Driver Fusions and Their Implications in the Development and Treatment of Human Cancers.

Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy

Perspective on Oncogenic Processes at the End of the Beginning of Cancer Genomics

The Cancer Genome Atlas (TCGA) has catalyzed systematic characterization of diverse genomic alterations underlying human cancers. At this historic junction marking the completion of genomic characterization of over 11,000 tumors from 33 cancer types, we present our current understanding of the molecular processes governing oncogenesis. We illustrate our insights into cancer through synthesis of the findings of the TCGA PanCancer Atlas project on three facets of oncogenesis: (1) somatic driver mutations, germline pathogenic variants, and their interactions in the tumor; (2) the influence of the tumor genome and epigenome on transcriptome and proteome; and (3) the relationship between tumor and the microenvironment, including implications for drugs targeting driver events and immunotherapies. These results will anchor future characterization of rare and common tumor types, primary and relapsed tumors, and cancers across ancestry groups and will guide the deployment of clinical genomic sequencing

Pathogenic Germline Variants in 10,389 Adult Cancers

We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer. A pan-cancer analysis identifies hundreds of predisposing germline variants

Study on locations for future coal-fired power plants

Evaluation of suitable sites for coal-fired thermal power plants is very important as there are several such plants to come up in the future. All generating plants except Upper Kotmale Hydro Power plant in "Long Term Generation Expansion Plan 2009-2022" published by the CEB are coal power plants. Two locations already have been identified for coal power plants at Norochcholei and Sampur for 900MW and 1000MW respectively. The study reveals that there is no provision to expand beyond the designed capacity at Norochcholei plant. There is no technical limitation to expand the designed capacity at Sampur plant. The aim of this study is to evaluate a further eight proposed sites analyzing following important factors which influence site suitability. These factors are; 1 Supply of coal and transportation facilities on land and at sea 2 Availability of sufficient cooling water and feed water 3 Proximity to the load centers / access to the national grid 4 Distance from populated area (Environmental aspects including impact on the population) 5 Depth of the sea near the coast 6 Availability of sufficient area for power plant, coal storage and ash disposal 7 Other factors 7.1 Access to the land 7.2 Topography/ geology 7.3 Meteorology 7.4 Hydrogeology 7.5 Natural hazards Of the eight sites to be evaluated the CEB has identified five tentative locations in its "Long Term Generation Expansion Plan 2009-2022" near Athuruwella, Mawella, Mirijjawela, Karagan Lewaya, and Mirissa along the southern coast. No detailed study has been done for these locations. Hence, initially, these five locations were taken into consideration for the study from among the eight proposed sites. Three additional locations are proposed by the author for consideration along the eastern coast. They are near Panama, Sangamankanda Point and Vakarei. Although CEB proposed Karagan Lewaya to be considered as a site it had to be abandoned subsequently because the GOSL has used this site for the recently commissioned Hambantota harbor. As a result of that the study is carried out based on the other seven proposed sites for detailed evaluation. Sri Lanka has no coal mines, thus coal needs to be imported to the sites from countries such as Indonesia, South Africa or Australia who have indigenous coal mines. Hence coal transporting has to be done by vessels to the site especially with Panamax size vessels and Cape size vessels to keep the cost at a minimum level. Another major factor is the supply sufficient water to the site in order to cool the process and process water. These two factors require that the site has to be close to the coast. It can be seen that the four sites Athuruwella, Mawella, Mirissa and Mirijjawela on the southern coast are close to the populated areas and the lands in the vicinity are ideal for agriculture as well as tourism. Some major resettlement plans are required with a suitable compensation scheme when acquiring the lands for the sites at these four locations in the southern province. In contrast, however, the population density at Panama, Sangamankanda Point and Vakarei in the eastern province is comparatively low but the infrastructure needs to be developed. The grid substations at Ambalangoda, Matara, Hambantota, Ampara and Valachchena are considered as gateways to the national grid from the proposed locations. These can access only the 132kV grid and needs to be augmented to handle 220kV at the substation andtransmission lines. Other major factor to be considered is the depth of the sea near the proposed site as this determines how far the vessels can approach the coast and hence estimates the distance of the coal unloading conveyor and the size of the jetty in the sea. Mirijjawela has the advantage of having use of the newly commissioned Hambantota harbor for this purpose as it is about 1 km away from the site. Acquiring of required land area for the proposed site needs to be carefully done. When it is needed to acquire the lands from the residents in the area a reasonable compensation scheme and resettlement plan has to be introduced. Therefore it is of great benefit and cost saving if government owned bare land is available in the proposed areas. Although access to the lands, topography/ geology, meteorology, hydrogeology, natural hazards are minor factors for site selection of a coal power plant, these should also be taken into consideration because the damages can be very high when natural hazards occur like the Tsunami in 2004, although this occurs rarely. The proposed locations should be selected away from any protected wildlife zones, sanctuaries and places with historical values in the country. Then proposed locations are analyzed based on the above factors and for comparison a site validation matrix is prepared with introducing a suitable marking scheme in order to select the best location for the next coal power generation plant

Direct writing of lead zirconate titanate piezoelectric structures by electrohydrodynamic atomisation.

Direct writing, consisting of the directed deposition of individual droplets of ceramic suspension using ink jet printing can be used to produce piezoelectric structures with feature sizes in excess of 100 μm. This work presents an alternative direct writing technique, consisting of directed individual droplets produced by electrohydrodynamic atomisation (EHDA), where feature sizes an order of magnitude smaller can be achieved. This technique opens up the possibility of using direct writing technology to produce integrated MEMS devices. Low toxicity lead zirconate titantate (PZT) sol has been used in conjunction with the EHDA process to produce isolated features and lines with dimensions as small as 20 μm. These features, when fired, form the perovskite PZT crystal structure. Using an X–Y stage to move the sample, it is possible to create a variety of struct