A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma / 癌症

<p><b>BACKGROUND</b>Epstein-Barr virus (EBV) commonly infects the general population and has been associated with nasopharyngeal carcinoma (NPC), which has a high incidence in certain regions. This study aimed to address how EBV variations contribute to the risk of NPC.</p><p><b>METHODS</b>Using logistic regression analysis and based on the sequence variations at EBV-encoded RPMS1, a multi-stage association study was conducted to identify EBV variations associated with NPC risk. A protein degradation assay was performed to characterize the functional relevance of the RPMS1 variations.</p><p><b>RESULTS</b>Based on EBV-encoded RPMS1 variations, a single nucleotide polymorphism (SNP) in the EBV genome (locus 155391: G>A, named G155391A) was associated with NPC in 157 cases and 319 healthy controls from an NPC endemic region in South China [P < 0.001, odds ratio (OR) = 4.47, 95% confidence interval (CI) 2.71-7.37]. The results were further validated in three independent cohorts from the NPC endemic region (P < 0.001, OR = 5.20, 95% CI 3.18-8.50 in 168 cases vs. 241 controls, and P < 0.001, OR = 5.27, 95% CI 4.06-6.85 in 726 cases vs. 880 controls) and a non-endemic region (P < 0.001, OR = 7.52, 95% CI 3.69-15.32 in 58 cases vs. 612 controls). The combined analysis in 1109 cases and 2052 controls revealed that the SNP G155391A was strongly associated with NPC (P(combined) < 0.001, OR = 5.27, 95% CI 4.31-6.44). Moreover, the frequency of the SNP G155391A was associated with NPC incidence but was not associated with the incidences of other EBV-related malignancies. Furthermore, the protein degradation assay showed that this SNP decreased the degradation of the oncogenic RPMS1 protein.</p><p><b>CONCLUSIONS</b>Our study identified an EBV variation specifically and significantly associated with a high risk of NPC. These findings provide insights into the pathogenesis of NPC and strategies for prevention.</p>

The propensity for tumorigenesis in human induced pluripotent stem cells is related with genomic instability / 癌症

The discovery of induced pluripotent stem cells(iPSCs) is a promising advancement in the field of regenerative medicine. Previous studies have indicated that the teratoma-forming propensity of iPSCs is variable; however, the relationship between tumorigenic potential and genomic instability in human iPSCs (HiPSCs) remains to be fully elucidated. Here, we evaluated the malignant potential of HiPSCs by using both colony formation assays and tumorigenicity tests. We demonstrated that HiPSCs formed tumorigenic colonies when grown in cancer cell culture medium and produced malignancies in immunodeficient mice. Furthermore, we analyzed genomic instability in HiPSCs using whole-genome copy number variation analysis and determined that the extent of genomic instability was related with both the cells' propensity to form colonies and their potential for tumorigenesis. These findings indicate a risk for potential malignancy of HiPSCs derived from genomic instability and suggest that quality control tests, including comprehensive tumorigenicity assays and genomic integrity validation, should be rigorously executed before the clinical application of HiPSCs. In addition, HiPSCs should be generated through the use of combined factors or other approaches that decrease the likelihood of genomic instability.

Association of nasopharyngeal carcinoma risk with cytochrome P450 CYP1A1 gene polymorphisms / 中华预防医学杂志

<p><b>OBJECTIVE</b>To investigate the association between CYP1A1 gene polymorphisms and susceptibility of nasopharyngeal carcinoma in Cantonese nuclear families through family-based association study.</p><p><b>METHODS</b>A total of 457 Cantonese nuclear families,consisting of 2134 members, were recruited as subjects. Each family included two parents and at least one offspring with nasopharyngeal carcinoma. Two single nucleotide polymorphisms (SNP) in CYP1A1 named m1 (rs4646903) and m2 (rs1048943), were genotyped by PCR-RFLP assay and verified by directly sequencing. The genotype data were analyzed with family-based association test (FBAT) software to check the linkage and association between the two genetic markers and susceptibility of nasopharyngeal carcinoma.</p><p><b>RESULTS</b>FBAT analysis showed that the minor allele frequencies (MAF) of the two SNP were 0.442 (C) and 0.339 (G) respectively. For m1 polymorphism in CYP1A1 gene was not significantly associated with nasopharyngeal carcinoma in our study population whether stratified with VCA-IgA or not (without stratification: chi2 = 2.399, P = 0.301; with stratification: low-titer group (VCA-IgA <1:80), MAF = 0.457 (C), chi2 = 1.221, P = 0.543; high-titer group (VCA-IgA > or = 1:80), MAF = 0.427 (C), chi2 =2.832, P = 0.243) . For m2 polymorphism, when VCA-IgA <1:80, the G allele showed decreased transmission under additive and dominant model (MAF = 0.347 (G); Zadditive = -2.120, Padditive = 0.034; Zdominant = - 2.303, Pdominant = 0.021) and a boundary P value was got with global statistic (chi2 = 5.394, P = 0.067) . Haplotype TG (0.057), constructed by m1 and m2, might decrease nasopharyngeal carcinoma risk (Z= -2.002, P=0.045). A boundary P value was also got with global statistic (chi2 =7.067, P=0.070).</p><p><b>CONCLUSION</b>There was no statistical significance between m1 polymorphism and susceptibility of nasopharyngeal carcinoma in Cantonese nuclear families. And this study showed that m2 polymorphism might associated with the decrease of nasopharyngeal carcinoma in Cantonese nuclear families.</p>

Comparative study on risk factors and family history of familial and sporadic nasopharyngeal carcinoma patients / 中华预防医学杂志

