Biology subjects

Yao, X.

Publications and source records attributed to Yao, X..

8 recordsLinked to original sources

bioRxiv2018

Multi-Center Study of Resectable Lung Lesions by Ultra-Deep Sequencing of Targeted Genes in Plasma Cell-Free DNA to Assess Nodule Malignancy and Detect Lung Cancers

BACKGROUNDEarly detection of lung cancer to allow curative treatment remains challenging. Cell-free circulating tumor DNA (ctDNA) analysis may aid in malignancy assessment and early cancer diagnosis of lung nodules found in screening imagery.\n\nMETHODSThe multi-center clinical study enrolled 192 patients with operable occupying lung diseases. Plasma ctDNA, white blood cell genomic DNA (gDNA) and tumor tissue gDNA of each patient were analyzed by ultra-deep sequencing to an average of 35,000X of the coding regions of 65 lung cancer-related genes.\n\nRESULTSThe cohort consists of a quarter of benign lung diseases and three quarters of cancer patients with all histopathology subtypes. 64% of the cancer patients is at Stage I. Gene mutations detection in tissue gDNA and plasma ctDNA results in a sensitivity of 91% and specificity of 88%. When ctDNA assay was used as the test, the sensitivity was 69% and specificity 96%. As for the lung cancer patients, the assay detected 63%, 83%, 94% and 100%, for Stage I, II, III and IV, respectively. In a linear discriminant analysis, combination of ctDNA, patient age and a panel of serum biomarkers boosted the overall sensitivity to 80% at a specificity of 99%. 29 out of the 65 genes harbored mutations in the lung cancer patients with the largest number found in TP53 (30% plasma and 62% tumor tissue samples) and EGFR (20% and 40%, respectively).\n\nCONCLUSIONPlasma ctDNA was analyzed in lung nodule assessment and early cancer detection while an algorithm combining clinical information enhanced the test performance.

clinical trials↗

bioRxiv2018

Using pan RNA-seq analysis to reveal the ubiquitous existence of 5′ end and 3′ end small RNAs

In this study, we used pan RNA-seq analysis to reveal the ubiquitous existence of 5 end and 3 end small RNAs. 5 and 3 sRNAs alone can be used to annotate mitochondrial with 1-bp resolution and nuclear non-coding genes and identify new steady-state RNAs, which are usually from functional genes. Using 5, 3 and intronic sRNAs, we revealed that the enzymatic dsRNA cleavage and RNAi could involve in the RNA degradation and gene expression regulation of U1 snRNA in human. The further study of 5, 3 and intronic sRNAs help rediscover double-stranded RNA (dsRNA) cleavage, RNA interference (RNAi) and the regulation of gene expression, which challenges the classical theories. In this study, we provided a simple and cost effective way for the annotation of mitochondrial and nuclear non-coding genes and the identification of new steady-state RNAs, particularly long non-coding RNAs (lncRNAs). We also provided a different point of view for cancer and virus, based on the new discoveries of dsRNA cleavage, RNAi and the regulation of gene expression.

bioinformatics↗

bioRxiv2018

The bunyavirus nonstructural protein NSs suppresses plant immunity to facilitate its own transmission by improving vector insect performance

