Yinyan Li

The Polymorphism and Haplotypes of PIN1 Gene are Associated with the Risk of Lung Cancer in Southern and Eastern Chinese Populations

Peptidyl‐prolyl cis/trans isomerase (PPIase), PIN1, has been found to be a critical catalyst that involves in multiple oncogenic signaling pathways. Recently, several putative functional polymorphisms of the PIN1 gene have been identified to be associated with cancer risk. In this study, we tested the hypothesis that two common polymorphisms, c.‐842G>C (rs2233678) and c.‐667C>T (rs2233679), in the PIN1 promoter are associated with risk of lung cancer. In two independent case‐control studies of 1,559 lung cancer cases and 1,679 controls conducted in Southern and Eastern Chinese population, we found that compared with the most common c.‐842GG genotype, the carriers of c.‐842C variant genotypes (GC + CC) had a decreased risk of lung cancer (odds ratio [OR] = 0.63, 95% confidence interval [CI] = 0.51–0.78, p = 1.13 × 10−5). Although no association was observed between the c.‐667C>T polymorphism and cancer risk, we found that the haplotype “C‐C” had a greater protective effect (OR = 0.39, 95% CI = 0.23–0.67, p = 5.03 × 10−4). The stratification analysis showed that the protective role of c.‐842C variants was more pronounced in current smokers (p = 4.45 × 10−5), especially in male smokers (p = 6.71 × 10−6) and in those who smoked more than 20 pack‐years (p = 2.30 × 10−5) and the c.‐842C variant genotypes interacted with smoking status (Pinteraction = 0.019) or pack‐years smoked (Pinteraction = 0.008) on reducing cancer risk. Further functional assay revealed that the c.‐842C variant allele had a lower transcription activity in luciferase assay and a lower DNA‐binding ability with nuclear proteins, and low transcription activity in western blot assay. In conclusions, our data suggest that functional c.‐842C variants and haplotype “C‐C” in the PIN1 promoter contribute to decreased risk of lung cancer by diminishing the promoter activity, which may be susceptibility biomarkers for lung cancer. Hum Mutat 32:1299–1308, 2011. ©2011 Wiley Periodicals, Inc.

A Functional Copy-Number Variation in MAPKAPK2 Predicts Risk and Prognosis of Lung Cancer

Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2) may promote cancer development and progression by inducing tumorigenesis and drug resistance. To assess whether the copy-number variation g.CNV-30450 located in the MAPKAPK2 promoter has any effect on lung cancer risk or prognosis, we investigated the association between g.CNV-30450 and cancer risk in three independent case-control studies of 2,332 individuals with lung cancer and 2,457 controls and the effects of g.CNV-30450 on cancer prognosis in 1,137 individuals with lung cancer with survival data in southern and eastern Chinese populations. We found that those subjects who had four copies of g.CNV-30450 had an increased cancer risk (odds ratio = 1.94, 95% confidence interval [CI] = 1.61-2.35) and a worse prognosis for individuals with lung cancer (with a median survival time of only 9 months) (hazard ratio = 1.47, 95% CI = 1.22-1.78) compared with those with two or three copies (with a median survival time of 14 months). Meanwhile, four copies of g.CNV-30450 significantly increased MAPKAPK2 expression, both in vitro and in vivo, compared with two or three copies. Our study establishes a robust association between the functional g.CNV-30450 in MAPKAPK2 and risk as well as prognosis of lung cancer, and it presents this functional copy-number variation as a potential biomarker for susceptibility to and prognosis for lung cancer.

A functional variant (-1304T > G) in the MKK4 promoter contributes to a decreased risk of lung cancer by increasing the promoter activity.

Mitogen-activated protein kinase kinase 4 (MKK4) is a critical mediator of stress-activated protein kinase signals that regulate apoptosis, inflammations and tumorigenesis. Several polymorphisms have been identified in the MKK4 gene. We hypothesized that genetic variants in the MKK4 promoter may alter its expression and thus cancer risk. In a case-control study of 1056 lung cancer cases and 1056 sex and age frequency-matched cancer-free controls, we genotyped two common polymorphisms in the MKK4 promoter region (-1304T>G and -1044A>T) with the Taqman assay, and we found that compared with the most common -1304TT genotype, carriers of -1304G variant genotypes had a decreased risk of lung cancer [odds ratio (OR) = 0.74; 95% confidence interval (CI) = 0.61-0.90 for TG, and OR = 0.62; 95% CI = 0.41-0.94 for GG] in an allele dose-response manner (adjusted P(trend) = 0.0005). Further stratification analysis showed that the protective role of the -1304G variant allele was more evident in low or normal body mass index (BMI) but restrained in the overweighters and that the -1304G variant genotypes interacted with BMI in reducing cancer risk (adjusted P(interaction) = 0.003). Moreover, the luciferase assay showed that the G allele in the promoter significantly increased the transcription activity of the MKK4 gene in vitro and that the MKK4 protein expression levels of the G variant carriers was significantly higher in tumor tissues than those of the -1304TT genotype. However, no significant association was observed between the -1044A>T polymorphism and risk of lung cancer. Our data suggest that the functional -1304G variant in the MKK4 promoter contributes to a decreased risk of lung cancer by increasing the promoter activity and that the G variant may be a marker for susceptibility to lung cancer.

