A Large-Scale Genome-Wide Gene-Gene Interaction Study of Lung Cancer Susceptibility in Europeans With a Trans-Ethnic Validation in Asians

Zhang, Ruyang; Shen, Sipeng; Wei, Yongyue; Zhu, Ying; Li, Yang; Chen, Jiajin; Guan, Jinxing; Pan, Zoucheng; Wang, Yuzhuo; Zhu, Meng; Xie, Jian; Xiao, Xiangjun; Zhu, Dakai; Li, Yafang; Albanes, Demetrios; Landi, Maria Teresa; Caporaso, Neil E.; Lam, Stephen; Tardón, Adonina; Chen, Chu; Bojesen, Stig E.; Risch, Angela; Bickeböller, Heike; Wichmann, H‐Erich; Rennert, Gad; Arnold, Susanne M.; Brennan, Paul; McKay, James; Field, John K.; Shete, Sanjay; Marchand, Loı̈c Le; Liu, Geoffrey; Andrew, Angeline S.; Kiemeney, Lambertus A.; Zienolddiny-Narui, Shan; Behndig, Annelie F.; Johansson, Mikael; Cox, Angela; Lazarus, Philip; Schabath, Matthew B.; Aldrich, Melinda C.; Dai, Juncheng; Ma, Hongxia; Zhao, Yang; Hu, Zhibin; Hung, Rayjean J.; Amos, Christopher I.; Shen, Hongbing; Chen, Feng; Christiani, David C.

doi:10.1016/j.jtho.2022.04.011

Cited by 21 publications

(11 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Statistical interaction between two factors can be defined as a phenomenon where the effect of one factor is modified by another one ( 19 ). Combined with our results, we observed that the effect of cg11676291 MORN1 was modified by age, where the CpG probe changed from a protective factor for OSCC survival in young patients to a risk factor in elderly patients ( Figure 2A ).…”

Section: Resultsmentioning

confidence: 99%

Epigenome-wide gene–age interaction study reveals reversed effects of MORN1 DNA methylation on survival between young and elderly oral squamous cell carcinoma patients

Chen

et al. 2022

Front. Oncol.

Self Cite

View full text Add to dashboard Cite

DNA methylation serves as a reversible and prognostic biomarker for oral squamous cell carcinoma (OSCC) patients. It is unclear whether the effect of DNA methylation on OSCC overall survival varies with age. As a result, we performed a two-phase gene–age interaction study of OSCC prognosis on an epigenome-wide scale using the Cox proportional hazards model. We identified one CpG probe, cg11676291MORN1, whose effect was significantly modified by age (HRdiscovery = 1.018, p = 4.07 × 10−07, FDR-q = 3.67 × 10−02; HRvalidation = 1.058, p = 8.09 × 10−03; HRcombined = 1.019, p = 7.36 × 10−10). Moreover, there was an antagonistic interaction between hypomethylation of cg11676291MORN1 and age (HRinteraction = 0.284; 95% CI, 0.135–0.597; p = 9.04 × 10−04). The prognosis of OSCC patients was well discriminated by the prognostic score incorporating cg11676291MORN1–age interaction (HRhigh vs. low = 3.66, 95% CI: 2.40–5.60, p = 1.93 × 10−09). By adding 24 significant gene–age interactions using a looser criterion, we significantly improved the area under the receiver operating characteristic curve (AUC) of the model at 3- and 5-year prognostic prediction (AUC3-year = 0.80, AUC5-year = 0.79, C-index = 0.75). Our study identified a significant interaction between cg11676291MORN1 and age on OSCC survival, providing a potential therapeutic target for OSCC patients.

show abstract

Section: Resultsmentioning

confidence: 99%

Epigenome-wide gene–age interaction study reveals reversed effects of MORN1 DNA methylation on survival between young and elderly oral squamous cell carcinoma patients

Chen

et al. 2022

Front. Oncol.