<p><b>OBJECTIVE</b>To explore the difference between familial and sporadic nasopharyngeal carcinoma patients on risk factors and family history and provide evidence on genetic counseling and screening strategy for relatives of nasopharyngeal carcinoma patients in Guangdong province.</p><p><b>METHODS</b>The Cantonese nasopharyngeal carcinoma patients diagnosed in Cancer Center, Sun Yat-sen University from October, 2005 to October, 2007 were recruited as subjects. 1877 patients were collected, including 181 familial nasopharyngeal carcinoma patients and 1696 sporadic nasopharyngeal carcinoma patients. The demographic characteristics, clinical characteristics, risk factors and family history between two groups were compared. Moreover, the distribution of nasopharyngeal carcinoma patients in first-degree relatives and the time interval between proband and the affected first-degree relatives in familial nasopharyngeal carcinoma patients was analyzed.</p><p><b>RESULTS</b>All 9.64% of 1877 nasopharyngeal carcinoma patients had affected relatives in first-degree relatives, among them, 58.49% (124/212) were siblings and 41.51% (88/212) were parents. The mean time interval between siblings and proband were (7.40 +/- 5.41) years while the mean time interval between parents and proband were (15.55 +/- 10.61) years when nasopharyngeal carcinoma occurred, and the difference was statistically significant (t = -5.78, P < 0.01). More than 80% patients of the two group were at advanced stage when they were diagnosed. There were no difference (P values were all > 0.05) both in adulthood and childhood in salted fish (OR = 1.01; 95% CI: 0.59 - 1.75 vs OR = 1.31; 95% CI: 0.92 - 1.86), preserved vegetables (OR = 0.93; 95% CI: 0.58 - 1.49 vs OR = 1.12; 95% CI: 0.80 - 1.57), fermented pastes (OR = 0.37; 95% CI: 0.14 - 1.01 vs OR = 1.61; 95% CI: 0.99 - 2.48), fresh fruits (OR = 0.87; 95% CI: 0.60 - 1.26 vs OR = 0.65; 95% CI: 0.20 - 2.12) and cured meat (OR = 1.26; 95% CI: 0.87 - 1.83 vs OR = 1.28; 95% CI: 0.71 - 2.30) diet. No significant difference (P > 0.05) was obtained on smoking (OR = 0.99; 95% CI: 0.68 - 1.45) and incidence of other cancers in first-degree relatives (OR = 0.85; 95% CI: 0.56 - 1.28) in the two groups.</p><p><b>CONCLUSION</b>Familial nasopharyngeal carcinoma was 9.64% in the observed subjects. In the familial nasopharyngeal carcinoma, the time interval at diagnosis was shorter between proband and siblings as compared with parents. Most of the patients were at advanced stage. So, we recommend the first-degree relatives of nasopharyngeal carcinoma patients, especially siblings, should be screened regularly according to the specific conditions.</p>

Family-based association study of XRCC1 gene polymorphisms in nasopharyngeal carcinoma / 中华预防医学杂志

<p><b>OBJECTIVE</b>To test the association between XRCC1 gene polymorphisms and susceptibility of nasopharyngeal carcinoma in Cantonese nuclear families through a family-based association study.</p><p><b>METHODS</b>A total of 2134 study subjects from 457 Cantonese nuclear families were recruited in the study. Each family had two parents and at least one offspring with nasopharyngeal carcinoma. Genotyping for three single nucleotide polymorphisms in XRCC1 gene, including rs1799782 (C > T), rs25489 (G > A) and rs25487 (G > A), were performed with PCR-RFLP assay. The genotype data were analyzed with family-based association test (FBAT) software to check linkage and association between the three genetic markers and susceptibility of nasopharyngeal carcinoma.</p><p><b>RESULTS</b>FBAT analysis showed XRCC1 gene genotypes and haplotypes were not significantly associated with nasopharyngeal carcinoma in our study population (rs1799782: chi(2) = 1.006, P = 0.605; rs25489: chi(2) = 0.470, P = 0.790; rs25487: chi(2) = 2.563, P = 0.278; haplotype: chi(2) = 3.004, P = 0.557, global statistic). For rs25487, the G allele (major allele) showed increased transmission under dominant model (Z = 1.985, P = 0.047). Whereas the C allele (minor allele) exhibited reduced transmission under recessive model (Z = -1.985, P = 0.047). However, no increased/reduced transmission was observed under additive model and with global statistic.</p><p><b>CONCLUSION</b>There is no evidence of an association between polymorphisms in XRCC1 gene and susceptibility of nasopharyngeal carcinoma in Cantonese nuclear families is observed in this study.</p>

Mutation and amplification of RIT1 gene in hepatocellular carcinoma / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To explore the mutation and amplification of RIT1 gene and their correlation with carcinogenesis of hepatocellular carcinoma (HCC).</p><p><b>METHODS</b>The polymerase chain reactioindirect sequencing method was used for detecting the mutations in the sequence of all 6 exons in the RIT1 gene of 50 HCC tissues and paratumor tissues. And the amplification of RIT1 gene was examined by fluorescence quantitative polymerase chain reaction method.</p><p><b>RESULTS</b>A nucleotide 241 G --> C substitution in exon 5 of RIT1 gene was detected in one patient's HCC tissue, but not in paratumor tissue; this 241 G --> C substitution leads to Glu81Gln amino acid alteration in the conservative domain binding GTP. A nucleotide G --> C substitution in 5'-UTR (-21 bp from initial codon) was detected in all of the 50 HCC tissues and paratumor tissues, and 2- to 297-fold amplification of RIT1 gene was detected in 11 of 43 qualified cases, the amplification frequency being 25.6%.</p><p><b>CONCLUSION</b>Gene amplification is one of the main activating ways of RIT1 gene in HCC, and its amplification might be correlated with HCC carcinogenesis, while point mutation might be not.</p>