Discovery Analysis of TCGA Data Reveals Association between Germline Genotype and Survival in Ovarian Cancer Patients

Background

Ovarian cancer remains a significant public health burden, with the highest mortality rate of all the gynecological cancers. This is attributable to the late stage at which the majority of ovarian cancers are diagnosed, coupled with the low and variable response of advanced tumors to standard chemotherapies. To date, clinically useful predictors of treatment response remain lacking. Identifying the genetic determinants of ovarian cancer survival and treatment response is crucial to the development of prognostic biomarkers and personalized therapies that may improve outcomes for the late-stage patients who comprise the majority of cases.

Methods

To identify constitutional genetic variations contributing to ovarian cancer mortality, we systematically investigated associations between germline polymorphisms and ovarian cancer survival using data from The Cancer Genome Atlas Project (TCGA). Using stage-stratified Cox proportional hazards regression, we examined 650,000 SNP loci for association with survival. We additionally examined whether the association of significant SNPs with survival was modified by somatic alterations.

Results

Germline polymorphisms at rs4934282 (AGAP11/C10orf116) and rs1857623 (DNAH14) were associated with stage-adjusted survival ( = 1.12e-07 and 1.80e-07, FDR  = 1.2e-04 and 2.4e-04, respectively). A third SNP, rs4869 (C10orf116), was additionally identified as significant in the exome sequencing data; it is in near-perfect LD with rs4934282. The associations with survival remained significant when somatic alterations.

Conclusions

Discovery analysis of TCGA data reveals germline genetic variations that may play a role in ovarian cancer survival even among late-stage cases. The significant loci are located near genes previously reported as having a possible relationship to platinum and taxol response. Because the variant alleles at the significant loci are common (frequencies for rs4934282 A/C alleles = 0.54/0.46, respectively; rs1857623 A/G alleles = 0.55/0.45, respectively) and germline variants can be assayed noninvasively, our findings provide potential targets for further exploration as prognostic biomarkers and individualized therapies.     

Factors Associated with Post-Seasonal Serological Titer and Risk Factors for Infection with the Pandemic A/H1N1 Virus in the French General Population

The CoPanFlu-France cohort of households was set up in 2009 to study the risk factors for infection by the pandemic influenza virus (H1N1pdm) in the French general population. The authors developed an integrative data-driven approach to identify individual, collective and environmental factors associated with the post-seasonal serological H1N1pdm geometric mean titer, and derived a nested case-control analysis to identify risk factors for infection during the first season. This analysis included 1377 subjects (601 households). The GMT for the general population was 47.1 (95% confidence interval (CI): 45.1, 49.2). According to a multivariable analysis, pandemic vaccination, seasonal vaccination in 2009, recent history of influenza-like illness, asthma, chronic obstructive pulmonary disease, social contacts at school and use of public transports by the local population were associated with a higher GMT, whereas history of smoking was associated with a lower GMT. Additionally, young age at inclusion and risk perception of exposure to the virus at work were identified as possible risk factors, whereas presence of an air humidifier in the living room was a possible protective factor. These findings will be interpreted in light of the longitudinal analyses of this ongoing cohort.     

An Investigation of Fecal Volatile Organic Metabolites in Irritable Bowel Syndrome

Diagnosing irritable bowel syndrome (IBS) can be a challenge; many clinicians resort to invasive investigations in order to rule out other diseases and reassure their patients. Volatile organic metabolites (VOMs) are emitted from feces; understanding changes in the patterns of these VOMs could aid our understanding of the etiology of the disease and the development of biomarkers, which can assist in the diagnosis of IBS. We report the first comprehensive study of the fecal VOMs patterns in patients with diarrhea-predominant IBS (IBS-D), active Crohn''s disease (CD), ulcerative colitis (UC) and healthy controls. 30 patients with IBS-D, 62 with CD, 48 with UC and 109 healthy controls were studied. Diagnosis of IBS-D was made using the Manning criteria and all patients with CD and UC met endoscopic, histologic and/or radiologic criteria. Fecal VOMs were extracted by solid phase microextraction (SPME) and analyzed by gas chromatography-mass spectrometry (GC-MS). 240 VOMs were identified. Univariate analysis showed that esters of short chain fatty acids, cyclohexanecarboxylic acid and its ester derivatives were associated with IBS-D (p<0.05), while aldehydes were more abundant in IBD (p<0.05). A predictive model, developed by multivariate analysis, separated IBS-D from active CD, UC and healthy controls with a sensitivity of 94%, 96% and 90%; and a specificity of 82%, 80% and 80% respectively (p<0.05). The understanding of the derivation of these VOMs may cast light on the etiology of IBS-D and IBD. These data show that fecal VOMs analyses could contribute to the diagnosis of IBS-D, for which there is no laboratory test, as well as IBD.     

