While Dr. Eng started with cancer gene mutations and discovered a link to autism, Dr. Eichler, of the University of Washington, started with autism and found a connection to cancer genes.
We carried out a haploid ENU (N-ethyl-N-nitrosourea) screen for endocrine pancreas mutations and discovered a mutant (88.21) that does not develop isl1 expression in the endocrine pancreas, but maintains isl1 expression in the CNS.
In this first WES approach from microdissected SMZL tissue we confirmed known mutations and discovered new somatic variants.
We evaluated three organs commonly affected by COL4A1 and COL4A2 mutations and discovered allelic heterogeneity in the penetrance and severity of ocular dysgenesis, myopathy and brain malformations.
Kandoth and colleagues characterized the presence of significant mutations in EMT-related genes and discovered mutations in multiple TGFβ-related pathways (Smad4: 2%; TGFBR2: 3%; ACVR1B: 1.3%; SMAD2: 1%; ACVR2A: 0.7% of the 301 HNC tumors sampled) [90].
We therefore screened all samples for mutations in this gene and discovered 9 acquired sequence mutations in 7/16 cases, leading to an overall frequency of somatic CREBBP aberrations in HD ALL relapse cases of 63% that is considerably higher than that of the reported, mainly non-HD ALL (18.3%).
However, we generated and analysed PHAII model mice (WNK4 D561A/+) carrying a PHAII-causing mutation in WNK4, and discovered a novel signalling cascade between WNK and NCC via OSR1 (oxidative stress-responsive 1) and SPAK (Ste20-like proline/alanine-rich kinase) in the kidney [ 9, 10].
New insights about that complexity have driven a variety of research developments and emerging therapies that are targeted toward targeting specific genetic mutations, discovering and managing the "on" and "off" switches that tell cells to grow out of control, and activating the body's immune system to attack invading malignant cells.
Using our UDT-Seq approach, we identified potentially actionable mutations in 14/19 patients whose tumor samples had less than 60% cellularity and discovered actionable mutations present at 10% allelic fraction or less in four patients, some of whom had tumors with high malignant cellularity.
Dr. Wilson looked at samples from patients who had relapsed and discovered additional mutations, in part because the technology had improved, but also because new mutations had cropped up.