Self Cite

View full text Add to dashboard Cite

show abstract

“…In this edition of the Journal of Thoracic Oncology, Zhang et al 12 report results from one of the first studies evaluating associations between GÂG interactions and risk of NSCLC. The authors used a multistage approach, starting by evaluating a large sample of (445,221) individuals of European descent.…”

mentioning

confidence: 99%

“…The authors used a multistage approach, starting by evaluating a large sample of (445,221) individuals of European descent. 12 In the first stage of the analysis, Zhang et al 12 identified two GÂG interactions that were significantly associated with lung cancer in a two-phase study among Europeans. They then identified six more significant GÂG interactions with meta-analysis among Europeans.…”

mentioning

confidence: 99%

“…On the basis of the GÂG interactions identified in these two cohorts, Zhang et al 12 updated lung cancer screening models based on polygenetic risk scores for individuals who smoked and those who did not. They developed the interaction-empowered polygenetic risk score using the UK Biobank data set.…”

mentioning

confidence: 99%

“…This work by Zhang et al 12 is a step toward more sophisticated use of genetic information for early lung cancer detection. But how practical is this approach?…”

mentioning

confidence: 99%

See 2 more Smart Citations

Genie Out of the Bottle: Is There a Role for Gene-Gene Interactions in Early Detection of Lung Cancer?

Smeltzer

Ray

Faris³

et al. 2022

Journal of Thoracic Oncology

View full text Add to dashboard Cite

A trans‐omics assessment of gene–gene interaction in early‐stage NSCLC

Chen

Song

et al. 2022

Molecular Oncology

Self Cite

View full text Add to dashboard Cite

Epigenome‐wide gene–gene (G × G) interactions associated with non‐small‐cell lung cancer (NSCLC) survival may provide insights into molecular mechanisms and therapeutic targets. Hence, we proposed a three‐step analytic strategy to identify significant and robust G × G interactions that are relevant to NSCLC survival. In the first step, among 49 billion pairs of DNA methylation probes, we identified 175 775 G × G interactions with PBonferroni ≤ 0.05 in the discovery phase of epigenomic analysis; among them, 15 534 were confirmed with P ≤ 0.05 in the validation phase. In the second step, we further performed a functional validation for these G × G interactions at the gene expression level by way of a two‐phase (discovery and validation) transcriptomic analysis, and confirmed 25 significant G × G interactions enriched in the 6p21.33 and 6p22.1 regions. In the third step, we identified two G × G interactions using the trans‐omics analysis, which had significant (P ≤ 0.05) epigenetic cis‐regulation of transcription and robust G × G interactions at both the epigenetic and transcriptional levels. These interactions were cg14391855 × cg23937960 (βinteraction = 0.018, P = 1.87 × 10−12), which mapped to RELA × HLA‐G (βinteraction = 0.218, P = 8.82 × 10−11) and cg08872738 × cg27077312 (βinteraction = −0.010, P = 1.16 × 10−11), which mapped to TUBA1B × TOMM40 (βinteraction =−0.250, P = 3.83 × 10−10). A trans‐omics mediation analysis revealed that 20.3% of epigenetic effects on NSCLC survival were significantly (P = 0.034) mediated through transcriptional expression. These statistically significant trans‐omics G × G interactions can also discriminate patients with high risk of mortality. In summary, we identified two G × G interactions at both the epigenetic and transcriptional levels, and our findings may provide potential clues for precision treatment of NSCLC.

show abstract

A Large-Scale Genome-Wide Gene-Gene Interaction Study of Lung Cancer Susceptibility in Europeans With a Trans-Ethnic Validation in Asians

Cited by 21 publications

References 76 publications

Epigenome-wide gene–age interaction study reveals reversed effects of MORN1 DNA methylation on survival between young and elderly oral squamous cell carcinoma patients

Epigenome-wide gene–age interaction study reveals reversed effects of MORN1 DNA methylation on survival between young and elderly oral squamous cell carcinoma patients

Genie Out of the Bottle: Is There a Role for Gene-Gene Interactions in Early Detection of Lung Cancer?

A trans‐omics assessment of gene–gene interaction in early‐stage NSCLC

Contact Info

Product

Resources

About