Genome-wide association study identifies common variants in SLC39A6 associated with length of survival in esophageal squamous-cell carcinoma

Wu, Chen; Liu, Dong; Jia, Wei‐Hua; Hu, Zhibin; Zhou, Yifeng; Yu, Dianke; Tong, Tong; Wang, Ming-Rong; Qiao, Yan; Zhou, Yumin; Chang, Jiang; Zhai, Kan; Wang, Menghan; Wei, Lixuan; Tan, Wen; Shen, Hongbing; Zeng, Yi‐Xin; Lin, Dong

doi:10.1038/ng.2638

Cited by 100 publications

(113 citation statements)

References 41 publications

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“…Collaboration within the international PSC study group enabled the establishment of a cohort of unprecedented size, for an orphan disease such as PSC, enabling the investigation of genetic variation underlying the progression of PSC through time. Overall, it is a major challenge to determine genetic variants associated with survival, and only few genetic studies investigating this have been published 26. We present a conceptually new method to determine associations between genetic variants and disease course, using genome-wide multivariable Cox proportional hazards regression analyses.…”

Section: Discussionmentioning

confidence: 99%

Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis

Alberts

Vries

Goode

et al. 2017

Gut

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Objective Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications. Design We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients—obtained using the Illumina immunochip—with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes. Results We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10−9). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells. Conclusion We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.

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Section: Discussionmentioning

confidence: 99%

Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis

Alberts

Vries

Goode

et al. 2017

Gut

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“…[5][6][7][8] Understanding the functions and consequences of these alterations requires careful attention to context, and to date, molecular biomarkers have not been integrated into clinical practice for ESCC. 7 In particular, the factors that predispose patients with squamous cell dysplasia to develop ESCC and the changes that lead to metastases from the primary tumor are not known.…”

Section: Introductionmentioning

confidence: 99%

KLF4 is downregulated but not mutated during human esophageal squamous cell carcinogenesis and has tumor stage-specific functions

Yang

Katz

2016

Cancer Biology & Therapy

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The transcriptional regulator Kr€ uppel-like factor 4 (KLF4) is decreased in human esophageal squamous cell cancer (ESCC), and Klf4 deletion in mice produces squamous cell dysplasia. Nonetheless the mechanisms of KLF4 downregulation in ESCC and the functions of KLF4 during ESCC development and progression are not well understood. Here, we sought to define the regulation of KLF4 and delineate the stage-specific effects of KLF4 in ESCC. We found that KLF4 expression was decreased in human ESCC and in 8 of 9 human ESCC cell lines. However, by genomic sequencing, we observed no KLF4 mutations or copy number changes in any of 52 human ESCC, suggesting other mechanisms for KLF4 silencing. In fact, KLF4 expression in human ESCC cell lines was increased by the DNA methylation inhibitor 5-azacytidine, suggesting an epigenetic mechanism for KLF4 silencing. Surprisingly, while KLF4 decreased in high-grade dysplasia and early stage tumors, KLF4 increased with advanced cancer stage, and KLF4 expression in ESCC was inversely correlated with survival. Interestingly, KLF4 promoted invasion of human ESCC cells, providing a functional link to the stage-specific expression of KLF4. Taken together, these findings suggest that KLF4 loss is necessary for esophageal tumorigenesis but that restored KLF4 expression in ESCC promotes tumor spread. Thus, the use of KLF4 as a diagnostic and therapeutic target in cancer requires careful consideration of context.Abbreviations: KLF4, Kr€ uppel-like factor 4; ESCC, esophageal squamous cell cancer; SNP, single nucleotide polymorphism; HDAC, histone deacetylase

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“…These results provide evidence that pooled analyses should be conducted to establish unique susceptibility loci for specific districts and nationalities. Secondly, until recently, little has been known about genetic loci associated with length of survival in ESCC, based on genome-wide examinations [11]. However, a genome-wide interrogation of genetic variants associated with length of survival in ESCC individuals might provide the most promising therapeutic targets and novel prognosis markers.…”

Section: Esophageal Squamous Cell Carcinomamentioning

confidence: 99%

“…Wu et al [11] carried out the first genome-wide interrogation of genetic variants associated with length of survival in 1,331 ESCC cases, for whom death or survival information was available, followed by replication in two independent data sets consisting of 1,962 cases. They identified rs1050631 in SLC39A6 as being associated with the survival times of affected individuals, with a hazard ratio of 1.30 for death from ESCC in the combined sample (95% CI: 1.19−1.43; p = 3.77 × 10− 8 ).…”

Section: Esophageal Squamous Cell Carcinomamentioning

confidence: 99%

Genetic Variations in Esophageal Cancer

Qian¹,

Fang²

2015

Gastrointest Tumors

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Background: Esophageal cancer is one of the most prevalent cancers worldwide, and occurs at a relatively high frequency in China and other Asian countries. The etiology of esophageal cancer remains unclear, making its early diagnosis and treatment difficult. Summary: In recent decades, efforts using candidate gene approaches have been made to identify genetic susceptibility factors for esophageal cancer in a series of genome-wide association studies. Here, we review the latest progress in research on genetic variations in esophageal cancer cases. Key Message: Genetic variations partially account for esophageal cancer incidence and mortality rates. A comparative genomic analysis of esophageal squamous cell carcinomas and esophageal adenocarcinomas suggests little overlap genetically. Current integrated studies using high-throughput approaches have unmasked a number of novel genetic lesions in both esophageal cancer and its precursor lesions, although distinct results obtained from different regions and cohorts remain to be investigated. Practical Implications: Pooled analyses of genome-wide association studies should be conducted to establish unique susceptibility loci for specific districts and nationalities. Meanwhile, the identification of ‘driver mutations' or mutations associated with prognosis in long-term follow-up studies is critical for the development of therapeutic and prognostic strategies.

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Genome-wide association study identifies common variants in SLC39A6 associated with length of survival in esophageal squamous-cell carcinoma

Cited by 100 publications

References 41 publications

Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis

Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis

KLF4 is downregulated but not mutated during human esophageal squamous cell carcinogenesis and has tumor stage-specific functions

Genetic Variations in Esophageal Cancer

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