Tongtong Huang

High mitochondrial DNA copy number was associated with an increased gastric cancer risk in a Chinese population.

Mitochondrial DNA (mtDNA) copy number (mtCN) may be a potential biomarker in relation to cancer risk. However, the role of mtCN in gastric cancer remains uncertain. We examined the association between peripheral blood leukocytes mtCN level and gastric cancer risk in a case‐control study including 984 gastric cancer cases and 984 controls. We measured relative mtCN level by real‐time quantitative PCR‐based assay, and used logistic regression models to assess the association between mtCN and risk of gastric cancer. The mtCN level in gastric cancer cases was significantly higher than that in controls (median value: 6.53 vs 4.12, P = 1.79 × 10−5). Compared with those with low mtCN, the risk for gastric cancer was 1.29 (95% confidence interval [CI] = 1.02‐1.63) in the median group and 1.74 (95%CI = 1.39‐2.18) in the high mtCN group (P for trend = 1.51 × 10−6). Because relative telomere length (RTL) has been associated with gastric cancer risk in our previous study, we also evaluated the combined effects of mtCN and RTL on gastric cancer risk. Multivariable regression model revealed that the effects of mtCN and RTL were independent on gastric cancer risk. Compared with those in the lowest risk group by combining mtCN and RTL, the odds ratio for gastric cancer was 4.30 (95%CI = 2.79‐6.63) in the highest risk group. Our results suggest that mtDNA may be implicated in gastric carcinogenesis and mtCN as well as RTL may serve as joint susceptible biomarkers for gastric cancer.

The known genetic loci for telomere length may be involved in the modification of telomeres length after birth

Telomere length varies considerably among individuals. It is highly heritable and decreases with ageing or ageing related diseases. Recently, genome-wide association studies (GWAS) have identified several genetic loci associated with telomere length in adults. However, it is unclear whether these loci represent the genetic basis of telomere length or determine the individual susceptibility to shortening during growth process. Using DNA extracted from peripheral and cord blood of 444 mother-newborn pairs from a Chinese population, we measured relative telomere length (RTL) and genotyped eight known telomere length related variants that were initially identified in populations of European descent. We observed the T allele of rs10936599 and the T allele of rs2736100 were norminally associated with shorter RTL (P = 0.041 and 0.046, respectively) in maternal samples. Furthermore, the Weighted genetic score (WGS) of eight variants was significantly associated with RTL in maternal samples (R2 = 0.012, P = 0.025). However, we didn’t detect any significant associations for any individual variant or the combined WGS with RTL in newborns. These findings didn’t support the hypothesis that telomere length related loci may affect telomere length at birth, and we suggested that these loci may play a role in telomere length modification during life course.

Genetic variants affecting telomere length are associated with the prognosis of esophageal squamous cell carcinoma in a Chinese population.

Telomeres are essential for maintaining chromosomal stability and are crucial in tumor progression. Previous studies have explored the associations between telomere length and cancer prognosis, but the findings are inconclusive. Genome‐wide association studies have identified several genetic variants associated with telomere length in Caucasians. However, the roles of telomere length and related genetic variants on esophageal squamous cell carcinoma (ESCC) prognosis are largely unknown. Therefore, we conducted a case‐cohort study with 431 ESCC patients to assess the associations between relative telomere length (RTL), eight known telomere length related variants and the overall survival of ESCC in Chinese population. We found that as compared with the reference group, patients in the fifth (the longest) quintile had a significantly better prognosis [(adjusted hazard ratio (HR) = 0.58, 95% confidence interval (CI) = 0.34–0.98, P = 0.041]. Furthermore, A allele of rs2736108 was significantly associated with both the increased RTL (P = 0.048) and the better prognosis of ESCC (adjusted HR = 0.55, 95%CI = 0.38–0.79, P = 1.31 × 10−3). Mediation analysis indicated that the effect of rs2736108 on ESCC prognosis was partly explained by RTL (1.99%). Stepwise Cox proportional hazard analysis suggested that rs2736108 played an important protective role in ESCC prognosis (HR = 0.57, 95%CI = 0.40–0.81, P = 1.97 × 10−3). Our findings provide evidence that prolonged telomere length is a protective factor for ESCC patients’ survival and the known telomere length related genetic variant rs2736108 can contribute to the prognosis of ESCC as well in Chinese population.

An esophageal adenocarcinoma susceptibility locus at 9q22 also confers risk to esophageal squamous cell carcinoma by regulating the function of BARX1

Genome wide association studies (GWAS) have identified a series of genetic variants associated with the risk of esophageal adenocarcinoma (EAC)/Barretts esophagus (BE), which was different from those loci for esophageal squamous cell carcinoma (ESCC). It is important to evaluate whether these susceptibility loci for EAC/BE are also implicated in ESCC development. In the current study, we analyzed genetic variants at 3p13, 9q22, 16q24 and 19p13 in a case-control study including 2139 ESCC patients and 2463 cancer-free controls in a Chinese population, and further characterized the biological relevance of genetic variants by functional assays. We found that the G allele of rs11789015 at 9q22, as compared with the A allele, was significantly associated with a decreased risk of ESCC with a per-allele odds ratio of 0.77 (95%CI, 0.65-0.90; P = 1.38 × 10-3), whereas the other three loci were not associated with ESCC risk. We further found that rs11789015-G allele correlated with decreased mRNA and protein levels of BARX1. Dual-luciferase reporter gene assay revealed that the A > G change at rs11789015 significantly decreased the promoter activity of BARX1. Both the mRNA and protein levels of BARX1 were significantly higher in ESCC tumor tissues compared with the corresponding normal tissues. Moreover, the deletion of BARX1 substantially reduced ESCC cells growth, migration and invasion. In conclusion, these results suggest that genetic variants at 9q22 are associated with the risk of both EAC/BE and ESCC, possibly by regulating the function of BARX1.

