Cancer Biology and Genetics, Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
Center for Biostatistics, Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
J Med Genet. 2020 Aug;57(8):519-527. doi: 10.1136/jmedgenet-2019-106554. Epub 2020 Feb 12.
Papillary thyroid carcinoma (PTC) demonstrates high heritability and a low somatic mutation burden relative to other cancers. Therefore, the genetic risk predisposing to PTC is likely due to a combination of low penetrance variants. A recent genome-wide association study revealed the association of PTC with a missense variant, rs6793295, at 3q26 in a gene called Leucine Repeat Rich Containing 34 ().
We report the mechanisms of PTC risk at 3q26 using a combination of overexpression, mass spectroscopy, knockdown, transcriptome profiling, migration assays and genetic analysis.
We observed differential binding of wild-type and missense LRRC34 to RANBP1. Overexpression of missense LRRC34 reduced RanGTP levels and increased apoptosis. We also identified a second linkage disequilibrium (LD) block upstream of containing regulatory variants with allele-specific expression. Transcriptome profiling of knockdown cells showed changes in genes involved with cellular movement. knockdown reduced the migration of thyroid cancer cell lines. Lastly, we assessed the relative contribution of PTC risk from each locus using haplotype analysis.
Our study demonstrates two separate mechanisms, one in G protein signalling and the other in transcriptional control, dictating PTC risk at 3q26 using both biochemical and genetic techniques.
甲状腺乳头状癌（PTC）相对于其他癌症具有较高的遗传性和较低的体细胞突变负担。因此，导致 PTC 的遗传风险可能是由于低外显率变异的组合。最近的全基因组关联研究揭示了 PTC 与位于基因 Leucine Repeat Rich Containing 34（LRRC34）的 3q26 上的错义变异 rs6793295 之间的关联。
我们使用过表达、质谱分析、敲低、转录组谱分析、迁移测定和遗传分析的组合来报告 3q26 处 PTC 风险的机制。
我们观察到野生型和错义 LRRC34 与 RANBP1 的差异结合。错义 LRRC34 的过表达降低了 RanGTP 水平并增加了细胞凋亡。我们还鉴定了位于含有调节变异的 LRRC34 上游的第二个连锁不平衡（LD）块。LRRC34 敲低细胞的转录组谱显示与细胞运动相关的基因发生变化。LRRC34 敲低降低了甲状腺癌细胞系的迁移能力。最后，我们使用单倍型分析评估了每个位点对 PTC 风险的相对贡献。
我们的研究使用生化和遗传技术，证明了两种独立的机制，一种是在 G 蛋白信号传导中，另一种是在转录控制中，决定了 3q26 处的 PTC 风险。
