The research team of Shenzhen Hospital collected 37 samples of bladder cancer patients, performed whole exon sequencing and gene editing techniques, and discovered the culprit of bladder cancer recurrence-“MLL gene”.
On the 7th, the reporter learned from Luohu People’s Hospital that recently, led by the precision medicine research team of the hospital, in conjunction with the Institute of Biophysics, Chinese Academy of Sciences, and Shenzhen Second People’s Hospital, new progress has been made in the recurrence of bladder cancer. The research team passed Collecting 37 samples of bladder cancer patients, performing whole exon sequencing and gene editing techniques, found the culprit of bladder cancer recurrence-“MLL gene”, related research results have been accepted online by the International Journal of Cancer Oncotarget (impact factor 6.359) .
Bladder cancer is the most common malignant tumor of the urinary system, accounting for the first incidence of urogenital tumors in China. In addition, compared with other cancers, the recurrence rate after bladder cancer surgery is relatively high (about 70%). So far, the genetic analysis of bladder cancer recurrence is still in the initial stage of research, and molecular targeted drugs have not been approved for marketing.
With the gene sequencing diagnosis technology widely used in clinical diagnosis, the research team collected 37 ex-bladder cancer samples, including 20 cases of primary bladder cancer and 17 cases of postoperative recurring bladder cancer. MLL, EP400, PRDM2, ANK3, and CHD5 have significant mutations. Among patients with primary bladder cancer, MLL gene mutations have not been detected, while patients with recurrent bladder cancer have detected MLL, EP400, PRDM2 genes. Significant high-frequency mutations, and in four recurrent bladder cancer patient tissues, MNL gene-specific nonsynonymous cell mutations were detected. “Compared with the MLL gene mutations reported in previous studies that may lead to the loss of its function, we found that the function of the MLL gene is enhanced during the recurrence of bladder cancer.” Song said.
The MLL gene encoding plays a key role as a transcriptional costimulatory factor during early embryonic development and hematopoiesis. The MLL family can specifically methylate histone H3. This modification process is closely related to the transcriptional activation region of the chromosome relationship. Therefore, the research team used CRISPR / CAS9 gene editing technology to induce MLL gene mutations in bladder cancer cell lines, and found that MLL mRNA and protein expression levels did not change significantly, but significantly increased histone H3 methylation. Grooming. The team also increased the expression levels of the downstream genes GATA4 and ETS1. At the same time, after trying to induce the resistance test of bladder cancer cells with MLL gene mutations, they found that they had developed resistance to epirubicin (chemotherapy for bladder cancer). And GATA4 and ETS1 are highly expressed at the protein level.
Interestingly, the research team found that the survival time of patients with recurrent bladder cancer with high expression of GATA4 and ETS1 was significantly shortened. Therefore, all research results show that MLL gene mutation can be a biological target for the diagnosis and clinical treatment of relapsed bladder cancer, but the expression profile of MLL mutant cells and the mechanism of GATA4 / ETS1-induced resistance of bladder cancer cells need to be further explored.