Germline polymorphisms of glutathione-S-transferase GSTM1, GSTT1 and p53 codon 72 in cervical carcinogenesis

The clinical significance of glutathione-S-transferase GSTM1, GSTT1 and p53 codon 72 polymorphisms in cervical carcinogenesis was investigated. Germline polymorphisms of GSTM1, GSTT1 and p53 codon 72 together with human papillomavirus (HPV) types were examined in a total of 457 blood and cervical smear samples from normal healthy women and the patients with premalignant and malignant cervical lesions. The 167 patients with low-grade squamous intraepithelial lesion (LSIL), 49 with high-grade SIL (HSIL) and 83 with squamous cell carcinoma (SCC) had significantly higher frequency of high-risk HPV than 158 controls. The 49 patients with HSIL and 83 with SCC had statistically higher frequency of null GSTT1 genotype than 158 controls. There was an increased odds ratio for null GSTT1 genotype in HSIL and SCC cases compared with controls among 191 patients with high-risk HPV. The 67 cases with HPV types 16 and/or 18 had higher frequency of the GSTT1 null genotype than 186 with other types of HPV. There was no statistical difference in the polymorphic frequency of GSTM1 and p53 codon 72 genotypes between SILs and controls with or without high-risk HPV. These results suggest that GSTT1 null genotype may increase the risk of cervical cancer particularly in the cases with high-risk HPV types in a Japanese population.     

Germline polymorphism of cancer susceptibility genes in gynecologic cancer

The multifactorial process of carcinogenesis involves mutations in oncogenes, or tumor suppressor genes, as well as the influence of environmental etiological factors. Common DNA polymorphisms in low penetrance genes have emerged as genetic factors that seem to modulate an individual’s susceptibility to malignancy. Genetic studies, which lead to a true association, are expected to increase understanding of the pathogenesis of each malignancy and to be a powerful tool for prevention and prognosis in the future. Here, we review the findings of genetic association studies of gene polymorphisms in gynecologic cancer with special reference to glutathione-S-transferase, FAS/CD95 and p53 genes including our recent research results.     

Polymorphisms of p53 codon 72 and MDM2 promoter 309 and the risk of endometrial cancer

Genetic polymorphisms of p53 and its negative regulator murine double minute 2 homolog (MDM2) have been shown to be closely associated with tumorigenesis in a variety of human cancers. In the present study, single nucleotide polymorphism (SNP) at p53 codon 72 and MDM2 promoter 309 was examined for germline DNA samples from 102 endometrial cancer cases and 95 controls using polymerase chain reaction-based fragment analysis. There were no significant differences in the genotype and allele prevalence between control subjects and endometrial cancer patients for p53 codon 72. The GG genotype frequency of MDM2-SNP309 was statistically higher in endometrial cancer patients than that in normal healthy women when compared with the TG genotype ( P = 0.0088). However, no statistically significant differences were found between the TT and TG or GG genotype frequencies and allele prevalence. Interestingly, the combination of the homozygous Arg/Arg genotype of p53 codon 72 and homozygous GG genotype of MDM2 SNP309 polymorphisms was significantly associated with the risk of endometrial cancer (odds ratio = 3.28, 95% confidence interval = 1.13 to 9.53, P = 0.0212). The homozygous variants of wild p53 codon 72 and mutant MDM2 promoter 309 may cooperatively increase the risk of endometrial cancer in a Japanese population.     

ALDH2 polymorphism for the risk of cervical carcinogenesis

To investigate the clinical significance of ALDH2 genetic polymorphisms in cervical carcinogenesis. ALDH2 polymorphisms together with human papillomavirus (HPV) types were examined in a total of 195 cervical smear in exfoliated cervical cell samples using Real-Time polymerase chain reaction (PCR) System. The frequency for the AG+AA genotype was seven in the normal group (70.0 %), 16 in the LSIL group (57.1 %), and 27 in the HSIL group (90.0 %). A significant difference was found between the LSIL and HSIL groups (P = 0.0064). Patients with HSIL lesions frequently had high-risk HPV infections and concurrently belonged to the AG+AA group. ALDH2 genotype in cervical cell samples may be associated with more severe precancerous lesions of the cervix in a Japanese population.     

