Yayun Gu

Telomere length, genetic variants and gastric cancer risk in a Chinese population

Telomeres maintain chromosomal stability and integrity and are crucial in carcinogenesis. Telomere length is implicated in multiple cancer risk, but the results are conflicting. Genome-wide association studies have identified several genetic loci associated with telomere length in Caucasians. However, the roles of telomere length and related variants on gastric cancer development are largely unknown. We conducted a case-control study including 1136 gastric cancer cases and 1012 controls to evaluate the associations between telomere length, eight telomere length-related variants identified in Caucasians and gastric cancer risk in Chinese population. We observed an obvious U-shaped association between telomere length and gastric cancer risk (P < 0.001), with odds ratios (95% confidence intervals) being 3.81 (2.82-5.13), 1.65 (1.21-2.26), 1.28 (0.93-1.77) and 1.78 (1.30-2.44) for individuals in the first (the shortest), second, third and fifth (the longest) quintile as compared with those in the fourth quintile as reference group. The weighted genetic score (WGS) of eight variants was significantly associated with telomere length (P < 0.001), and in particular, the G allele of rs2736100 in TERT at 5p15.33 exhibited a significant association with long telomeres (P = 0.047). However, we did not observe significant associations between these genetic variants and gastric cancer risk for both single-variant and WGS analyses. These findings suggest that either short or extreme long telomeres may be risk factor for gastric cancer. Genetic variants identified in Caucasians may also contribute to the variation of telomere length in Chinese but seems not to gastric cancer susceptibility.

Systematic identification of genes with a cancer-testis expression pattern in 19 cancer types

Cancer-testis (CT) genes represent the similarity between the processes of spermatogenesis and tumorigenesis. It is possible that their selective expression pattern can help identify driver genes in cancer. In this study, we integrate transcriptomics data from multiple databases and systematically identify 876 new CT genes in 19 cancer types. We explore their relationship with testis-specific regulatory elements. We propose that extremely highly expressed CT genes (EECTGs) are potential drivers activated through epigenetic mechanisms. We find mutually exclusive associations between EECTGs and somatic mutations in mutated genes, such as PIK3CA in breast cancer. We also provide evidence that promoter demethylation and close non-coding RNAs (namely, CT-ncRNAs) may be two mechanisms to reactivate EECTG gene expression. We show that the meiosis-related EECTG (MEIOB) and its nearby CT-ncRNA have a role in tumorigenesis in lung adenocarcinoma. Our findings provide methods for identifying epigenetic-driver genes of cancer, which could serve as targets of future cancer therapies.

A functional variant in miR-155 regulation region contributes to lung cancer risk and survival

Emerging evidence suggested that upregulation of miR-155 could serve as a promising marker for the diagnosis and prognosis of non-small cell lung cancer (NSCLC). In the present study, we genotyped rs767649 (A > T) located in miR-155 regulation region in 1341 cases and 1982 controls, and analyzed the associations of rs767649 with NSCLC risk and survival. Consequently, rs767649 exhibited the significant associations with the risk (adjusted OR = 1.12, 95% CI = 1.01–1.24, P = 0.031) and prognosis of NSCLC (adjusted HR = 1.17, 95% CI = 1.03–1.32, P = 0.014). Meanwhile, rs767649 specifically interacted with radio-chemotherapy (Pint = 0.013), and patients with both the rs767649-TT genotype and radio-chemotherapy had the highest hazard ratio (adjusted HR = 1.65, 95% CI = 1.26–2.16, P < 0.001). Furthermore, using functional assays and The Cancer Genome Atlas (TCGA) Lung Adenocarcinoma (LUAD) dataset, we found that rs767649 variant allele could increase the transcriptional activity of miR-155, which in turn facilitated tumor growth and metastasis by inhibiting HBP1, TJP1, SMAD5 and PRKAR1A expression. Our findings suggested that rs767649 A > T might contribute to the increased risk and poor prognosis of NSCLC, highlighting the importance of rs767649 in the prevention and therapy of NSCLC.

