TY - JOUR
T1 - Mutational Impacts on the N and C Terminal Domains of the MUC5B Protein
T2 - A Transcriptomics and Structural Biology Study
AU - Mehmood, Aamir
AU - Nawab, Sadia
AU - Jin, Yifan
AU - Kaushik, Aman Chandra
AU - Wei, Dong Qing
N1 - Funding Information:
D.-Q.W. is supported by grants from the National Science Foundation of China (Grant Nos. 32070662, 61832019, 32030063), the Science and Technology Commission of Shanghai Municipality (Grant No. 19430750600), as well as the SJTU JiRLMDS Joint Research Fund and Joint Research Funds for Medical and Engineering and Scientific Research at Shanghai Jiao Tong University (YG2021ZD02). The computations were partially performed at the Pengcheng Lab. and the Center for High-Performance Computing, Shanghai Jiao Tong University.
Publisher Copyright:
© 2023 The Authors. Published by American Chemical Society.
PY - 2023/1/20
Y1 - 2023/1/20
N2 - Cholangiocarcinoma (CCA) involves various epithelial tumors historically linked with poor prognosis because of its aggressive sickness course, delayed diagnosis, and limited efficacy of typical chemotherapy in its advanced stages. In-depth molecular profiling has exposed a varied scenery of genomic alterations as CCA’s oncogenic drivers. Previous studies have mainly focused on commonly occurring TP53 and KRAS alterations, but there is limited research conducted to explore other vital genes involved in CCA. We retrieved data from The Cancer Genome Atlas (TCGA) to hunt for additional CCA targets and plotted a mutational landscape, identifying key genes and their frequently expressed variants. Next, we performed a survival analysis for all of the top genes to shortlist the ones with better significance. Among those genes, we observed that MUC5B has the most significant p-value of 0.0061. Finally, we chose two missense mutations at different positions in the vicinity of MUC5B N and C terminal domains. These mutations were further subjected to molecular dynamics (MD) simulation, which revealed noticeable impacts on the protein structure. Our study not only reveals one of the highly mutated genes with enhanced significance in CCA but also gives insights into the influence of its variants. We believe these findings are a good asset for understanding CCA from genomics and structural biology perspectives.
AB - Cholangiocarcinoma (CCA) involves various epithelial tumors historically linked with poor prognosis because of its aggressive sickness course, delayed diagnosis, and limited efficacy of typical chemotherapy in its advanced stages. In-depth molecular profiling has exposed a varied scenery of genomic alterations as CCA’s oncogenic drivers. Previous studies have mainly focused on commonly occurring TP53 and KRAS alterations, but there is limited research conducted to explore other vital genes involved in CCA. We retrieved data from The Cancer Genome Atlas (TCGA) to hunt for additional CCA targets and plotted a mutational landscape, identifying key genes and their frequently expressed variants. Next, we performed a survival analysis for all of the top genes to shortlist the ones with better significance. Among those genes, we observed that MUC5B has the most significant p-value of 0.0061. Finally, we chose two missense mutations at different positions in the vicinity of MUC5B N and C terminal domains. These mutations were further subjected to molecular dynamics (MD) simulation, which revealed noticeable impacts on the protein structure. Our study not only reveals one of the highly mutated genes with enhanced significance in CCA but also gives insights into the influence of its variants. We believe these findings are a good asset for understanding CCA from genomics and structural biology perspectives.
UR - http://www.scopus.com/inward/record.url?scp=85146891098&partnerID=8YFLogxK
U2 - 10.1021/acsomega.2c04871
DO - 10.1021/acsomega.2c04871
M3 - Article
C2 - 36743039
AN - SCOPUS:85146891098
SN - 2470-1343
VL - 8
SP - 3726
EP - 3735
JO - ACS Omega
JF - ACS Omega
IS - 4
ER -
