Potentially functional variants of ERAP1, PSMF1 and NCF2 in the MHC-I-related pathway predict non-small cell lung cancer survival
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 c...
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Published in | Cancer Immunology, Immunotherapy Vol. 70; no. 10; pp. 2819 - 2833 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Berlin/Heidelberg
Springer Berlin Heidelberg
01.10.2021
Springer Nature B.V |
Subjects | |
Online Access | Get full text |
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Summary: | 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 (
P
trend
< 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. |
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Bibliography: | Authors’ contributions Sen Yang and Dongfang Tang contributed equally to this work. Sen Yang, Dongfang Tang, Qiming Wang, Qingyi Wei contributed to the study conception and design. Material preparation, data collection and analysis were performed by Sen Yang, Dongfang Tang, Yu Chen Zhao, Hongliang Liu, Sheng Luo, Thomas E. Stinchcombe., Carolyn Glass, Li Su, Sipeng Shen, David C. Christiani, Qiming Wang, Qingyi Wei. The first draft of the manuscript was written by Sen Yang and Dongfang Tang and critically reviewed and revised by Qiming Wang and Qingyi Wei, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. |
ISSN: | 0340-7004 1432-0851 |
DOI: | 10.1007/s00262-021-02877-9 |