes Are Novel Susceptibility Loci for Esophageal Cancer Risk

Wang

et al. 2008

Cancer Prevention Research

200

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MicroRNAs (miRNA) can act as oncogenes or tumor suppressors and modulate the expression of approximately one third of all human genes. To test the hypothesis that adverse alleles in miRNA-related genes may increase the risk for esophageal cancer, we assessed the associations between esophageal cancer risk and 41 potentially functional single nucleotide polymorphisms (SNP) in 26 miRNA-related genes in a case-control study of 346 Caucasian esophageal cancer patients (85.5% with esophageal adenocarcinoma) and 346 frequency-matched (age, gender, and ethnicity) controls. Seven SNPs were significantly associated with esophageal cancer risk. The most notable finding was that the SNP rs6505162, which is located in the pre-mir423 region, was associated with a per-allele odds ratio of 0.64 [95% confidence interval (95% CI), 0.51-0.80; P for trend < 0.0001]. This association remained significant after we corrected for multiple comparisons. A common haplotype of the GEMIN4 gene was associated with a significantly reduced risk of esophageal cancer (odds ratio, 0.65; 95% CI, 0.42-0.99). We did a combined unfavorable genotype analysis to further evaluate the cumulative effects of the promising (risk associated) SNPs. In comparison with the low-risk group (fewer than three unfavorable genotypes), the medium-risk group (three unfavorable genotypes) had a 2.00-fold (95% CI, 1.31-3.08) increased risk and the high-risk group (more than three unfavorable genotypes) had a 3.14-fold (95% CI, 2.03-4.85) increased risk (P for trend < 0.0001). Results for the risk of esophageal adenocarcinoma were similar to the overall risk results. The present study provides the first evidence that miRNAs may affect esophageal cancer risk in general and that specific genetic variants in miRNA-related genes may affect esophageal cancer risk individually and jointly.Esophageal cancer ranks sixth in cancer-related deaths worldwide with an increasing incidence rate (1, 2). It is estimated that there will be 16,470 new cases and 14,280 deaths in the United States in 2008 (3). The majority of the esophageal cancer patients are diagnosed at advanced stage with poor prognosis and the overall 5-year survival rate is 16% in the United States (3), highlighting the importance of targeted prevention and early detection in the control of this disease. Major risk factors for esophageal squamous cell cancer are tobacco smoking and alcohol consumption (3, 4), whereas reflux disease is the most common risk factor for esophageal adenocarcinoma. The distinct risks exhibited by individuals exposed to similar known risk factors implied that genetic predisposition might play an important role in esophageal cancer etiology (2, 5).MicroRNAs (miRNA) are a class of noncoding RNA molecules with ∼22 nucleotides in length. A large number of miR-NA genes (∼1,000) were predicted to exist in the human genome, accounting for 1% to 5% of all predicted human genes (6). To date, there are 678 human miRNAs deposited in the miRBase miRNA registry (7). miRNAs play important roles in ...

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“…The observed reductions in levels of Ga olf , Gb 1 , and Gb 2 in these different models provide further evidence of cell-type-specific post-translational mechanisms where Gg subunits stabilize partner subunits of the heterotrimeric G protein. This is interesting in the context of esophageal cancer, where levels of Gg 7 are reduced (Ohta et al, 2008), suggesting that the effects again go beyond a simple signaling phenotype. Furthermore, it was reported that, in wild-type mice, there is a 4-fold molar excess of Gg 2 yet equimolar amounts of Gg 3 compared with Gg 7 in the striatum, and surprisingly, a 40% increase in Gg 3 and slight decrease in Gg 2 was noted upon loss of Gg 7 , a possible reflection of an adaptive mechanism in which Ga i/o and Ga olf signaling are involved in a common neurologic pathway (Schwindinger et al, 2010).…”

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confidence: 98%