Polymorphism in protein tyrosine phosphatase receptor delta is associated with the risk of clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is a common urological malignancy. Our previous study has indicated that the protein tyrosine phosphatase receptor type delta (PTPRD) gene may play a role. To determine the effect of PTPRD genetic polymorphisms on ccRCC occurrence and progression, a total of 377 ccRCC cases and 754 matched controls were enrolled in the study. DNA sequencing and genotyping, and immunohistochemistry were conducted to test the associations of genotypes with ccRCC risk and PTPRD expression level in somatic tissues. The C allele of PTPRD rs2279776 was associated with a higher risk of ccRCC (per allele OR = 1.23, P = 0.03). Patients without distant metastasis at the time of surgery were followed for a median of 33.1 months. Overall survival was not different between different rs2279776 genotype groups (P = 0.30). The C allele was associated with a higher percentage of negative immunostaining in adjacent normal renal tissues (P = 0.02). PTPRD rs2279776 SNP may be a novel genetic risk factor of ccRCC.     

Clinical and biological significance of Cdk10 in hepatocellular carcinoma

Cyclin-dependent kinase 10 (Cdk10) is a Cdc2-related kinase and plays an essential role in the progression from the G2 to M phase of the cell cycle. However, relative little is known about its expression pattern, clinical relevance, and biological function in hepatocellular carcinoma (HCC). In the present study, we investigated the mRNA and protein expression levels of Cdk10 in 127 pairs of HCC samples and adjacent nontumorous liver tissues and evaluated its clinical significance. Additionally, we assessed the effects of restoration of Cdk10 on cell proliferation and drug sensitivity in HCC cells. We showed that the Cdk10 mRNA and protein expression was markedly decreased in HCC samples compared to adjacent nontumorous liver tissues. Quantitative real-time polymerase chain reaction and immunohistochemical studies revealed that reduced Cdk10 expression was significantly associated with alpha-fetoprotein levels, tumor size, and tumor stage. Ectopic expression of Cdk10 reduced HCC cell proliferation, blocked the cell cycle at the G0-G1 phase, as well as inhibited cell migration and anchorage-independent growth. Additionally, Cdk10 overexpression enhanced the chemosensitivity of HCC cells to cisplatin and epidoxorubicin, two chemotherapeutic agents commonly used in HCC. These data collectively demonstrate that reduced Cdk10 expression is closely linked to HCC development and progression. Restoration of its expression may have therapeutic benefits in treating this malignancy.     

Somatic recombination in adult tissues: What is there to learn?

Somatic recombination is essential to protect genomes of somatic cells from DNA damage but it also has important clinical implications, as it is a driving force of tumorigenesis leading to inactivation of tumor suppressor genes. Despite this importance, our knowledge about somatic recombination in adult tissues remains very limited. Our recent work, using the Drosophila adult midgut has demonstrated that spontaneous events of mitotic recombination accumulate in aging adult intestinal stem cells and result in frequent loss of heterozygosity (LOH). In this Extra View article, we provide further data supporting long-track chromosome LOH and discuss potential mechanisms involved in the process. In addition, we further discuss relevant questions surrounding somatic recombination and how the mechanisms and factors influencing somatic recombination in adult tissues can be explored using the Drosophila midgut model.     

Identification of different tumor escape mechanisms in several metastases from a melanoma patient undergoing immunotherapy

The cytotoxic activity of T cells selects the outgrowth of tumor cells that escape from immune surveillance by different strategies. The different mechanisms that interfere with immune recognition and limit vaccination efficiency are still poorly understood. We analysed six cell lines established from different metastases of melanoma patient UKRV-Mel-20 for specific characteristics known to have an impact on the tumor-T cell interaction: (1) alterations in the HLA class I phenotype, (2) expression of Fas/CD95, and (3) expression of specific cytokines and chemokines. One of the cell lines, UKRV-Mel-20f, exhibited an HLA class I haplotype loss and just this cell line was also characterised by the expression of Fas/CD95 and of relatively high levels of proinflammatory chemokines suggesting that the cytotoxic activity of tumor-infiltrating T cells might have selected the outgrowth of this tumor cell variant. All other cell lines analysed showed no alterations in HLA class I expression, but, in contrast to UKRV-Mel-20f, expressed much lower levels of Fas/CD95 and of proinflammatory chemokines and some of them produced high levels of immunosuppressive TGF-beta1. These results suggest that in patient UKRV-Mel-20, tumor cells interfere with T cell recognition by different strategies which might partially explain why this patient did not have a clinical response to an autologous tumor cell vaccine.     