Role of ATG10 expression quantitative trait loci in non‐small cell lung cancer survival

The aim of this article was to evaluate whether genetic variants in autophagy‐related genes affect the overall survival (OS) of non‐small cell lung cancer (NSCLC) patients. We analyzed 14 single nucleotide polymorphisms (SNPs) in core autophagy‐related genes for OS in 1,001 NSCLC patients. Three promising SNPs in ATG10 were subsequently annotated by the expression quantitative trait loci (eQTL) and methylation quantitative trait loci (meQTL) analyses based on Genotype‐Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets. We observed that the variants of rs10514231, rs1864182 and rs1864183 were associated with poor lung cancer survival (HR = 1.33, 95% CI = 1.07–1.65; HR = 1.43, 95% CI = 1.13–1.81; HR = 1.38, 95% CI = 1.14–1.68, respectively) and positively correlated with ATG10 expression (all p < 0.05) from GTEx and TCGA datasets. The elevated expression of ATG10 may predict shorter survival time in lung cancer patients in TCGA dataset (HR = 2.10, 95% CI = 1.33–3.29). Moreover, the variants of rs10514231 and rs1864182 were associated with the increased methylation levels of cg17942617 (meQTL), which in turn contributed to the elevated ATG10 expression and decreased survival time. Further functional assays revealed that ATG10 facilitated lung cancer cell proliferation and migration. Our findings suggest that eQTL/meQTL variations of ATG10 could influence lung cancer survival through regulating ATG10 expression.

Genetic Variation in the 3'-Untranslated Region of NBN Gene Is Associated with Gastric Cancer Risk in a Chinese Population.

NBN plays a crucial role in carcinogenesis as a core component for both homologous recombination (HR) and non-homologous end-joining (NHEJ) DNA double-strand breaks (DSBs) repair pathways. Genetic variants in the NBN gene have been associated with multiple cancers risk, suggesting pleiotropic effect on cancer. We hypothesized that genetic variants in the NBN gene may modify the risk of gastric cancer. To test this hypothesis, we evaluated the association between four potentially functional single nucleotide polymorphisms in NBN and gastric cancer risk in a case–control study of 1,140 gastric cancer cases and 1,547 controls in a Chinese population. We found that the A allele of rs10464867 (G>A) was significantly associated with a decreased risk of gastric cancer (odds ratio [OR] = 0.81, 95% confidence interval [95% CI] = 0.71–0.94; P = 4.71×10−3). Furthermore, the association between A allele of rs10464867 and decreased risk of gastric cancer was more significantly in elder individuals (per-allele OR = 0.72[0.59–0.88], P = 1.07×10−3), and male individuals (per-allele OR = 0.73[0.62–0.87], P = 3.68×10−4). We further conducted a haplotype analysis and identified that the NBN Ars10464867Grs14448Grs1063053 haplotype conferred stronger protective effect on gastric cancer (OR = 0.76[0.65–0.89], P = 6.39×10−4). In summary, these findings indicate that genetic variants at NBN gene may contribute to gastric cancer susceptibility and may further advance our understanding of NBN gene in cancer development.

U-shaped association between telomere length and esophageal squamous cell carcinoma risk: a case-control study in Chinese population

Telomeres play a critical role in biological ageing by maintaining chromosomal integrity and preventing chromosome ends fusion. Epidemiological studies have suggested that inter-individual differences of telomere length could affect predisposition to multiple cancers, but evidence regarding esophageal squamous cell carcinoma (ESCC) was still uncertain. Several telomere length-related single nucleotide polymorphisms (TLSNPs) in Caucasians have been reported in genome-wide association studies. However, the effects of telomere length and TL-SNPs on ESCC development are unclear. Therefore, we conducted a case-control study (1045 ESCC cases and 1433 controls) to evaluate the associations between telomere length, TL-SNPs, and ESCC risk in Chinese population. As a result, ESCC cases showed overall shorter relative telomere length (RTL) (median: 1.34) than controls (median: 1.50, P < 0.001). More interestingly, an evident nonlinear U-shaped association was observed between RTL and ESCC risk (P < 0.001), with odds ratios (95% confidence interval) equal to 2.40 (1.84–3.14), 1.36 (1.03–1.79), 1.01 (0.76–1.35), and 1.37 (1.03–1.82) for individuals in the 1st (the shortest), 2nd, 3rd, and 5th (the longest) quintile, respectively, compared with those in the 4th quintile as reference group. No significant associations were observed between the eight reported TL-SNPs and ESCC susceptibility. These findings suggest that either short or extremely long telomeres may be risk factors for ESCC in the Chinese population.