A Common Genetic Variant (97906C>A) of DAB2IP/AIP1 Is Associated with an Increased Risk and Early Onset of Lung Cancer in Chinese Males

DOC-2/DAB2 interactive protein (DAB2IP) is a novel identified tumor suppressor gene that inhibits cell growth and facilitates cell apoptosis. One genetic variant in DAB2IP gene was reported to be associated with an increased risk of aggressive prostate cancer recently. Since DAB2IP involves in the development of lung cancer and low expression of DAB2IP are observed in lung cancer, we hypothesized that the variations in DAB2IP gene can increase the genetic susceptibility to lung cancer. In a case-control study of 1056 lung cancer cases and 1056 sex and age frequency-matched cancer-free controls, we investigated the association between two common polymorphisms in DAB2IP gene (−1420T>G, rs7042542; 97906C>A, rs1571801) and the risk of lung cancer. We found that compared with the 97906CC genotypes, carriers of variant genotypes (97906AC+AA) had a significant increased risk of lung cancer (adjusted odds ratio [OR] = 1.33, 95%CI = 1.04–1.70, P = 0.023) and the number of variant (risk) allele worked in a dose-response manner (P trend = 0.0158). Further stratification analysis showed that the risk association was more pronounced in subjects aged less than 60 years old, males, non-smokers, non-drinkers, overweight groups and in those with family cancer history in first or second-degree relatives, and the 97906A interacted with overweight on lung cancer risk. We further found the number of risk alleles (97906A allele) were negatively correlated with early diagnosis age of lung cancer in male patients (P = 0.003). However, no significant association was observed on the −1420T>G polymorphism. Our data suggested that the 97906A variant genotypes are associated with the increased risk and early onset of lung cancer, particularly in males.

The polymorphisms and haplotypes of WWOX gene are associated with the risk of lung cancer in southern and eastern Chinese populations.

The WW domain‐containing oxidoreductase (WWOX) gene is an identified tumor suppressor gene, of which several single nucleotide polymorphisms have been reported to contribute to cancer susceptibility. We hypothesized that genetic variations in WWOX are associated with lung cancer risk. In two independent case–control studies conducted in southern and eastern Chinese, we genotyped five tagSNPs of WWOX gene (rs10220974C > T, rs3764340C > G, rs12918952G > A, rs383362G > T, and rs12828G > A) in 1,559 lung cancer cases and 1,679 controls. Logistic regression analysis showed that two tagSNPs (rs3764340C > G; rs383362G > T) were significantly associated with lung cancer risk in dominant model (rs3764340C > G, GC/GG vs. CC: adjust OR = 1.35, 95% CI = 1.11–1.65; rs383362G > T, TG + TT vs. GG: adjust OR = 1.33, 95% CI = 1.14–1.55). The haplotype analysis further shown that the haplotype “G‐T” was associated with the highest increased risk of lung cancer (OR = 2.20; 95% CI = 1.43–3.37). After combined these two loci, the number of the risk genotypes was associated with increased cancer risk in a dose–response manner (Ptrend = 3.16 × 10−6). In addition, a gene‐based association analysis by using VEGAS software suggested the WWOX as a susceptible gene for lung cancer (P = 0.009). However, for rs10220974C > T, rs12918952G > A, and rs12828G > A, no significant association was observed for lung cancer risk. Taken together, our data suggested that genetic variants in WWOX may be genetic biomarkers for susceptibility to lung cancer. Copyright

A functional polymorphism in the promoter of ERK5 gene interacts with tobacco smoking to increase the risk of lung cancer in Chinese populations

Mitogen/extracellular signal-regulated kinase-5 (MEK5)/extracellular signal-regulated protein kinase-5 (ERK5) pathway plays a pro-oncogenic role in tumourigenesis by anticell apoptosis, promoting cell proliferation and differentiation in response to extracellular stimuli. As overexpressed MEK5/ERK5 is involved in the development of lung cancer, we hypothesised that the single nucleotide polymorphisms (SNPs) in MEK5 and ERK5 genes may influence gene expression and thus be associated with lung cancer risk. Five putative functional polymorphisms (rs3743353T>C, rs7172582C>T and rs2278076A>G of MEK5 and rs3866958G>T and rs2233083C>T of ERK5) were genotyped in two independent case-control studies with a total of 1559 lung cancer patients and 1679 controls in southern and eastern Chinese population. We found the rs3866958G>T of ERK5 was significantly associated with lung cancer risk, while other SNPs were not. Compared with the rs3866958TG/TT genotypes, the GG genotype conferred an increased risk of lung cancer (odds ratio = 1.30, 95% confidence interval = 1.12-1.51, P = 5.0×10(-4)), and this effect was more pronounced in smokers, accompanying with a significant interaction with smoking (P interaction = 0.013). The GG genotype also had significant higher mRNA levels of ERK5 in lung cancer tissues than TG/TT genotypes (P = 1.0×10(-4)); the luciferase reporter with the G allele showed significant higher transcription activities than the T allele, especially after the treatment with tobacco extract in vitro. Our data indicated that the functional polymorphism rs3866958G>T in ERK5 was associated with an increased lung cancer risk in smokers by virtue of the positive interaction with smoking on promoting the ERK5 expression, which might be a valuable indicator for predicting lung cancer risk in smokers.

