Chinese Medical Journal Study Finds New Genetic Variant Linked to Pancreatic Cancer Prognosis

Quantitative trait loci analysis identifies a novel regulatory variant of the RFWD3 gene associated with the prognosis of pancreatic cancer

BEIJING, Jan. 9, 2023 /PRNewswire/ -- Pancreatic adenocarcinoma (PAAD) is a malignancy with an extremely poor prognosis and high fatality rate. Despite advances in medical technologies over the past decades, early detection and effective treatments are limited. Genetic factors considerably influence the overall survival of patients with PAAD. Naturally, several studies have attempted to discover genes associated with PAAD prognosis or overall survival. However, the findings were not consistent owing to limited sample sizes and the heterogeneity in studies' design.

To address this, a research team from China performed a meta-analysis to systematically discover the candidate genes whose expression is associated with survival in PAAD. Their paper, published in Volume 135, Issue 11 of the Chinese Medical Journal, was made available online on July 13, 2022. Prof. Xiaoping Miao, senior author on the study, comments, "The regulatory genetic variants that affect PAAD prognosis are largely unknown. We performed a meta-analysis of seven published datasets which collectively contained the expression data of 11,666 shared genes and the clinical information of 812 PAAD patients."

The team identified a total of 128 genes associated with PAAD prognosis. To explore information that could have potential diagnostic and therapeutic applications, the team targeted genetic elements called single nucleotide polymorphisms (SNPs) that regulate the expression of these candidate genes. For this, they used a comprehensive technique known as tissue-specific expression quantitative trait loci (eQTL) analysis and discovered 14 regulatory loci in 12 of the 128 genes.

To validate the findings, the team conducted a two-stage association study in 893 patients with PAAD to examine the regulatory variants and identify prognostic loci. After conducting multiple biochemical experiments and phenotype assays, the team found that of the 14 regulatory loci, only rs4887783—the functional variant in the promoter of the RFWD3 gene— was strongly associated with PAAD prognosis in both stages of the population study. RFWD3, involved in DNA damage repair, was also found to be highly expressed in PAAD. Further phenotypic assays revealed that overexpression of RFWD3 promoted tumor cell migration without affecting their proliferation rate.

To sum up, this is the first study to demonstrate that the SNP rs4887783 could predict poor survival by increasing the expression of RFWD3. Prof. Miao explains, "What we found might contribute, to some extent, not only to identification of a prognostic biomarker but also to uncovering the mechanism of PAAD progression and finding the effective therapeutic targets."

Reference
DOI: https://doi.org/10.1097/CM9.0000000000002180

Title of original paper: Systematic analysis on expression quantitative trait loci identifies a novel regulatory variant in ring finger and WD repeat domain 3 associated with prognosis of pancreatic cancer 

Journal:           Chinese Medical Journal

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SOURCE Chinese Medical Journal