Pandemics of vector-borne human and plant pathogens often rely on the behaviors of their arthropod vectors. Arboviruses, including many bunyaviruses, manipulate vector behavior to accelerate their own transmission to vertebrates, birds, insects, and plants. However, the molecular mechanism underlying this manipulation remains elusive. Here, we report that the non-structural protein NSs of orthotospovirus (order Bunyavirales, family Tospoviridae), is a key viral factor that indirectly modifies vector preference and increases vector performance. NSs suppresses the biosynthesis of volatile monoterpenes, which serve as repellents of the vector Western flower thrips (WFT, Frankliniella occidentalis) instead of using its known silencing suppressor activity. NSs directly interacts with and relocalizes the jasmonate (JA) signaling master regulator MYC2 and its two close homologs, MYC3 and MYC4, to disable JA-mediated activation of terpene synthase genes. The dysfunction of the MYCs subsequently attenuates host defenses, increases the attraction of thrips, and improves thrips fitness. These findings elucidate the molecular mechanism through which a bunyavirus manipulates vector behaviors and therefore facilitate disease transmission. Our results provide important insights into the molecular mechanisms by which tospoviruses NSs counteracts host immunity for pathogen transmission.\n\nAuthor summaryMost bunyaviruses are transmitted by insect vectors, and some of them can modify the behaviors of their arthropod vectors to increase transmission to mammals, birds, and plants. NSs is a non-structural bunyavirus protein with multiple functions that acts as an avirulence determinant and silencing suppressor. In this study, we identified a new function of NSs as a manipulator of vector behavior, independent of its silencing suppressor activity. NSs manipulates jasmonate-mediated immunity against thrips by directly interacting with several homologs of MYC transcription factors, the core regulators of the jasmonate-signaling pathway. This hijacking by NSs enhances thrips preference and performance. Many human- and animal-infecting members of the Bunyaviridales also encode NSs and could manipulate vector behavior to accelerate their own transmission. Therefore, our data support the hypothesis that the NSs protein may play conserved roles among various members of the Bunyaviridales in the modification of vector feeding behavior that evolved as a mechanism to enhance virus transmission.

microbiology↗

bioRxiv2018

Portraits of genetic intra-tumour heterogeneity and subclonal selection across cancer types

Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin and drivers of ITH across cancer types are poorly understood. To address this question, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples, spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions, with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types, and identify cancer type specific subclonal patterns of driver gene mutations, fusions, structural variants and copy-number alterations, as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution, and provide an unprecedented pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.

cancer biology↗

bioRxiv2017

The Early Diagnosis in Lung Cancer by the Detection of Circulating Tumor DNA

BackgroundRemarkable advances for clinical diagnosis and treatment in cancers including lung cancer involve cell-free circulating tumor DNA (ctDNA) detection through next generation sequencing. However, before the sensitivity and specificity of ctDNA detection can be widely recognized, the consistency of mutations in tumor tissue and ctDNA should be evaluated. The urgency of this consistency is extremely obvious in lung cancer to which great attention has been paid to in liquid biopsy field.\n\nMethodsWe have developed an approach named systematic error correction sequencing (Sec-Seq) to improve the evaluation of sequence alterations in circulating cell-free DNA. Averagely 10 ml preoperative blood samples were collected from 30 patients containing pulmonary space occupying pathological changes by traditional clinic diagnosis. cfDNA from plasma, genomic DNA from white blood cells, and genomic DNA from solid tumor of above patients were extracted and constructed as libraries for each sample before subjected to sequencing by a panel contains 50 cancer-associated genes encompassing 29 kb by custom probe hybridization capture with average depth >40000, 7000, or 6300 folds respectively.\n\nResultsDetection limit for mutant allele frequency in our study was 0.1%. The sequencing results were analyzed by bioinformatic expertise based on our previous studies on the baseline mutation profiling of circulating cell-free DNA and the clinicopathological data of these patients. Among all the lung cancer patients, 78% patients were predicted as positive by ctDNA sequencing when the shreshold was defined as at least one of the hotspot mutations detected in the blood (ctDNA) was also detected in tumor tissue. Pneumonia and pulmonary tuberculosis were detected as negative according to the above standard. When evaluating all hotspots in driver genes in the panel, 24% mutations detected in tumor tissue (tDNA) were also detected in patients blood (ctDNA). When evaluating all genetic variations in the panel, including all the driver genes and passenger genes, 28% detected in tumor tissue (tDNA) were also detected in patients blood (ctDNA). Positive detection rates of plasma ctDNA in stage I lung cancer patients is 85%, compared with 17% of tumor biomarkers.\n\nConclusionWe demonstrated the importance of sequencing both circulating cell-free DNA and genomic DNA in tumor tissue for ctDNA detection in lung cancer currently. We also determined and confirmed the consistency of ctDNA and tumor tissue through NGS according to the criteria explored in our studies. Our strategy can initially distinguish the lung cancer from benign lesions of lung. Our work shows that the consistency will be benefited from the optimization in sensitivity and specificity in ctDNA detection.

