Pathway-based Analysis of the Hidden Genetic Heterogeneities in Cancers

Many cancers apparently showing similar phenotypes are actually distinct at the molecular level, leading to very different responses to the same treatment. It has been recently demonstrated that pathway-based approaches are robust and reliable for genetic analysis of cancers. Nevertheless, it remains unclear whether such function-based approaches are useful in deciphering molecular heterogeneities in cancers. Therefore, we aimed to test this possibility in the present study. First, we used a NCI60 dataset to validate the ability of pathways to correctly partition samples. Next, we applied the proposed method to identify the hidden subtypes in diffuse large B-cell lymphoma (DLBCL). Finally, the clinical significance of the identified subtypes was verified using survival analysis. For the NCI60 dataset, we achieved highly accurate partitions that best fit the clinical cancer phenotypes. Subsequently, for a DLBCL dataset, we identified three hidden subtypes that showed very different 10-year overall survival rates (90%, 46% and 20%) and were highly significantly (P = 0.008) correlated with the clinical survival rate. This study demonstrated that the pathway-based approach is promising for unveiling genetic heterogeneities in complex human diseases

Genomic Scan Reveals Loci under Altitude Adaptation in Tibetan and Dahe Pigs

<div><p>High altitude environments are of particular interest in the studies of local adaptation as well as their implications in physiology and clinical medicine in human. Some Chinese pig breeds, such as Tibetan pig (TBP) that is well adapted to the high altitude and Dahe pig (DHP) that dwells at the moderate altitude, provide ideal materials to study local adaptation to altitudes. Yet, it is still short of in-depth analysis and understanding of the genetic adaptation to high altitude in the two pig populations. In this study we conducted a genomic scan for selective sweeps using <i>F_ST</i> to identify genes showing evidence of local adaptations in TBP and DHP, with Wuzhishan pig (WZSP) as the low-altitude reference. Totally, we identified 12 specific selective genes (<i>CCBE1, F2RL1, AGGF1, ZFPM2, IL2, FGF5, PLA2G4A, ADAMTS9, NRBF2, JMJD1C</i>, <i>VEGFC</i> and <i>ADAM19</i>) for TBP and six (<i>OGG1</i>, <i>FOXM</i>, <i>FLT3</i>, <i>RTEL1</i>, <i>CRELD1</i> and <i>RHOG</i>) for DHP. In addition, six selective genes (<i>VPS13A</i>, <i>GNA14, GDAP1, PARP8, FGF10 and ADAMTS16</i>) were shared by the two pig breeds. Among these selective genes, three (<i>VEGFC</i>, <i>FGF10</i> and <i>ADAMTS9</i>) were previously reported to be linked to the local adaptation to high altitudes in pigs, while many others were newly identified by this study. Further bioinformatics analysis demonstrated that majority of these selective signatures have some biological functions relevant to the altitude adaptation, for examples, response to hypoxia, development of blood vessels, DNA repair and several hematological involvements. These results suggest that the local adaptation to high altitude environments is sophisticated, involving numerous genes and multiple biological processes, and the shared selective signatures by the two pig breeds may provide an effective avenue to identify the common adaptive mechanisms to different altitudes.</p></div

Functional enrichment analysis of genes within the selected regions identified in comparison of TBP and WZSP.

<p>Notes: GO term, subcategory of biological process.</p><p>Functional enrichment analysis of genes within the selected regions identified in comparison of TBP and WZSP.</p

Genomic <i>F_ST</i> distribution of selective signatures identified in comparison of TBP and WZSP.

<p>Red dots represent significant sites (<i>F_ST</i>≥0.362, and <i>P_E</i>≤0.01, data not shown) within selected regions containing adaptive genes.</p

Summary of shared selective sweeps.

<p>Summary of shared selective sweeps.</p

Genomic distribution of signatures of selection identified in comparison of DHP and WZSP.

<p>Red dots represent significant sites (<i>F_ST</i>≥0.450, and <i>P_E</i>≤0.01, data not shown) within selected regions containing adaptive genes.</p

Functional enrichment analysis of genes within selected regions identified in comparison of DHP and WZSP.

<p>Notes: GO term, subcategory of biological process.</p><p>Functional enrichment analysis of genes within selected regions identified in comparison of DHP and WZSP.</p

Principle component analysis of TBP, DHP and WZSP individuals.

<p>TBP, Tibetan pig; DHP, Dahe pig; WZSP, Wuzhishan pig.</p