Whole Exome Sequencing of Papillary Type 2 Renal Cell Carcinoma and matched normal kidney tissue reveals NRF2 activation

NRF2 activation in sporadic Papillary Type 2 Renal Cell Carcinoma can be a result of loss of function mutation to CUL3, dominant negative mutation to SIRT1, as well as, gain of function mutation to NRF2. The expressions of these driver genes as well as NRF2 activation in the clinical samples were validated through transcriptome sequencing. Knocking down endogenous expression of CUL3 or ectopic expression of mutant SIRT1 and NRF2 in primary kidney tubular epithelial cells activates NRF2, solidifying the role of those identified mutations in driving the primary biochemical phenotype of the PRCC2.

散发性2型乳头状肾细胞癌中的核因子E2相关因子2（NRF2）激活，可由CUL3功能丧失突变、沉默信息调节因子1（SIRT1）显性负突变以及NRF2功能获得突变所导致。临床样本中的上述驱动基因表达水平及NRF2激活状态，均通过转录组测序得到验证。在原代肾管状上皮细胞中敲低CUL3的内源性表达，或异位表达突变型SIRT1与突变型NRF2，均可激活NRF2，从而证实了上述已鉴定突变在驱动2型乳头状肾细胞癌（PRCC2）主要生化表型中的作用。