Citations 2
Building the vertebrate codex using the gene breaking protein trap library
Ichino, Noriko , Serres, MaKayla R., Urban, Rhianna , Urban, Mark D. , Treichel, Anthony J. , Schaefbauer, Kyle, Tallant, Lauren , Varshney, Gaurav K. , Skuster, Kimberly J., McNulty, Melissa S. , Daby, Camden L. , Wáng, Ying , Liao, Hsin‐Kai, El‐Rass, Suzan , Liu, Weibin , Anderson, Jennifer L. , Wishman, Mark , Sabharwal, Ankit , Schimmenti, Lisa A. , Sivasubbu, Sridhar , Balciunas, Darius , Hammerschmidt, Matthias , Farber, Steven , Wen, Xiao‐Yan , McGrail, Maura , Burgess, Shawn M. , Ekker, Stephen C. , Urban, Rhianna M , Schaefbauer, Kyle J., Tallant, Lauren E., Ding, Yonghe , Wishman, Mark D, Sabharwal, Ankit , Balciunas, Darius , Hammerschmidt, Matthias , Farber, Steven Arthur , Lin, Xueying , McGrail, Maura , Essner, Jeffrey , Burgess, Shawn M , Clark, Karl J , Ekker, Stephen C , Wen, Xiao-Yan , Schimmenti, Lisa A , Treichel, Anthony J , Ichino, Noriko , Xu, Xiaolei , Essner, Jeffrey J. , Clark, Karl J.
eLife | August 11, 2020 | Volume: 9 | Issue: No issue available | Pages: No page available
One key bottleneck in understanding the human genome is the relative under-characterization of 90% of protein coding regions. We report a collection of 1200 transgenic zebrafish strains made with the gene-break transposon (GBT) protein trap to simultaneously report and reversibly knockdown the tagged genes. Protein trap-associated mRFP expression shows previously undocumented expression of 35% and 90% of cloned genes at 2 and 4 days post-fertilization, respectively. Further, investigated alleles regularly show 99% gene-specific mRNA knockdown. Homozygous GBT animals in ryr1b , fras1 , tnnt2a , edar and hmcn1 phenocopied established mutants. 204 cloned lines trapped diverse proteins, including 64 orthologs of human disease-associated genes with 40 as potential new disease models. Severely reduced skeletal muscle Ca 2+ transients in GBT ryr1b homozygous animals validated the ability to explore molecular mechanisms of genetic diseases. This GBT system facilitates novel functional genome annotation towards understanding cellular and molecular underpinnings of vertebrate biology and human disease.
Cholangiocarcinoma With FGFR Genetic Aberrations: A Unique Clinical Phenotype
Jain, Apurva , Kelley, Robin Kate , Wáng, Ying , Baggerly, Keith, Al‐Shamsi, Humaid O. , Ahn, Daniel H. , DeLeon, Thomas, Bocobo, Andrea Grace, Bekaii‐Saab, Tanios , Shroff, Rachna T. , Javle, Milind , Abdel-Wahab, Reham, Meric-Bernstam, Funda, Baggerly, Keith A, Kaseb, Ahmed Omar, Al-Shamsi, Humaid O, Bekaii-Saab, Tanios S , Borad, Mitesh J. , Abdel‐Wahab, Reham , Meric‐Bernstam, Funda , Kaseb, Ahmed O , Al-Shamsi, Humaid O
JCO Precision Oncology | January 17, 2018 | Volume: No volume available | Issue: 2 | Pages: 1-12
Purpose FGFR genetic aberrations (GAs) occur in an estimated 10% to 16% of intrahepatic cholangiocarcinomas (CCAs). The natural history of CCA with FGFR GAs, the prognostic role of coexisting GAs, and the outcome with FGFR-targeted inhibitors are unknown. Patients and Methods Patients with CCA with FGFR GAs were identified using next-generation sequencing or fluorescence in situ hybridization from four tertiary cancer centers and compared with FGFR wild-type counterparts. Data reviewed included demographic, treatment, overall survival (OS), and GA data. Fisher’s exact test, Kaplan-Meier plots, and log-rank tests were used for statistical analysis. Results Three hundred seventy-seven patients with CCA were identified, and 95 had FGFR GAs. FGFR2 GA was most common (n = 74, with 63 fusions) and seen in intrahepatic CCA. In patients with CCA, FGFR GAs occurred more frequently in younger patients (≤ 40 years; 20%) compared with older patients (> 40 years; 6.7%; P < .001), presented at an earlier stage (TNM stage I/II v III/IV: 35.8% v 22%, respectively; P = .001), and were associated with a longer OS compared with patients without FGFR GAs (37 v 20 months, respectively; P < .001). This difference remained significant after excluding 36 patients treated with FGFR inhibitors. There was no OS difference ( P = .60) between CCA with FGFR2 fusions (n = 63) versus other FGFR GAs (n = 29). Patients with FGFR GAs had a better OS with FGFR-targeted therapy compared with standard treatment ( P = .01). BAP1 mutation was the most common coexisting mutation without prognostic impact, whereas TP53 ( P = .04) and CDKN2A/B ( P = .04) were correlated with a shorter OS. Conclusion CCA with FGFR GAs represents a unique subtype occurring in younger patients with an indolent disease course. FGFR-targeted therapy may have a positive impact on OS in this subgroup.