The evolutionary history of 2,658 cancers.

Cancer develops through a process of somatic evolution1,2. Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes3. Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA)4, we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection

Inferring structural variant cancer cell fraction

Abstract: We present SVclone, a computational method for inferring the cancer cell fraction of structural variant (SV) breakpoints from whole-genome sequencing data. SVclone accurately determines the variant allele frequencies of both SV breakends, then simultaneously estimates the cancer cell fraction and SV copy number. We assess performance using in silico mixtures of real samples, at known proportions, created from two clonal metastases from the same patient. We find that SVclone’s performance is comparable to single-nucleotide variant-based methods, despite having an order of magnitude fewer data points. As part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) consortium, which aggregated whole-genome sequencing data from 2658 cancers across 38 tumour types, we use SVclone to reveal a subset of liver, ovarian and pancreatic cancers with subclonally enriched copy-number neutral rearrangements that show decreased overall survival. SVclone enables improved characterisation of SV intra-tumour heterogeneity

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Polymorphism and Genome Assembly

When Darwin introduced natural selection in 1859 as a key mechanism of evolution, little was known about the underlying cause of variation within a species. Today we know that this variation is caused by the acquired genomic differences between individuals. Polymorphism, defined as the existence of multiple alleles or forms at a genomic locus, is the technical term used for such genetic variations. Polymorphism, along with reproduction and inheritance of genetic traits, is a necessary condition for natural selection and is crucial in understanding how species evolve and adapt. Many questions regarding polymorphism, such as why certain species are more polymorphic than others or how different organisms tend to favor some types of polymorphism among others, when solved, have the potential to shed light on important problems in human medicine and disease research. Some of these studies require more diverse species and/or individuals to be sequenced. Of particular interest are species with the highest rates of polymorphisms. For instance, the sequencing of the sea squirt genome lead to exciting studies that would not be possible to conduct on species that possess lower levels of polymorphism. Such studies form the motivation of this thesis. Sequencing of genomes is, nonetheless, subject to its own research. Recent advances in DNA sequencing technology enabled researchers to lead an unprecedented amount of sequencing projects. These improvements in cost and abundance of sequencing revived a greater interest in advancing the algorithms and tools used for genome assembly. A majority of these tools, however, have no or little support for highly polymorphic genomes; which, we believe, require specialized methods. In this thesis, we look at challenges imposed by polymorphism on genome assembly and develop methods for polymorphic genome assembly via an overview of current and past methods. Though we borrow fundamental ideas from the literature, we introduce several novel concepts that can be useful not only for assembly of highly polymorphic genomes but also genome assembly and analysis in general.Ph

Polymorphism Due to Multiple Amino Acid Substitutions at a Codon Site Within Ciona savignyi

We compared two haploid genotypes of one Ciona savignyi individual and identified codons at which these genotypes differ by two nonsynonymous substitutions. Using the C. intestinalis genome as an outgroup, we showed that both substitutions tend to occur in the same genotype. Only in 53 (34.4%) of 154 codons, one substitution occurred in each of the two genotypes, although 77 (50%) of such codons are to be expected if substitutions were independent. We considered two feasible evolutionary causes for the observed pattern: substitutions driven by positive selection and compensatory substitutions, as well as several potential biases. However, none of these explanations is fully compelling, and data on multiple genotypes of C. savignyi would help to elucidate the causes of this pattern

High-Performance Thienothiophene and Single Wall Carbon Nanotube-Based Supercapacitor as a Free-Standing and Flexible Hybrid Energy Storage Material

Long cycle life and high energy/power density are imperative for energy storage systems. Similarly, flexible and free-standing electrodes are important for supercapacitor applications. Herein, we report, for the first time, use of thienothiophene (TT) and a single-walled carbon nanotube (SWCNT)-based free-standing and flexible hybrid material (TT-TPA-SWCNT) as a high-performance supercapacitor. The synthesized TT derivative, TT-TPA, was directly attached to SWCNT through noncovalent interactions to obtain the TT-based SWCNT hybrid, TT-TPA-SWCNT, as a flexible film. The hybrid film was clarified by surface analysis methods of scanning electron microscopy and atomic force microscopy. TT-TPA-SWCNT was used as a flexible and free-standing electrode in a two-electrode system for supercapacitor and energy storage applications. It displayed a high energy storage capacity of 83.2 F g–1 at 5 mV s–1 scan rate, an excellent cyclic stability with 110% retention of its initial specific capacitance after 7000 cycles and a long power density ranged from 100 to 3000 W·kg–1, demonstrating that TT-TPA-SWCNT is a promising hybrid nanomaterial for high-performance energy storage applications

