Browsing by Author "Yang, Sen"

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    Novel genetic variants in KIF16B and NEDD4L in the endosome-related genes are associated with non-small cell lung cancer survival.
    (International journal of cancer, 2019-10-16) Yang, Sen; Tang, Dongfang; Zhao, Yu C; Liu, Hongliang; Luo, Sheng; Stinchcombe, Thomas E; Glass, Carolyn; Su, Li; Shen, Sipeng; Christiani, David C; Wang, Qiming; Wei, Qingyi
    The endosome is a membrane-bound organ inside most eukaryotic cells, playing an important role in adaptive immunity by delivering endocytosed antigens to both MHC class I and II pathways. Here, by analyzing two published genome-wide association studies (GWASs), we evaluated associations between genetic variants in the endosome-related gene-set and survival of patients with non-small cell lung cancer (NSCLC). The discovery included 44,112 (3,478 genotyped and 40,634 imputed) single-nucleotide polymorphisms (SNPs) in 220 genes in a single locus analysis for their associations with survival of 1,185 NSCLC patients from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. After validation of the 821 survival-associated significant SNPs in additional 984 NSCLC patients from the Harvard Lung Cancer Susceptibility study, 14 SNPs remained significant. The final multivariate stepwise Cox proportional hazards regression model in the PLCO datasets identified three potentially functional and independent SNPs (KIF16B rs1555195 C>T, NEDD4L rs11660748 A>G and rs73440898 A>G) with an adjusted hazards ratio (HR) of 0.86 [95% confidence interval (CI)=0.79-0.94, P=0.0007], 1.31 (1.16-1.47, P=6.0×10-5 ) and 1.27 (1.12-1.44, P=0.0001) for overall survival (OS), respectively. Combined analysis of the adverse genotypes of these three SNPs revealed a trend in the genotype-survival association (Ptrend <0.0001 for OS and Ptrend <0.0001 for disease-specific survival). Furthermore, the survival-associated KIF16B rs1555195T allele was significantly associated with decreased mRNA expression levels of KIF16B in both lung tissues and blood cells. Therefore, genetic variants of the endosome-related genes may be biomarker for NSCLC survival, possibly through modulating the expression of corresponding genes. This article is protected by copyright. All rights reserved.
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    Novel genetic variants of KIR3DL2 and PVR involved in immunoregulatory interactions are associated with non-small cell lung cancer survival.
    (American journal of cancer research, 2020-01) Wu, Yufeng; Yang, Sen; Liu, Hongliang; Luo, Sheng; Stinchcombe, Thomas E; Glass, Carolyn; Su, Li; Shen, Sipeng; Christiani, David C; Wang, Qiming; Wei, Qingyi
    Immunoregulatory interactions play a pivotal role in immune surveillance, recognition, and killing, particularly its internal pathway, likely playing an important role in immune escape. By using two genotyping datasets, one from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer screening trial (n = 1,185) as the discovery, and the other from Harvard Lung Cancer Susceptibility (HLCS) study (n = 984) as the validation, we evaluated associations between 4,713 genetic variants (338 genotyped and 4,375 imputed) in 60 genes involved in immunoregulatory interactions and survival of non-small cell lung cancer (NSCLC). We found that 115 SNPs were significantly associated with NSCLC overall survival in the discovery, of which four remained significant after validation by the HLCS dataset after multiple test correction by Bayesian false discovery probability. Final combined analysis identified two independent SNPs (KIR3DL2 rs4487030 A>G and PVR rs35385129 C>A) that predicted NSCLC survival with a combined hazards ratio of 0.84 (95% confidence interval = 0.76-0.93, P = 0.001) and 0.84 (95% confidence interval = 0.73-0.97, P = 0.021), respectively. Besides, expression quantitative trait loci analyses showed that these two survival-associated SNPs of KRI3DL2 and PVR were significantly associated with their mRNA expression levels in both normal lung tissues and whole blood cells. Additional analyses suggested an oncogenic role for KRI3DL2 and a suppressor role for PVR on the survival. Once further validated, genetic variants of KIR3DL2 and PVR may be potential prognostic markers for NSCLC survival.
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    Novel variants of ELP2 and PIAS1 in the interferon gamma signaling pathway are associated with non-small cell lung cancer survival.
    (Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2020-06-03) Zhao, Yu Chen; Tang, Dongfang; Yang, Sen; Liu, Hongliang; Luo, Sheng; Stinchcombe, Thomas E; Glass, Carolyn; Su, Li; Shen, Sipeng; Christiani, David C; Wei, Qingyi
    BACKGROUND:Interferon gamma (IFNγ) is a pleiotropic cytokine that plays critical immunomodulatory roles in intercellular communication in innate and adaptive immune responses. Despite recognition of IFNγ signaling effects on host defense against viral infection and its utility in immunotherapy and tumor progression, the roles of genetic variants of the IFNγ signaling pathway genes in cancer patient survival remain unknown. METHODS:We used a discovery genotyping dataset from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (n=1,185) and a replication genotyping dataset from the Harvard Lung Cancer Susceptibility Study (n=984) to evaluate associations between 14,553 genetic variants in 150 IFNγ pathway genes and survival of non-small cell lung cancer (NSCLC). RESULTS:The combined analysis identified two independent potentially functional single-nucleotide polymorphisms (SNPs), ELP2 rs7242481G>A and PIAS1 rs1049493T>C, to be significantly associated with NSCLC survival, with a combined hazards ratio (HR) of 0.85 [95% CI= 0.78-0.92, P<0.0001] and 0.87 (0.81-0.93, P<0.0001), respectively. Expression quantitative trait loci analyses showed that the survival-associated ELP2 rs7242481A allele was significantly associated with increased mRNA expression levels of ELP2 in 373 lymphoblastoid cell lines and 369 whole blood samples. The PIAS1 rs1049493C allele was significantly associated with decreased mRNA expression levels of PIAS1 in 383 normal lung tissues and 369 whole blood samples. CONCLUSIONS:Genetic variants of IFNγ signaling genes are potential prognostic markers for NSCLC survival, likely through modulating the expression of key genes involved in host immune response. IMPACT:Once validated, these variants could be useful predictors of NSCLC survival.
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    Potentially functional variants of ERAP1, PSMF1 and NCF2 in the MHC-I-related pathway predict non-small cell lung cancer survival.
    (Cancer immunology, immunotherapy : CII, 2021-03-02) Yang, Sen; Tang, Dongfang; Zhao, Yu Chen; Liu, Hongliang; Luo, Sheng; Stinchcombe, Thomas E; Glass, Carolyn; Su, Li; Shen, Sipeng; Christiani, David C; Wang, Qiming; Wei, Qingyi