Reproductive demographics,intersex, and altered hormone levels in shortnose sturgeon,Acipenser brevirostrum,from Delaware River,USA

Non‐lethal sampling techniques were used to document the reproductive structure of the shortnose sturgeon (Acipenser brevirostrum) population at a fish aggregation site (near Bordentown, New Jersey) in the Delaware River. A total of 68 fish were captured using gill nets (100 × 1.8 m, 12.7 or 15.2 cm mesh) and examined laparoscopically in May–June, and 61 additional fish captured and examined in November during 2006–2011. Six stages of reproductive development were identified in females and five stages were identified in males, encompassing differentiation through maturity in both sexes. Fish captured in the spring were predominantly immature with a higher proportion of females (1 : 1.2 M : F sex ratio), while mature males predominated in the autumn (5.7 : 1 M : F), indicating that the Bordentown area serves as an overwintering/pre‐spawn aggregation site. Three distinct forms of intersex were noted in gonads of 11.6% of fish examined: ovo‐testis, consisting of scattered spermatic cysts in predominantly immature ovary (3.9%); testis‐ova, consisting of ovarian lamellae projecting from a predominantly immature testes (4.7%); and zonal distribution, consisting of multiple, nearly‐homogenous pockets of either testicular or ovarian tissues along the gonad (3%). The hormone profile in fish with ovo‐testis was similar to that of immature males, while the hormone profile in fish with testis‐ova was similar to that of immature females. The relatively high prevalence of intersex raises concerns regarding potential reproductive effects and long‐term impacts on shortnose sturgeon in the Delaware River.     

Brief communication: Evolution of a specific O allele (O1vG542A) supports unique ancestry of Native Americans

In this study, we explore the geographic and temporal distribution of a unique variant of the O blood group allele called O1v^G542A, which has been shown to be shared among Native Americans but is rare in other populations. O1v^G542A was previously reported in Native American populations in Mesoamerica and South America, and has been proposed as an ancestry informative marker. We investigated whether this allele is also found in the Tlingit and Haida, two contemporary indigenous populations from Alaska, and a pre‐Columbian population from California. If O1v^G542A is present in Na‐Dene speakers (i.e., Tlingits), it would indicate that Na‐Dene speaking groups share close ancestry with other Native American groups and support a Beringian origin of the allele, consistent with the Beringian Incubation Model. If O1v^G542A is found in pre‐Columbian populations, it would further support a Beringian origin of the allele, rather than a more recent introduction of the allele into the Americas via gene flow from one or more populations which have admixed with Native Americans over the past five centuries. We identified this allele in one Na‐Dene population at a frequency of 0.11, and one ancient California population at a frequency of 0.20. Our results support a Beringian origin of O1v^G542A, which is distributed today among all Native American groups that have been genotyped in appreciable numbers at this locus. This result is consistent with the hypothesis that Na‐Dene and other Native American populations primarily derive their ancestry from a single source population. Am J Phys Anthropol 151:649–657, 2013. © 2013 Wiley Periodicals, Inc.     

Structure-based design and synthesis of potent benzothiazole inhibitors of interleukin-2 inducible T cell kinase (ITK)

Inhibition of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signalling cascade, may represent a novel treatment for allergic asthma. Here we report the structure-based optimization of a series of benzothiazole amides that demonstrate sub-nanomolar inhibitory potency against ITK with good cellular activity and kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of several inhibitor-ITK complexes.     