The Anterior Insula Tracks Behavioral Entropy during an Interpersonal Competitive Game

In competitive situations, individuals need to adjust their behavioral strategy dynamically in response to their opponent’s behavior. In the present study, we investigated the neural basis of how individuals adjust their strategy during a simple, competitive game of matching pennies. We used entropy as a behavioral index of randomness in decision-making, because maximizing randomness is thought to be an optimal strategy in the game, according to game theory. While undergoing functional magnetic resonance imaging (fMRI), subjects played matching pennies with either a human or computer opponent in each block, although in reality they played the game with the same computer algorithm under both conditions. The winning rate of each block was also manipulated. Both the opponent (human or computer), and the winning rate, independently affected subjects’ block-wise entropy during the game. The fMRI results revealed that activity in the bilateral anterior insula was positively correlated with subjects’ (not opponent’s) behavioral entropy during the game, which indicates that during an interpersonal competitive game, the anterior insula tracked how uncertain subjects’ behavior was, rather than how uncertain subjects felt their opponent''s behavior was. Our results suggest that intuitive or automatic processes based on somatic markers may be a key to optimally adjusting behavioral strategies in competitive situations.     

Processing of social and monetary rewards in the human striatum

Despite an increasing focus on the neural basis of human decision making in neuroscience, relatively little attention has been paid to decision making in social settings. Moreover, although human social decision making has been explored in a social psychology context, few neural explanations for the observed findings have been considered. To bridge this gap and improve models of human social decision making, we investigated whether acquiring a good reputation, which is an important incentive in human social behaviors, activates the same reward circuitry as monetary rewards. In total, 19 subjects participated in functional magnetic resonance imaging (fMRI) experiments involving monetary and social rewards. The acquisition of one's good reputation robustly activated reward-related brain areas, notably the striatum, and these overlapped with the areas activated by monetary rewards. Our findings support the idea of a "common neural currency" for rewards and represent an important first step toward a neural explanation for complex human social behaviors.     

Murine double-minute 2 homolog single nucleotide polymorphism 309 and the risk of gynecologic cancer

A functional T to G germline polymorphism in the promoter region of murine double-minute 2 homolog single nucleotide polymorphism 309 (MDM2-SNP309) has been reported to profoundly accelerate tumor formation, suggesting that it may also represent a powerful cancer predisposing allele. In this study, MDM2-SNP309 was examined in a total of 400 blood samples from 108 normal, 88 cervical, 119 endometrial and 85 ovarian cancer cases using two independent polymerase chain reaction assays for each allele. When the MDM2-SNP309 genotype was classified into two subgroups of TT+TG and GG, the GG genotype was associated with an increased risk for the development of endometrial cancer (odds ratio [OR]= 1.91, 95% confidence interval [CI] = 1.05 to 3.47) compared with the TT+TG genotype ( P  = 0.0353). The G allele also increased the risk of endometrial cancer (OR = 1.20, 95% CI = 0.83 to 1.74) compared with the T allele, but no statistical difference was found ( P  = 0.3333). The homozygous GG genotype was also associated with postmenopausal status and type I endometrial cancer ( P  = 0.0306 and 0.0326, respectively). There was no significant difference in the genotype or allele prevalence between control subjects and cervical or ovarian cancer patients. These results suggest that homozygous GG genotype of MDM2-SNP309 may be a risk factor for postmenopausal and type I endometrial cancer in a Japanese population.     

Mutational analysis of the BRAF gene in human tumor cells

Genes of the RAF family, which mediate cellular responses to growth signals, encode kinases that are regulated by RAS and participate in the RAS, RAF, mitogen/extracellular signal-regulated kinase, extracellular signal-regulated kinase and mitogen-activated protein kinase pathway. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation, it may provide possible diagnostic and therapeutic targets in human malignant tumors. We analyzed exon 15 of the BRAF gene for mutations in 58 lung, 12 breast, six kidney, 14 cervical, four endometrial and 10 ovarian carcinoma cell lines by PCR-SSCP and direct sequencing. The T1796A transversion was found in one (2.9%) of 34 small cell lung carcinoma and one (8.3%) of 12 breast carcinoma cell lines, resulting in a valine-to-glutamate substitution at residue 599 (V599E). One (4.2%) of 24 non-small cell lung carcinoma cell line showed the C1786G transversion, leading to a leucine-to-valine substitution at residue 596 (L596V). No BRAF point mutations were found in any of the other cell lines examined. Our present results suggest that BRAF may not be a frequent target of mutations involved in the pathogenesis of human lung, breast, kidney, cervical, endometrial and ovarian carcinomas.