Identity by Descent Mapping of Founder Mutations in Cancer Using High-Resolution Tumor SNP Data

Dense genotype data can be used to detect chromosome fragments inherited from a common ancestor in apparently unrelated individuals. A disease-causing mutation inherited from a common founder may thus be detected by searching for a common haplotype signature in a sample population of patients. We present here FounderTracker, a computational method for the genome-wide detection of founder mutations in cancer using dense tumor SNP profiles. Our method is based on two assumptions. First, the wild-type allele frequently undergoes loss of heterozygosity (LOH) in the tumors of germline mutation carriers. Second, the overlap between the ancestral chromosome fragments inherited from a common founder will define a minimal haplotype conserved in each patient carrying the founder mutation. Our approach thus relies on the detection of haplotypes with significant identity by descent (IBD) sharing within recurrent regions of LOH to highlight genomic loci likely to harbor a founder mutation. We validated this approach by analyzing two real cancer data sets in which we successfully identified founder mutations of well-characterized tumor suppressor genes. We then used simulated data to evaluate the ability of our method to detect IBD tracts as a function of their size and frequency. We show that FounderTracker can detect haplotypes of low prevalence with high power and specificity, significantly outperforming existing methods. FounderTracker is thus a powerful tool for discovering unknown founder mutations that may explain part of the “missing” heritability in cancer. This method is freely available and can be used online at the FounderTracker website

Antitumor and Antimetastatic Effect of Small Immunostimulatory RNA against B16 Melanoma in Mice.

Small interfering RNAs, depending on their structure, delivery system and sequence, can stimulate innate and adaptive immunity. The aim of this study was to investigate the antitumor and antimetastatic effects of immunostimulatory 19-bp dsRNA with 3'- trinucleotide overhangs (isRNA) on melanoma B16 in C57Bl/6 mice. Recently developed novel cationic liposomes 2X3-DOPE were used for the in vivo delivery of isRNA. Administration of isRNA/2X3-DOPE complexes significantly inhibits melanoma tumor growth and metastasis. Histopathological analysis of spleen cross sections showed hyperplasia of the lymphoid white pulp and formation of large germinal centers after isRNA/2X3-DOPE administration, indicating activation of the immune system. The treatment of melanoma-bearing mice with isRNA/2X3-DOPE decreases the destructive changes in the liver parenchyma. Thus, the developed isRNA displays pronounced immunostimulatory, antitumor and antimetastatic properties against melanoma B16 and may be considered a potential agent in the immunotherapy of melanoma

PVP-stabilized tungsten oxide nanoparticles: pH sensitive anti-cancer platform with high cytotoxicity

Photochromic tungsten oxide (WO3) nanoparticles stabilized by polyvinylpyrrolidone (PVP) were synthesized to evaluate their potential for biomedical applications. PVP-stabilized tungsten oxide nanoparticles demonstrated a highly selective cytotoxic effect on normal and cancer cells in vitro. WO3 nanoparticles were found to induce substantial cell death in osteosarcoma cells (MNNG/HOS cell line) with a half-maximal inhibitory concentration (IC50) of 5 mg/mL, while producing no, or only minor, toxicity in healthy human mesenchymal stem cells (hMSc). WO3 nanoparticles induced intracellular oxidative stress, which led to apoptosis type cell death. The selective anti-cancer effects of WO3 nanoparticles are due to the pH sensitivity of tungsten oxide and its capability of reactive oxygen species (ROS) generation, which is expressed in the modulation of genes involved in reactive oxygen species metabolism, mitochondrial dysfunction, and apoptosis

The treatment of melanoma B16-bearing mice with isRNA increases the white pulp area in the spleen.

<p>(A) Cross sections of the spleens of the representative mice with subcutaneous melanoma on day 18 after tumor initiation. Arrows show follicles on each image. Paraffin sections, hematoxylin and eosin stain. (B, C) The ratio of the total follicles area to the total area of the spleen for subcutaneous (B) and metastatic (C) melanoma (for details see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0150751#sec002" target="_blank">Materials & Methods</a>). I. v. administration–black bars, p.t. administration–white bars. The data represent mean ± SEM (n = 9). Statistically significant differences between experimental and control groups are indicated by asterisks (**, P<0.01; *, P<0.05); and differences between experimental and Mock groups are indicated by crosses (††, P<0.01; †, P<0.05); Mann-Whitney U test.</p