Functional Polymorphisms in IRAKs Are Related to Hepatocellular Carcinoma Risk in Chinese Population

Background Interleukin 1 receptor associated kinases (IRAKs) play a central role in TLR signaling pathway. Scarce literature has investigated the association of potential functional genetic variants of IRAKs with Hepatitis B Virus- (HBV-) related hepatocellular carcinoma (HCC). Methods A case-control study with 1,538 HBV-positive HCC patients and 1,465 chronic HBV carriers was conducted to evaluate the effects of common missense variants of IRAK family members on HCC. Proliferation assays and real-time polymerase chain reactions were carried out to evaluate the functions. Multivariable adjusted logistic regression was adopted to estimate effect size and identify risk factors. Results Association analysis indicated that rs4251545 A allele of IRAK4 (p.Ala428Thr) was positively associated with HBV-related HCC risk (OR = 1.30, 95% CI: 1.09–1.54, P = 0.003). Functional annotation indicated that rs4251545 reduced its own expression in liver (P = 0.031). Further molecular functional analysis detected that rs4251545 increased the proliferation rate of L02 cells (P < 0.05). Meanwhile, rs4251545 reduced mRNA expressions of IL-6, IL-8, CXCL-1, and CXCL-2 in L02 cells (P < 0.01). Conclusion rs4251545 of IRAK4 (p.Ala428Thr) modified the susceptibility to HBV-related HCC via increased proliferation rate and reduced production of inflammatory cytokines and chemokines. Further well-designed experiments are warranted to validate our findings.

Genetic variants in PPP2CA are associated with gastric cancer risk in a Chinese population

Protein phosphatase 2A (PP2A), a tumor suppressor protein, has been implicated in cell cycle and apoptosis. Additionally, studies have illustrated its crucial roles in transformation of normal human cells to tumorigenic status. PPP2CA, which encodes the alpha isoform of the catalytic subunit of PP2A, has been recently reported to be associated with several types of cancers. Therefore, we hypothesized that genetic variants in PPP2CA might influence susceptibility of gastric cancer. To test this hypothesis, three tagging single nucleotide polymorphisms (SNPs) in PPP2CA were genotyped in a case-control study including 1,113 cases and 1,848 controls in a Chinese population. Three tagging SNPs in PPP2CA were genotyped using Illumina Human Exome BeadChip. We observed that the A allele of rs13187105 was associated with an increased risk of gastric cancer (adjusted odds ratio (OR) = 1.14, 95% confidence interval (CI): 1.02–1.28, P = 0.017). Further analyses showed that rs13187105 [A] was associated with decreased expression of PPP2CA mRNA (P = 5.1 × 10−6), and PPP2CA mRNA was significantly lower in gastric tumor tissues when comparing that in their adjacent normal tissues (P = 0.037). These findings support our hypothesis that genetic variants in PPP2CA may be implicated in gastric cancer susceptibility in Chinese population.

Functional polymorphisms in NR3C1 are associated with gastric cancer risk in Chinese population

Recently promoter of NR3C1 has been found to be high methylated in gastric cancer tissues which might be involved in the initiation of gastric carcinoma development. To test whether the variants in NR3C1 could modify the risk of gastric cancer, we evaluated the association between four SNPs (rs6194, rs12521436, rs33388 and rs4912913) in NR3C1 and gastric cancer risk in a case-control study with 1,113 gastric cancer cases and 1,848 cancer-free controls in a Chinese population. We found a significant association between rs4912913 and gastric cancer risk (OR=1.18, 95%CI=1.05-1.33, P=5.49×10−3). We also observed that the A-allele of rs12521436 and rs33388 were significantly associated with a decreased risk of gastric cancer (OR=0.84, 95%CI=0.76-0.94, P=2.78×10−3; OR=0.85, 95%CI=0.75-0.97; P=0.018). Finally, we made a joint effect analysis of rs12521436, rs33388 and rs4912913 on risk of gastric cancer (PTrend=2.83×10−5). These findings indicate that the variants rs4912913, rs33388 and rs12521436 of NR3C1 may contribute to gastric cancer susceptibility.

Genetic variants at 9p21.3 are associated with risk of esophageal squamous cell carcinoma in a Chinese population

Genome‐wide association studies have linked genetic variants at 9p21.3 to the risk of multiple cancers. However, the roles of genetic variants at 9p21.3 in esophageal squamous cell carcinoma (ESCC) development are largely unknown. We evaluated the genetic variants at 9p21.3 reported in cancer genome‐wide association studies with a case–control study including 2139 ESCC cases and 2273 controls in a Chinese population, and measured the mRNA expression levels of MTAP, CDKN2A, CDKN2B, and CDKN2B‐AS1 in paired ESCC tumor and adjacent normal tissues. We found that the G allele of rs7023329 was significantly associated with a decreased risk of ESCC with a per‐allele odds ratio of 0.84 (95% confidence interval, 0.77–0.91; P = 2.95 × 10−5). The rs7023329‐G allele was related to a high expression of MTAP (P = 0.020). The rs1679013‐C allele was independently associated with an increased risk of ESCC with a per‐allele odds ratio of 1.12 (95% confidence interval, 1.01–1.24; P = 0.039). We also found that the carriers of the risk allele rs1679013‐C had lower expression of CDKN2B than non‐carriers (P = 0.035). CDKN2B was also significantly downregulated in ESCC tumor tissues compared with adjacent normal tissues (P = 3.50×10−5). Therefore, our findings indicate that genetic variants at 9p21.3 may modulate the expression of MTAP and CDKN2B and contribute to ESCC susceptibility. This may further advance our understanding of the 9p21.3 locus in cancer development.