GWAS follow-up study of esophageal squamous cell carcinoma identifies potential genetic loci associated with family history of upper gastrointestinal cancer

Song, Xin; Li, Wenqing; Hu, Nan; Zhao, Xue; Wang, Zhaoming; Hyland, Paula L.; Jiang, Tao; Kong, Guo Qiang; Su, Hua; Wang, Chaoyu; Wang, Lemin; Sun, Li; Fan, Zong Min; Meng, Hua; Zhang, Tang Juan; Ji, Lele; Hu, Shou Jia; Han, Wei; Wu, Min; Zheng, Peng; Liu, Shuang; Li, Xue Min; Zhou, Fu You; Burdett, Laurie; Ding, Ti; Qiao, You‐Lin; Fan, Jin‐Hu; Han, Xiao-You; Giffen, Carol; Tucker, Margaret A.; Dawsey, Sanford M.; Freedman, Neal D.; Chanock, Stephen J.; Abnet, Christian C.; Taylor, Philip R.; Wang, Lidong; Goldstein, Alisa M.

doi:10.1038/s41598-017-04822-2

Cited by 9 publications

(12 citation statements)

References 25 publications

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“…It is interesting that the inhibition of CYP21A2 by 1 μM abiraterone was observed in a recent study (Malikova et al, 2017). Song et al found 3 SNPs in CYP19A1, which also encodes a cytochrome P450 enzyme, that were associated with a FH of UGI cancer in ESCC cases ( P < 10 −5 ) in a meta-analysis performed by the National Cancer Institute (NCI) and in the Henan GWAS data (Song et al, 2017). As described above, crosstalk between CYP21A2 p.Gln319 * and smoking may promote ESCC progression.…”

Section: Discussionmentioning

confidence: 99%

Identification of the Germline Mutation Profile in Esophageal Squamous Cell Carcinoma by Whole Exome Sequencing

Deng¹,

Weng²,

Ye³

et al. 2019

Front. Genet.

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Background: Esophageal squamous cell carcinoma (ESCC) is associated with poor prognosis and occurs with high frequency in China. The germline mutation profile in ESCC remains unclear, and therefore, the discovery of oncogenic alterations in ESCC is urgently needed. This study investigates the germline mutation profile and reveals associations among genotype-environment interactions in ESCC. Methods: Whole exome sequencing and follow-up analysis were performed in 77 matched tumor-normal ESCC specimens to examine the germline profiles. Additionally, associations among genotype-environment interactions were investigated. Results: We identified 84 pathogenic/likely pathogenic mutations and 51 rare variants of uncertain significance (VUS). Twenty VUS with InterVar evidence of a score of moderate pathogenicity (PM) 2/PM2+ supporting pathogenicity (PP) 1 were found to have pathogenic significance. CYP21A2 was the most frequently mutated gene, and the p.Gln319 * variant was identified in 6.5% (5/77) of patients. The TP53 p.V197E mutation, located within the DNA binding domain, was found in 1.3% (1/77) of patients. In total, the 11.7% (9/77) of individuals with homologous recombination (HR) VUS were more likely to have well-differentiated tumors than those without ( P = 0.003). The degree of lymph node metastasis was correlated with homologous recombination deficiency (HRD) and VUS group ( P < 0.05). Moreover, the 10.4% (8/77) of individuals with mismatch repair (MMR) VUS had a higher tumor mutational burden (TMB), although the correlation was not significant. Conclusions: Our study identified the germline mutation profiles in ESCC, providing novel insights into the molecular pathogenesis of this disease. Our results may also serve as a useful resource for the exploration of the underlying mechanism of ESCC and may provide information for the prevention, diagnosis and risk management of ESCC.

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Section: Discussionmentioning

confidence: 99%

Identification of the Germline Mutation Profile in Esophageal Squamous Cell Carcinoma by Whole Exome Sequencing

Deng¹,

Weng²,

Ye³

et al. 2019

Front. Genet.

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“…After collecting 331 LSCC patients and 349 healthy controls samples and genotyped with PLCE1 rs2274223, we found that the PLCE1 rs2274223-G was significantly associated with a higher LSCC risk, which is similar with its association in ESCC [13][14][15][16][17]. Further stratified analysis demonstrated that age, sex, and smoking status may affect the association.…”

Section: Discussionmentioning

confidence: 54%

“…Different expression profiles of PLCE1, like overexpression or down-regulation, could be found in different types of cancer, and functioned in diverse manners [9][10][11][12]. Large scale genome-wide association (GWAS) studies from different groups had demonstrated that the rs2274223, located in exon 26 of PLCE1, was strongly associated with the risk of ESCC [13][14][15][16][17]. The PLCE1 polymorphisms and its distribution have been…”

Section: Introductionmentioning

confidence: 99%

The PLCE1 rs2274223 variant is associated with the risk of laryngeal squamous cell carcinoma

Zhang

Wang

et al. 2020

Int. J. Med. Sci.