The effect of functional MAPKAPK2 copy number variation CNV-30450 on elevating nasopharyngeal carcinoma risk is modulated by EBV infection

UNLABELLED Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2) is recognized as oncogenic and simulative role on tumorigenesis by virtue of abnormal expression in cancer including nasopharyngeal carcinoma (NPC). We hypothesized that the copy number variation (CNV)-30450, which duplicates the MAPKAPK2 promoter, may affect MAPKAPK2 expression and be associated with NPC risk. In two independent case-control panels of southern and eastern Chinese with a total of 1590 NPC patients and 1979 cancer-free controls, we investigated the association between CNV-30450 and NPC risk by genotyping the CNV-30450 with the TaqMan assay, and tested its biological effect. Consistent findings were observed in the two populations, that the increased copy number of CNV-30450 was associated with increased risk of NPC (3/4-copy versus 2-copy: odds ratio = 1.28, 95% confidence interval = 1.10-1.49), in which lies a biological mechanism that the adverse genotypes enhanced the promoter activity of MAPKAPK2 and elevated MAPKAPK2 expression. Moreover, the CNV-30450 adverse genotypes significantly interacted with Epstein-Barr virus (EBV) infection on increasing NPC risk (P = 0.035), and the genotype-phenotype correlation was only significant in EBV-positive cases (P = 0.037) but not in EBV-negative ones (P = 0.366). These data suggest that the functional CNV-30450 in the MAPKAPK2 promoter elevates the NPC risk with a modulation by EBV infection, which may be an indicator of susceptibility to NPC. SUMMARY This case-control study suggests that the functional CNV-30450 in the MAPKAPK2 promoter elevates the NPC risk with a modulation by EBV infection, which may be an indicator of susceptibility to NPC.

Whole exome sequencing as a diagnostic adjunct to clinical testing in fetuses with structural abnormalities

To evaluate the diagnostic yield of prenatal whole exome sequencing (WES) for monogenic disorders in fetuses with structural malformations and normal results on cytogenetic testing, and to describe information on pathogenic variants that is provided by WES.

Rare variant of MAP2K7 is associated with increased risk of COPD in southern and eastern Chinese

A wide range of common loci have been extensively screened and evaluated for their associations with various complex diseases; however, the relevance of rare variants causing missense substitutions in the protein‐coding genes in human diseases is still poorly understood.

A functional CNVR_3425.1 damping lincRNA FENDRR increases lifetime risk of lung cancer and COPD in Chinese

Genomic imbalance referring to somatic variation in chromosome copies represents the most frequent event in tumorigenesis. Germline copy number variations (gCNVs) overlapping regions of genomic imbalance harbor similar structural characteristics and thus influence tumor susceptibility. We aimed to test effects of such gCNVs on the risk of lung cancer and chronic obstructive pulmonary disease (COPD). Genomic imbalance of lung cancer was determined by the array comparative genomic hybridization (aCGH), and common gCNVs at these imbalance regions were genotyped in lung cancer-based and COPD-based retrospective studies. Functional assays were conducted to assess function of promising CNVs. A total of 115 genomic imbalances were discovered occurring at a frequency of more than 25%. The CNVR_3425.1, overlapping the chr16q24.1 with genomic imbalance, was significantly associated with increased risks of lung cancer (OR = 1.76; 95% CI = 1.46-2.11) and COPD (OR = 1.98; 95% CI = 1.57-2.51). The increase copy of CNVR_3425.1 forms a new additional truncated FOXF1 adjacent non-coding developmental regulatory RNA (FENDRR) sequences comparing the gene promoter and perturbs the transcriptional factors (TFs) binding to the original FENDRR promoter and further downregulates FENDRR, a long intergenic non-coding RNA (lincRNA) that functions to inhibit lung cancer by affecting expressions of an abundant number of genes, including the tumor suppressor FOXF1. FENDRR can upregulate FOXF1 by competitively binding to miR-424. The TFs early growth response 1 (EGR1) and transcription factor AP-2 alpha (TFAP2A) were further found to involve the CNVR_3425.1-mediated FENDRR dysregulation. These findings suggested the CNVR_3425.1 to be a possibly predictive biomarker for the risk of lung cancer and COPD, and targeted molecular therapy pertaining to FENDRR upregulation may be a valuable pathway to fight two diseases.