Genetic diversity and spatial genetic structure of African wild dogs (<Emphasis Type="Italic">Lycaon pictus</Emphasis>) in the Greater Limpopo transfrontier conservation area

The Greater Limpopo Transfrontier Conservation Area (GLTFCA) is one of the last refuges for the endangered African wild dog and hosts roughly one-tenth of the global population. Wild dogs in this area are currently threatened by human encroachment, habitat fragmentation and scarcity of suitable connecting habitat between protected areas. We derived genetic data from mitochondrial and nuclear markers to test the following hypotheses: (i) demographic declines in wild dogs have caused a loss of genetic variation, and (ii) Zimbabwean and South African populations in the GLTFCA have diverged due to the effects of isolation and genetic drift. Genetic patterns among five populations, taken with comparisons to known information, illustrate that allelic richness and heterozygosity have been lost over time, presumably due to effects of inbreeding and genetic drift. Genetic structuring has occurred due to low dispersal rates, which was most apparent between Kruger National Park and the Zimbabwean Lowveld. Immediate strategies to improve gene flow should focus on increasing the quality of habitat corridors between reserves in the GLTFCA and securing higher wild dog survival rates in unprotected areas, with human-mediated translocation only undertaken as a last resort.     

BIITE: A Tool to Determine HLA Class II Epitopes from T Cell ELISpot Data

Activation of CD4⁺ T cells requires the recognition of peptides that are presented by HLA class II molecules and can be assessed experimentally using the ELISpot assay. However, even given an individual’s HLA class II genotype, identifying which class II molecule is responsible for a positive ELISpot response to a given peptide is not trivial. The two main difficulties are the number of HLA class II molecules that can potentially be formed in a single individual (3–14) and the lack of clear peptide binding motifs for class II molecules. Here, we present a Bayesian framework to interpret ELISpot data (BIITE: Bayesian Immunogenicity Inference Tool for ELISpot); specifically BIITE identifies which HLA-II:peptide combination(s) are immunogenic based on cohort ELISpot data. We apply BIITE to two ELISpot datasets and explore the expected performance using simulations. We show this method can reach high accuracies, depending on the cohort size and the success rate of the ELISpot assay within the cohort.     

Dengue Outbreak in Mombasa City,Kenya, 2013–2014: Entomologic Investigations

Dengue outbreaks were first reported in East Africa in the late 1970s to early 1980s including the 1982 outbreak on the Kenyan coast. In 2011, dengue outbreaks occurred in Mandera in northern Kenya and subsequently in Mombasa city along the Kenyan coast in 2013–2014. Following laboratory confirmation of dengue fever cases, an entomologic investigation was conducted to establish the mosquito species, and densities, causing the outbreak. Affected parts of the city were identified with the help of public health officials. Adult Ae. aegypti mosquitoes were collected using various tools, processed and screened for dengue virus (DENV) by cell culture and RT-PCR. All containers in every accessible house and compound within affected suburbs were inspected for immatures. A total of 2,065 Ae. aegypti adults were collected and 192 houses and 1,676 containers inspected. An overall house index of 22%, container index, 31.0% (indoor = 19; outdoor = 43) and Breteau index, 270.1, were observed, suggesting that the risk of dengue transmission was high. Overall, jerry cans were the most productive containers (18%), followed by drums (17%), buckets (16%), tires (14%) and tanks (10%). However, each site had specific most-productive container-types such as tanks (17%) in Kizingo; Drums in Nyali (30%) and Changamwe (33%), plastic basins (35%) in Nyali-B and plastic buckets (81%) in Ganjoni. We recommend that for effective control of the dengue vector in Mombasa city, all container types would be targeted. Measures would include proper covering of water storage containers and eliminating discarded containers outdoors through a public participatory environmental clean-up exercise. Providing reliable piped water to all households would minimize the need for water storage and reduce aquatic habitats. Isolation of DENV from male Ae. aegypti mosquitoes is a first observation in Kenya and provides further evidence that transovarial transmission may have a role in DENV circulation and/or maintenance in the environment.