Novel variants inMLLconfer to bladder cancer recurrence identified by whole-exome sequencing

Abstract

Bladder cancer (BC) is distinguished by high rate of recurrence after surgery, but the underlying mechanisms remain poorly understood. Here we performed the wholeexome sequencing of 37 BC individuals including 20 primary and 17 recurrent samples in which the primary and recurrent samples were not from the same patient. We uncovered that MLL, EP400, PRDM2, ANK3 and CHD5 exclusively altered in recurrent BCs. Specifically, the recurrent BCs and bladder cancer cells with MLL mutation displayed increased histone H3 tri-methyl K4 (H3K4me3) modification in tissue and cell levels and showed enhanced expression of GATA4 and ETS1 downstream. What's more, MLL mutated bladder cancer cells obtained with CRISPR/Cas9 showed increased ability of drug-resistance to epirubicin (a chemotherapy drug for bladder cancer) than wild type cells. Additionally, the BC patients with high expression of GATA4 and ETS1 significantly displayed shorter lifespan than patients with low expression. Our study provided an overview of the genetic basis of recrudescent bladder cancer and discovered that genetic alterations of MLL were involved in BC relapse. The increased modification of H3K4me3 and expression of GATA4 and ETS1 would be the promising targets for the diagnosis and therapy of relapsed bladder cancer.

Genetic and Epigenetic Alterations in Bladder Cancer

“…In addition, ARID1A , which encodes for a component of the SWI/SNF chromatin-remodeling complex, is altered in 22% of bladder tumors, while MLL2 , which encodes for an H3K4 methylase, is altered in 17% of bladder cancer patients [18]. Wu et al [82] reported that mutations in MLL, EP400 (a component of the NuA4 histone acetyltransferase complex) and PRDM2 (a nuclear histone/protein methyltransferase) are associated with bladder cancer relapse. MLL mutations in recurrent bladder cancers result in elevated H3K4me3 levels and increased expression of GATA4 and ETS1 [82].…”

“…Wu et al [82] reported that mutations in MLL, EP400 (a component of the NuA4 histone acetyltransferase complex) and PRDM2 (a nuclear histone/protein methyltransferase) are associated with bladder cancer relapse. MLL mutations in recurrent bladder cancers result in elevated H3K4me3 levels and increased expression of GATA4 and ETS1 [82]. Interestingly, MLL3 , which also encodes for an H3K4 methylase, is exclusively mutated in primary tumors, suggesting distinct histone modification signatures between primary and recurrent tumors [82].…”

“…MLL mutations in recurrent bladder cancers result in elevated H3K4me3 levels and increased expression of GATA4 and ETS1 [82]. Interestingly, MLL3 , which also encodes for an H3K4 methylase, is exclusively mutated in primary tumors, suggesting distinct histone modification signatures between primary and recurrent tumors [82]. Recently, the coexistence of the active H3K27Ac marker and DNA methylation at a subset of enhancers was reported, suggesting the dual roles of DNA methylation, either alone or via cooperation with histone modifications, is an important aspect of bladder cancer [83].…”

Application of CRISPR/Cas9 gene editing technique in the study of cancer treatment

“…The correction or deletion of resistance‐related genes is a promising development for tumor therapy. Current studies on drug resistance of tumor cells using CRISPR/Cas9 in lung cancer, breast cancer, melanoma, urogenital tumors, and gastrointestinal tumors about chemotherapy drugs, targeted drugs, and inhibitors were summarized in Table . Besides the above‐mentioned studies, there are other studies on the mechanisms related to drug resistance of other malignant tumors cells by using CRISPR/Cas9.…”

“…Current studies on drug resistance of tumor cells using CRISPR/Cas9 in lung cancer, breast cancer, melanoma, urogenital tumors, and gastrointestinal tumors about chemotherapy drugs, targeted drugs, and inhibitors were summarized in Table 2. 56,88,94,97,100,113,[141][142][143][144][145][146][147][148][149][150][151][152][153][154][155] Compared with wild-type cells, ATG5 KO cells had stronger migration ability and significantly increased resistance to the Src tyrosine kinase inhibitor PP2. 156 The results showed that autophagy deficiency can induce malignant cell transformation and resistance to PP2.…”