cancer biology↗

bioRxiv2017

Selective and mechanistic sources of recurrent rearrangements across the cancer genome

Cancer cells can acquire profound alterations to the structure of their genomes, including rearrangements that fuse distant DNA breakpoints. We analyze the distribution of somatic rearrangements across the cancer genome, using whole-genome sequencing data from 2,693 tumor-normal pairs. We observe substantial variation in the density of rearrangement breakpoints, with enrichment in open chromatin and sites with high densities of repetitive elements. After accounting for these patterns, we identify significantly recurrent breakpoints (SRBs) at 52 loci, including novel SRBs near BRD4 and AKR1C3. Taking into account both loci fused by a rearrangement, we observe different signatures resembling either single breaks followed by strand invasion or two separate breaks that become joined. Accounting for these signatures, we identify 90 pairs of loci that are significantly recurrently juxtaposed (SRJs). SRJs are primarily tumor-type specific and tend to involve genes with tissue-specific expression. SRJs were frequently associated with disruption of topology-associated domains, juxtaposition of enhancer elements, and increased expression of neighboring genes. Lastly, we find that the power to detect SRJs decreases for short rearrangements, and that reliable detection of all driver SRJs will require whole-genome sequencing data from an order of magnitude more cancer samples than currently available.

cancer biology↗

bioRxiv2017

The evolutionary history of 2,658 cancers

Cancer develops through a process of somatic evolution. Here, we use whole-genome sequencing of 2,778 tumour samples from 2,658 donors to reconstruct the life history, evolution of mutational processes, and driver mutation sequences of 39 cancer types. The early phases of oncogenesis are driven by point mutations in a small set of driver genes, often including biallelic inactivation of tumour suppressors. Early oncogenesis is also characterised by specific copy number gains, such as trisomy 7 in glioblastoma or isochromosome 17q in medulloblastoma. By contrast, increased genomic instability, a nearly four-fold diversification of driver genes, and an acceleration of point mutation processes are features of later stages. Copy-number alterations often occur in mitotic crises leading to simultaneous gains of multiple chromosomal segments. Timing analysis suggests that driver mutations often precede diagnosis by many years, and in some cases decades, providing a window of opportunity for early cancer detection.

cancer biology↗

bioRxiv2017

Genome-wide detection of structural variants and indels by local assembly

Structural variants (SVs), including small insertion and deletion variants (indels), are challenging to detect through standard alignment-based variant calling methods. Sequence assembly offers a powerful approach to identifying SVs, but is difficult to apply at-scale genome-wide for SV detection due to its computational complexity and the difficulty of extracting SVs from assembly contigs. We describe SvABA, an efficient and accurate method for detecting SVs from short-read sequencing data using genome-wide local assembly with low memory and computing requirements. We evaluated SvABAs performance on the NA12878 human genome and in simulated and real cancer genomes. SvABA demonstrates superior sensitivity and specificity across a large spectrum of SVs, and substantially improved detection performance for variants in the 20-300 bp range, compared with existing methods. SvABA also identifies complex somatic rearrangements with chains of short (< 1,000 bp) templated-sequence insertions copied from distant genomic regions. We applied SvABA to 344 cancer genomes from 11 cancer types, and found that templated-sequence insertions occur in ~4% of all somatic rearrangements. Finally, we demonstrate that SvABA can identify sites of viral integration and cancer driver alterations containing medium-sized SVs.

genomics↗