Comparison of array-based comparative genomic hybridization with gene expression-based regional expression biases to identify genetic abnormalities in hepatocellular carcinoma

BACKGROUND: Regional expression biases (REBs) are genetic intervals where gene expression is coordinately changed. For example, if a region of the genome is amplified, often the majority of genes that map within the amplified region show increased expression when compared to genes located in cytogenetically normal regions. As such, REBs have the potential to act as surrogates for cytogenetic data traditionally obtained using molecular technologies such as comparative genomic hybridization. However as REBs are identified using transcriptional information, detection of REBs may also identify local transcriptional abnormalities produced by both genetic and epigenetic mechanisms. RESULTS: REBs were identified from a set of hepatocellular carcinoma (HCC) gene expression profiles using a multiple span moving binomial test and compared to genetic abnormalities identified using array-based comparative genomic hybridization (aCGH). In the majority of cases, REBs overlapped genetic abnormalities as determined by aCGH. For example, both methods identified narrow regions of frequent amplification on chromosome 1p and narrow regions of frequent deletion on 17q. In a minority of cases, REBs were identified in regions not determined to be abnormal via other cytogenetic technologies. Specifically, expression biases reflective of cell proliferation were frequently identified on chromosome 6p21-23. CONCLUSION: Identification of REBs using a multiple span moving binomial test produced reasonable approximations of underlying cytogenetic abnormalities. However, caution should be used when attributing REBs identified on chromosome 6p to cytogenetic events in rapidly proliferating cells

Integration of DNA Copy Number Alterations and Transcriptional Expression Analysis in Human Gastric Cancer

Background: Genomic instability with frequent DNA copy number alterations is one of the key hallmarks of carcinogenesis. The chromosomal regions with frequent DNA copy number gain and loss in human gastric cancer are still poorly defined. It remains unknown how the DNA copy number variations contributes to the changes of gene expression profiles, especially on the global level. Principal Findings: We analyzed DNA copy number alterations in 64 human gastric cancer samples and 8 gastric cancer cell lines using bacterial artificial chromosome (BAC) arrays based comparative genomic hybridization (aCGH). Statistical analysis was applied to correlate previously published gene expression data obtained from cDNA microarrays with corresponding DNA copy number variation data to identify candidate oncogenes and tumor suppressor genes. We found that gastric cancer samples showed recurrent DNA copy number variations, including gains at 5p, 8q, 20p, 20q, and losses at 4q, 9p, 18q, 21q. The most frequent regions of amplification were 20q12 (7/72), 20q12-20q13.1 (12/72), 20q13.1-20q13.2 (11/72) and 20q13.2-20q13.3 (6/72). The most frequent deleted region was 9p21 (8/72). Correlating gene expression array data with aCGH identified 321 candidate oncogenes, which were overexpressed and showed frequent DNA copy number gains; and 12 candidate tumor suppressor genes which were down-regulated and showed frequent DNA copy number losses in human gastric cancers. Three networks of significantly expressed genes in gastric cancer samples were identified by ingenuity pathway analysis. Conclusions: This study provides insight into DNA copy number variations and their contribution to altered gene expression profiles during human gastric cancer development. It provides novel candidate driver oncogenes or tumor suppressor genes for human gastric cancer, useful pathway maps for the future understanding of the molecular pathogenesis of this malignancy, and the construction of new therapeutic targets. © 2012 Fan et al.published_or_final_versio

Sensory Communication

Contains table of contents for Section 2, an introduction and reports on fourteen research projects.National Institutes of Health Grant RO1 DC00117National Institutes of Health Grant RO1 DC02032National Institutes of Health/National Institute on Deafness and Other Communication Disorders Grant R01 DC00126National Institutes of Health Grant R01 DC00270National Institutes of Health Contract N01 DC52107U.S. Navy - Office of Naval Research/Naval Air Warfare Center Contract N61339-95-K-0014U.S. Navy - Office of Naval Research/Naval Air Warfare Center Contract N61339-96-K-0003U.S. Navy - Office of Naval Research Grant N00014-96-1-0379U.S. Air Force - Office of Scientific Research Grant F49620-95-1-0176U.S. Air Force - Office of Scientific Research Grant F49620-96-1-0202U.S. Navy - Office of Naval Research Subcontract 40167U.S. Navy - Office of Naval Research/Naval Air Warfare Center Contract N61339-96-K-0002National Institutes of Health Grant R01-NS33778U.S. Navy - Office of Naval Research Grant N00014-92-J-184

Sensory Communication

Contains table of contents for Section 2, an introduction and reports on fifteen research projects.National Institutes of Health Grant RO1 DC00117National Institutes of Health Grant RO1 DC02032National Institutes of Health Contract P01-DC00361National Institutes of Health Contract N01-DC22402National Institutes of Health/National Institute on Deafness and Other Communication Disorders Grant 2 R01 DC00126National Institutes of Health Grant 2 R01 DC00270National Institutes of Health Contract N01 DC-5-2107National Institutes of Health Grant 2 R01 DC00100U.S. Navy - Office of Naval Research/Naval Air Warfare Center Contract N61339-94-C-0087U.S. Navy - Office of Naval Research/Naval Air Warfare Center Contract N61339-95-K-0014U.S. Navy - Office of Naval Research/Naval Air Warfare Center Grant N00014-93-1-1399U.S. Navy - Office of Naval Research/Naval Air Warfare Center Grant N00014-94-1-1079U.S. Navy - Office of Naval Research Subcontract 40167U.S. Navy - Office of Naval Research Grant N00014-92-J-1814National Institutes of Health Grant R01-NS33778U.S. Navy - Office of Naval Research Grant N00014-88-K-0604National Aeronautics and Space Administration Grant NCC 2-771U.S. Air Force - Office of Scientific Research Grant F49620-94-1-0236U.S. Air Force - Office of Scientific Research Agreement with Brandeis Universit

Discovery of common and rare genetic risk variants for colorectal cancer.

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.Goncalo R Abecasis has received compensation from 23andMe and Helix. He is currently an employee of Regeneron Pharmaceuticals. Heather Hampel performs collaborative research with Ambry Genetics, InVitae Genetics, and Myriad Genetic Laboratories, Inc., is on the scientific advisory board for InVitae Genetics and Genome Medical, and has stock in Genome Medical. Rachel Pearlman has participated in collaborative funded research with Myriad Genetics Laboratories and Invitae Genetics but has no financial competitive interest

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research