Integrative analysis and validation of robust gene signature in lung cancer

We studied robust gene signature (RGS) in lung cancer by using an approach of integrating a highly diverse collection of cancer genome-wide datasets, which were six public microarray datasets, one pair of Suppression Subtractive Hybridization EST library, one pair of Serial Analysis of Gene Expression (SAGE) experiments, and 191 Loss of Heterozygosity (LOH) reports obtained from 388 publications. Among the 109 RGS genes identified from our study, 14 of the 15 reported differentially expressed genes (DEGs) based on literature verification were consistent with our predictions. Out of the remaining 94 genes that were not reported as DEGs in lung cancer by any publication, we randomly picked eight and verified their expression in lung cancer versus normal tissues by semi-quantitative RT-PCR amplification, and all showed consistent expression pattern with our findings. System assessment analysis revealed that our integrative method had an accuracy of 95% and a correlation coefficients value of 0.92.     

A hypothetical anti-neoplastic mechanism associated to reserve cells

Reserve-stem cells, the permanent cells of body tissues, are thought to be the progenitor cells of cancer. This concept originates from the assumption that accumulation of somatic mutations necessary for malignant transformation can only take place in cellular targets with a prolonged life span. The progeny of reserve cells entering the differentiative pathway would be protected from potential critical mutations happening later than the reserve cell stage by normal cell population replacement unless possible targets would escape the replacement process by further mutations extending the cell's life span, impairment of physiological apoptosis. The existence of a mechanism for maintenance of genetic integrity in stem/reserve cells has previously been proposed. This mechanism differs from already identified DNA repair systems and, potentially, could prevent malignant transformation at the reserve cell stage, counteracting the expected high propensity of stem/reserve cells to neoplastic proliferation. Here, we show some histopathological observations suggesting that an anti-cancer mechanism might be associated to reserve/stem cells and that it could be responsible for huge differences in cancer incidence between closely related body sites. Furthermore, primary impairment of this protective mechanism might characterize the oncogenic pathway responsible for tumors of primitive cells. Several features of the histopathological observations presented lead us to propose that the underlying molecular mechanism may involve the telomere complex.     

Polymorphism of estrogen response element in TFF1 gene promoter is associated with an increased susceptibility to gastric cancer

TFF1 is a cysteine-rich protein that forms a characteristic trefoil domain through disulfide bonds, which render it resistant to vigorous conditions and it involves in maintaining the integrity of the gastric mucosa. Decreased expression of TFF1 gene plays a role in the development of gastric cancer. We examined the association between the promoter polymorphisms of the TFF1 gene and the risk of development of gastric cancer, in a case-control study including 199 controls and 141 patients with gastric cancer. Assessment of single nucleotide polymorphisms in the promoter region of the TFF1 gene was performed by sequencing and polymerase chain reaction-based restriction fragment length polymorphism. We found a statistically significant increased risk of gastric cancer associated with − 394 TT genotypes (OR = 8.78, CI = 2.85-27.05, p < 0.001) and CT (OR = 1.64, CI = 1.04-2.60, p = 0.033). This single nucleotide polymorphism occurs naturally in an estrogen response element. According to induction of the TFF1 gene by estrogen, it is possible that the substitution of C to T results in a decreased estrogen receptor binding affinity to the estrogen response element and in turn it decreases the expression of the TFF1 gene that may be involved in development of gastric cancer over a lifetime.