Real-World Clinical Performance of a DNA-Based Comprehensive Genomic Profiling Assay for Detecting Targetable Fusions in Nonsquamous NSCLC.

Background: Genomic fusions are potent oncogenic drivers across cancer types and many are targetable. We demonstrate the clinical performance of DNA-based comprehensive genomic profiling (CGP) for detecting targetable fusions.

Materials And Methods: We analyzed targetable fusion genes in >450 000 tissue specimens profiled using DNA CGP (FoundationOne CDx, FoundationOne).

Circulating Tumor DNA Enables Sensitive Detection of Actionable Gene Fusions and Rearrangements Across Cancer Types.

Purpose: Genomic rearrangements can generate potent oncogenic drivers or disrupt tumor suppressor genes. This study examines the landscape of fusions and rearrangements detected by liquid biopsy (LBx) of circulating tumor DNA (ctDNA) across different cancer types.

Experimental Design: LBx from 53,842 patients with 66 solid tumor types were profiled using FoundationOneLiquid CDx, a hybrid-capture sequencing platform that queries 324 cancer-related genes.

Activating IGF1R hotspot non-frameshift insertions define a novel, potentially targetable molecular subtype of adenoid cystic carcinoma.

Activation of the tyrosine kinase receptor IGF1R is targetable with existing tyrosine kinase inhibitors (TKIs) and monoclonal antibodies, but mutations in IGF1R have not been systematically characterized. Pan-cancer analysis of 326,911 tumors identified two distinct, activating non-frameshift insertion hotspots in IGF1R, which were significantly enriched in adenoid cystic carcinomas (ACCs). IGF1R alterations from 326,911 subjects were analyzed by variant effect prediction class, position within the gene, and cancer type.

Patients with NSCLCs Harboring Internal Inversions or Deletion Rearrangements of the Gene Have Durable Responses to ALK Kinase Inhibitors.

Background: fusions are targetable drivers in non-small-cell lung cancer (NSCLC). However, patients with NSCLC harboring rearrangements without a fusion partner identified in DNA have also been shown to respond to ALK inhibitors. We aimed to characterize complex variants that may predict sensitivity to multiple approved ALK inhibitors.

SMARCA4 inactivation defines a subset of undifferentiated uterine sarcomas with rhabdoid and small cell features and germline mutation association.

A rare subset of aggressive SMARCA4-deficient uterine sarcomas has been recently proposed, with only a limited number of cases having been previously described. Here, we identify 16 additional cases of SMARCA4-deficient uterine sarcoma from the database of a large, CLIA-certified and CAP-accredited, reference molecular laboratory, and we expand on their clinicopathological and genomic features. Median patient's age was 49 years (range 32-70).

Identification of NTRK fusions in pediatric mesenchymal tumors.

Background: NTRK fusions are known oncogenic drivers and have recently been effectively targeted by investigational agents in adults. We sought to assess the frequency of NTRK fusions in a large series of pediatric and adolescent patients with advanced cancers.

Procedure: Genomic profiles from 2,031 advanced cancers from patients less than 21 years old who were assayed with comprehensive genomic profiling were reviewed to identify NTRK fusions.

Lubricin restoration in a mouse model of congenital deficiency.

Objective: Congenital deficiency of the principal boundary lubricant in cartilage (i.e., lubricin, encoded by the gene PRG4) increases joint friction and causes progressive joint failure.

Autopodial development is selectively impaired by misexpression of chordin-like 1 in the chick limb.

Chordin-like 1 (CHRDL1) is a secreted bone morphogenetic protein (BMP) antagonist expressed in mesenchymal tissues whose function in development of the skeleton has not been examined in detail. Here we show Chrdl1 is dynamically expressed in the early distal limb bud mesenchyme, with expression becoming downregulated as development proceeds. Chrdl1 expression is largely excluded from the critical signaling center of the posterior limb bud, the Zone of Polarizing Activity (ZPA), as has been described for the BMP antagonist Gremlin (GREM1) (Scherz et al.

WARP interacts with collagen VI-containing microfibrils in the pericellular matrix of human chondrocytes.

Collagen VI and WARP are extracellular structural macromolecules present in cartilage and associated with BM suprastructures in non-skeletal tissues. We have previously shown that in WARP-deficient mice, collagen VI is specifically reduced in regions of the peripheral nerve ECM where WARP is expressed, suggesting that both macromolecules are part of the same suprastructure. The object of this study was to conduct a detailed analysis of WARP-collagen VI interactions in vitro in cartilage, a tissue rich in WARP and collagen VI.

Designing passive MRI-safe implantable conducting leads with electrodes.

Purpose: The presence of implanted electronic devices with conducting leads and electrodes are contraindicated for magnetic resonance imaging (MRI), denying many patients its potential benefits. The prime concern is MRI's radio frequency (RF) fields, which can cause elevated local specific absorption rates (SARs) and potential heat injury. The purpose of this article is to develop and compare a range of passive implantable "MRI-safe" lead designs.

Mice lacking the extracellular matrix protein WARP develop normally but have compromised peripheral nerve structure and function.

WARP is a recently identified extracellular matrix molecule with restricted expression in permanent cartilages and a distinct subset of basement membranes in peripheral nerves, muscle, and the central nervous system vasculature. WARP interacts with perlecan, and we also demonstrate here that WARP binds type VI collagen, suggesting a function in bridging connective tissue structures. To understand the in vivo function of WARP, we generated a WARP-deficient mouse strain.

The extracellular matrix protein WARP is a novel component of a distinct subset of basement membranes.

WARP is a recently described member of the von Willebrand factor A domain superfamily of extracellular matrix proteins, and is encoded by the Vwa1 gene. We have previously shown that WARP is a multimeric component of the chondrocyte pericellular matrix in articular cartilage and intervertebral disc, where it interacts with the basement membrane heparan sulfate proteoglycan perlecan. However, the tissue-specific expression of WARP in non-cartilaginous tissues and its localization in the extracellular matrix of other perlecan-containing tissues have not been analyzed in detail.

The C5 domain of the collagen VI alpha3(VI) chain is critical for extracellular microfibril formation and is present in the extracellular matrix of cultured cells.

Collagen VI, a microfibrillar protein found in virtually all connective tissues, is composed of three distinct subunits, alpha1(VI), alpha2(VI), and alpha3(VI), which associate intracellularly to form triple helical heterotrimeric monomers then dimers and tetramers. The secreted tetramers associate end-to-end to form beaded microfibrils. Although the basic steps in assembly and the structure of the tetramers and microfibrils are well defined, details of the interacting protein domains involved in assembly are still poorly understood.

WARP is a novel multimeric component of the chondrocyte pericellular matrix that interacts with perlecan.

WARP is a novel member of the von Willebrand factor A domain superfamily of extracellular matrix proteins that is expressed by chondrocytes. WARP is restricted to the presumptive articular cartilage zone prior to joint cavitation and to the articular cartilage and fibrocartilaginous elements in the joint, spine, and sternum during mouse embryonic development. In mature articular cartilage, WARP is highly specific for the chondrocyte pericellular microenvironment and co-localizes with perlecan, a prominent component of the chondrocyte pericellular region.