Cranial Magnetic Resonance Imaging Findings in Patients with Indirect Hyperbilirubinemia

Abstract Purpose: To describe the magnetic resonance imaging (MRI) changes in the patients with indirect hyperbilirubinemia. Methods: MRI findings of eighteen neonates with indirect hyperbilirubinemia were reported by us. The differences in imaging, clinical and biochemical data between three groups were evaluated statistically. Results: Peak bilirubin levels were between 20 and 24 mg per deciliter in 5 of the newborns (group 1), 25 and 29 mg per deciliter in 6 of the newborns (group 2) and 30 mg per deciliter or more in 7 newborns (group 3). There was statistically significant difference between the neurological findings and MRI findings of the patients between three groups. Conclusion: We always demonstrated MRI changes in the patients with kernicterus. Firstly, T1 weighted changes were described in patients with hyperbilirubinemia despite normal neurological examinations. Larger studies with clinical follow up are needed for further understanding of toxic effect of bilirubin in brain. Key words: Ozet [Cukurova Med J 2012; 37(3.000): 139-145

The effects of prolonged CO 2 insufflation on kidney function in a rat pneumoperitoneum model

Introduction : Pneumoperitoneum (PP) is known to cause ischemia in kidneys and other intra-abdominal organs because of decreased splanchnic blood flow. Aim : We aimed to determine the degree of renal injury that occurs due to a PP and prolonged PP. We measured renal injury biomarkers and made a histopathological evaluation to estimate the degree of injury and assessed the correlation of biomarkers with histopathological findings. Material and methods : Twenty-one female Sprague Dawley rats were separated randomly into three groups. Group 1 was the control group and was given anesthesia for 3 h. In group 2, a PP was administered under anesthesia for 1 h. A pneumoperitoneum was administered under anesthesia to animals in group 3 for 3 h. Results : Pathological analysis showed a significant statistical difference between the 3 groups. In particular, neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C (Cys C) levels at the 24th h and preoperative mean urea levels showed a significant difference between the groups. The 24th-hour NGAL level in group 3 was significantly higher than that of group 1. The preoperative Cys C level was higher in group 1 than in either group 2 or 3. Cys C was decreased significantly in group 1 and increased significantly in both groups 2 and 3. Conclusions : The increase in NGAL and Cys C levels directly correlated with the duration of PP and intra-abdominal pressure, and they are therefore good biomarkers in diagnosing acute renal injury in the early phase. Serum creatinine level is not a good biomarker in the early phase of renal injury

The Effect of Sterilization Methods of Endoscopic Instruments on the Body: A Study on Rat Model

Purpose: Laparoscopy is widely used in many surgical areas for diagnosis and treatment. The need for sterilization of reusable instruments is an important issue. Ensuring patient safety, preventing infection, and protecting the functionality of the instruments are the most important points to be considered. We aimed to investigate two sterilization methods and their effects generated by their distribution into intra-abdominal tissues during insufflation. Materials and Methods: 21 rats were used in the study. The Control Group (Group 1) received anesthesia for 1 hour; Group 2 (Glutaraldehyde (GA)-Pneumoperitoneum Group) received anesthesia for 1 hour; Group 3 (Ethylene Oxide (EO)-Pneumoperitoneum Group) received anesthesia for 1 hour. After 24 hours, the animals were sacrificed, and the kidneys and omentum of the animals were analyzed in a histopathological manner. Blood samples were analyzed at preoperative 24th hour and at postoperative 24th hour. Results: There was a statistically significant difference in omentum, endothelium, and glomerular scores between the groups (p < 0.001 for all groups). Endothelial and glomerular scores were different at a statistically significant level in the EO and GA groups compared to the Control Group. The total score was higher at a statistically significant level in the EO and GA groups compared to the Control Group (p < 0.001 for both groups). Conclusion: It was determined in our study that sterilization methods such as EO and GA cause damage in intra-abdominal tissues. In the light of these results, we consider that the most ideal laparoscopic surgery set is the single-use laparoscopy set. However, this does not seem possible especially in developing countries in practice

Hereditary renal tubular disorders in Turkey: demographic, clinical, and laboratory features

The Turkish Renal Tubular Disorders Working Group aimed to form a patient registry database and gathered demographic, clinical, and laboratory data in various hereditary renal tubular disorders (HRTDs)