Telomere length, genetic variants and risk of squamous cell carcinoma of the head and neck in Southeast Chinese

Telomere dysfunction participates in malignant transformation and tumorigenesis. Previous studies have explored the associations between telomere length (TL) and cancer susceptibility; however, the findings are inconclusive. The associations between genetic variants and TL have been verified by quite a few genome-wide association studies (GWAS). Yet, to date, there was no published study on the relationship between TL, related genetic variants and susceptibility to squamous cell carcinoma of the head and neck (SCCHN) in Chinese. Hence, we detected relative telomere length (RTL) by using quantitative PCR and genotyped seven selected single nucleotide polymorphisms by TaqMan allelic discrimination assay in 510 SCCHN cases and 913 controls in southeast Chinese. The results showed that RTL was significantly associated with SCCHN risk [(adjusted odds ratio (OR) = 1.19, 95% confidence interval (CI) = 1.08–1.32, P = 0.001]. Furthermore, among seven selected SNPs, only G allele of rs2736100 related to RTL in Caucasians was significantly associated with both the decreased RTL (P = 0.002) and the increased susceptibility to SCCHN in Chinese (additive model: adjusted OR = 1.17, 95%CI = 1.00–1.38, P = 0.049). These findings provide evidence that shortened TL is a risk factor for SCCHN, and genetic variants can contribute to both TL and the susceptibility to SCCHN in southeast Chinese population.

Whole-genome sequencing reveals genomic signatures associated with the inflammatory microenvironments in Chinese NSCLC patients

Chinese lung cancer patients have distinct epidemiologic and genomic features, highlighting the presence of specific etiologic mechanisms other than smoking. Here, we present a comprehensive genomic landscape of 149 non-small cell lung cancer (NSCLC) cases and identify 15 potential driver genes. We reveal that Chinese patients are specially characterized by not only highly clustered EGFR mutations but a mutational signature (MS3, 33.7%), that is associated with inflammatory tumor-infiltrating B lymphocytes (P = 0.001). The EGFR mutation rate is significantly increased with the proportion of the MS3 signature (P = 9.37 × 10−5). TCGA data confirm that the infiltrating B lymphocyte abundance is significantly higher in the EGFR-mutated patients (P = 0.007). Additionally, MS3-high patients carry a higher contribution of distant chromosomal rearrangements >1 Mb (P = 1.35 × 10−7), some of which result in fusions involving genes with important functions (i.e., ALK and RET). Thus, inflammatory infiltration may contribute to the accumulation of EGFR mutations, especially in never-smokers.The distinct genomic and epidemiological features of Chinese lung cancer patients suggest the presence of alternative causal mechanisms. Here, the authors present the genomic landscape of 149 Chinese NSCLC patients and reveal distinct mutational signatures associated with inflammatory microenvironments.

A functional SNP rs1892901 in FOSL1 is associated with gastric cancer in Chinese population

FOSL1 (FOS like antigen 1) is one kind of proto-oncogene, and may play a vital role in carcinogenesis of multiple cancers. However, studies about the relationship between SNPs in FOSL1 and gastric cancer are still lacking. Thus, we investigated the association of seven SNPs in FOSL1 with gastric cancer using case-control design in a two-stage strategy (Screening stage: 1,140 gastric cancer cases and 1,547 controls; Replication stage: 1,006 cases and 2,273 controls). We found that rs1892901 was significantly associated with increased risk of gastric cancer in additive model (adjusted OR = 1.25, 95%CI: 1.06–1.47, P = 0.008) in first stage. Following replication results revealed that the relationship between rs1892901 and gastric cancer risk was consistent with our primary results. In silico analysis showed that rs1892901 might alter multiple regulatory motifs, disturb protein binding, and affect the expression of FOSL1 and other important gastric cancer-related genes such as EGR1, CHD, EP300, FOS, JUN and FOSL2. Our findings indicated that functional SNP rs1892901 in FOSL1 might affect the expression of FOSL1, and ultimately increase the risk of gastric cancer. Further functional studies and large-scale population studies are warranted to confirm our findings.

A cancer-testis non-coding RNA LIN28B-AS1 activates driver gene LIN28B by interacting with IGF2BP1 in lung adenocarcinoma

Our previous work found cancer-testis (CT) genes as a new source of epi-driver candidates of cancer. LIN28B was a CT gene, but the “driver” ability and the activation mechanism in lung adenocarcinoma (LUAD) remain unclear. We observed that LIN28B expression was restricted in testis. It was re-activated in LUAD patients without known genomic alterations in oncogenes and was related to poorer survival. In vitro and In vivo experiments confirmed that the activation of LIN28B could promote the proliferation and metastasis of LUAD cells and can influence cell cycle, DNA damage repair, and genome instability. In addition to the known let-7-LIN28B regulation loop, our results further revealed a let-7-independent Cis-regulator of LIN28B: LIN28B-AS1. LIN28B-AS1 is a CT long non-coding RNA (CT-lncRNA). It altered the messenger RNA stability of LIN28B by directly interacting with another CT protein IGF2BP1 but not with LIN28B and constituted a novel regulation network. In sum, we identify that LIN28B is an “epi-driver” of LUAD and clarify a new lncRNA-activated mechanism of LIN28B, which provide new candidate targets for precise anticancer therapy in the future.