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Background: Laryngeal squamous cell carcinoma (LSCC) ranks second in the mortality rate in respiratory malignant tumors and has potential similarity in genomic alterations with the esophageal squamous cell carcinoma (ESCC). The PLCE1 rs2274223 variant is the most significant susceptibility loci identified in ESCC. Whether it is also associated with LSCC susceptibility is still unclear. Materials and Methods: A total of 331 LSCC patients and 349 healthy controls were recruited in this study. The PLCE1 rs2274223 variant was genotyped by using the Taqman SNP Genotyping Assay. Association between PLCE1 rs2274223 variant and LSCC risk was estimated by logistic regression analysis, which was performed using SAS software. Results: The PLCE1 rs2274223 variant was identified to be significantly associated with the susceptibility of LSCC in the additive model (OR = 1.40, 95% CI: 1.06-1.86, P=0.019). Compared with the wild-type (AA) carriers, the risk genotype (GG) carriers had a 2.8-fold risk of LSCC (95% CI: 1.13-7.06, P=0.026). Stratified analysis showed that the association between rs2274223 and LSCC risk was with higher significance in individuals above 60 (P = 0.027) males (P = 0.030) or non-smokers (P = 0.026). Conclusion: The PLCE1 rs2274223 variant was significantly associated with risk of LSCC, which may be a potential biomarker and therapeutic target for the LSCC.

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“…Previous studies have indicated that family history, smoking, alcohol consumption, aging, and gender are risk factors for ESCC. [10,31,32] Our results demonstrated that family history ( P = .004) and tumor size ( P = .029) were preferentially associated with HLA-DQA1 expression. The percentage of patients expressing HLA-DQA1 is higher for negative family history than that of positive family history.…”

Section: Discussionmentioning

confidence: 65%

High expression of HLA-DQA1 predicts poor outcome in patients with esophageal squamous cell carcinoma in Northern China

Shen

Pan

et al. 2019

Medicine

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Background: Our previous studies demonstrate that the major histocompatibility complex (MHC) is associated with the progression of esophageal squamous cell carcinoma (ESCC). HLA-DQA1, which belongs to the MHC Class II family, may be a potential biomarker in ESCC progression. However, the association between HLA-DQA1 and ESCC in high-incidence area of northern China has not been well characterized. The purpose of this study is to investigate the relationship of HLA-DQA1 expression with the progression and prognosis of ESCC. Methods: We analyzed the expression profiles of HLA-DQA1 in esophageal cancer (EC) samples in the TCGA database and validated HLA-DQA1 expression by immunohistochemistry, western blotting, and quantitative reverse-transcription polymerase chain reaction in matched EC and normal tissues, respectively. The correlation between HLA-DQA1 expression and clinicopathologic characteristics of ESCC was further analyzed. Result: Immunohistochemical analysis indicated that the expression level of HLA-DQA1 in ESCC tissues was significantly higher than the matched normal tissues ( P < .001). HLA-DQA1 mRNA and protein expression were significantly higher in ESCC tissues compared to the matched normal tissues. Patients with family history negative or with tumor sizes >4 cm were associated with higher HLA-DQA1 expression levels. A prognostic significance of HLA-DQA1 was also found by the Log-rank method, in which high expression of HLA-DQA1 was correlated with a shorter overall survival time. The receiver operating characteristic (ROC) curve analysis yielded the area under the ROC curve value of 0.693. Univariate and multivariate analyses also suggest that high expression of HLA-DQA1 is a potential indicator for poor prognosis of ESCC. Conclusions: Our results demonstrate that HLA-DQA1 plays an important role in ESCC progression and may be a biomarker for ESCC diagnosis and prognosis, as well as a potential target for the treatment of patients with ESCC.

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GWAS follow-up study of esophageal squamous cell carcinoma identifies potential genetic loci associated with family history of upper gastrointestinal cancer

Cited by 9 publications

References 25 publications

Identification of the Germline Mutation Profile in Esophageal Squamous Cell Carcinoma by Whole Exome Sequencing

Identification of the Germline Mutation Profile in Esophageal Squamous Cell Carcinoma by Whole Exome Sequencing

The PLCE1 rs2274223 variant is associated with the risk of laryngeal squamous cell carcinoma

High expression of HLA-DQA1 predicts poor outcome in patients with esophageal squamous cell carcinoma in Northern China

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