    Background

    Cellular immunity against tumor cells is highly dependent on antigen presentation by major histocompatibility complex class I (MHC-I) molecules. However, few published studies have investigated associations between functional variants of MHC-I-related genes and clinical outcomes of lung cancer patients.

    Methods

    We performed a two-phase Cox proportional hazards regression analysis by using two previously published genome-wide association studies to evaluate associations between genetic variants in the MHC-I-related gene set and the survival of non-small cell lung cancer (NSCLC) patients, followed by expression quantitative trait loci analysis.

    Results

    Of the 7811 single-nucleotide polymorphisms (SNPs) in 89 genes of 1185 NSCLC patients in the discovery dataset of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, 24 SNPs remained statistically significant after validation in additional 984 NSCLC patients from the Harvard Lung Cancer Susceptibility Study. In a multivariate stepwise Cox model, three independent functional SNPs (ERAP1 rs469783 T > C, PSMF1 rs13040574 C > A and NCF2 rs36071574 G > A) remained significant with an adjusted hazards ratio (HR) of 0.83 [95% confidence interval (CI) = 0.77-0.89, P = 8.0 × 10-7], 0.86 (0.80-0.93, P = 9.4 × 10-5) and 1.31 (1.11-1.54, P = 0.001) for overall survival (OS), respectively. Further combined genotypes revealed a poor survival in a dose-response manner in association with the number of unfavorable genotypes (Ptrend < 0.0001 and 0.0002 for OS and disease-specific survival, respectively). Also, ERAP1 rs469783C and PSMF1 rs13040574A alleles were associated with higher mRNA expression levels of their genes.

    Conclusion

    These potentially functional SNPs of the MHC-I-related genes may be biomarkers for NSCLC survival, possibly through modulating the expression of corresponding genes.