Spatiotemporal genomic analysis reveals distinct molecular features in recurrent stage I non-small cell lung cancers

Stage I non-small cell lung cancer (NSCLC) presents diverse outcomes. To identify molecular features leading to tumor recurrence in early-stage NSCLC, we perform multiregional whole-exome sequencing (WES), RNA sequencing, and plasma-targeted circulating tumor DNA (ctDNA) detection analysis between recurrent and recurrent-free stage I NSCLC patients (CHN-P cohort) who had undergone R0 resection with a median 5-year follow-up time. Integrated analysis indicates that the multidimensional clinical and genomic model can stratify the prognosis of stage I NSCLC in both CHN-P and EUR-T cohorts and correlates with positive pre-surgical deep next generation sequencing (NGS) ctDNA detection. Increased genomic instability related to DNA interstrand crosslinks and double-strand break repair processes is significantly associated with early tumor relapse. This study reveals important molecular insights into stage I NSCLC and may inform clinical postoperative treatment and follow-up strategies

Phylogeny of C₄-Photosynthesis Enzymes Based on Algal Transcriptomic and Genomic Data Supports an Archaeal/Proteobacterial Origin and Multiple Duplication for Most C₄-Related Genes

<div><p>Both Calvin-Benson-Bassham (C₃) and Hatch-Slack (C₄) cycles are most important autotrophic CO₂ fixation pathways on today’s Earth. C₃ cycle is believed to be originated from cyanobacterial endosymbiosis. However, studies on evolution of different biochemical variants of C₄ photosynthesis are limited to tracheophytes and origins of C₄-cycle genes are not clear till now. Our comprehensive analyses on bioinformatics and phylogenetics of novel transcriptomic sequencing data of 21 rhodophytes and 19 Phaeophyceae marine species and public genomic data of more algae, tracheophytes, cyanobacteria, proteobacteria and archaea revealed the origin and evolution of C₄ cycle-related genes. Almost all of C₄-related genes were annotated in extensive algal lineages with proteobacterial or archaeal origins, except for phosphoenolpyruvate carboxykinase (<i>PCK</i>) and aspartate aminotransferase (<i>AST</i>) with both cyanobacterial and archaeal/proteobacterial origin. Notably, cyanobacteria may not possess complete C₄ pathway because of the flawed annotation of pyruvate orthophosphate dikinase (<i>PPDK</i>) genes in public data. Most C₄ cycle-related genes endured duplication and gave rise to functional differentiation and adaptation in different algal lineages. C₄-related genes of NAD-ME (NAD-malic enzyme) and PCK subtypes exist in most algae and may be primitive ones, while NADP-ME (NADP-malic enzyme) subtype genes might evolve from NAD-ME subtype by gene duplication in chlorophytes and tracheophytes.</p></div

Bayesian phylogenetic trees of PEPC (A) PPDK (B), ALT (C) and PK (D) enzymes with bootstrap values (when >50%) indicated at the nodes.

<p>The PEPCs are classified as PTPCs (in dark gray boxes) and BTPCs (in light gray boxes). ChlP, chlorophytes and plants. Gla, glaucophytes. Rho, rhodophytes. Och, ochrophytes. Cry, cryptophytes. Tri, trichomonad. Amo, amoeba. Cil, ciliates.</p

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Alignments of partial amino acid sequences of PEPC isoenzymes between species of Rhodophyta, Ochrophyta, chlorophytes, Cryptophta, bacteria and archaea.

<p>The deduced PEPC sequences were aligned using ClustalX 1.83 software. Numbering indicates the position of the first and last residue in each aligned sequence. Semi-colons and asterisks indicate identical and conserved amino acids respectively. The C-terminal tetrapeptide (R/K)NTG for BTPCs is highlighted in blue color, whereas QNTG for PTPCs is highlighted in orange. The amino acid residue of No. 774 or around it is highlighted in green (non-photosynthetic PEPCs) or red (C4-type PEPCs).</p

Partial sequence alignment of the N-terminal domains of PEPS and PPDK enzymes.

<p>Numbering indicates the position of the first and last residue in each aligned sequence. Proteins with biochemically confirmed enzyme activity are indicated by gray shading. Grey shading indicate the identified sequence signatures specific for PEPS and PPDK respectively.</p

Plasma cell-free DNA 5-hydroxymethylcytosine and whole-genome sequencing signatures for early detection of esophageal cancer

Abstract Esophageal cancer is a highly incidence and deadly disease with a poor prognosis, especially in developing countries. Owing to the lack of specific symptoms and early diagnostic biomarkers, most patients are diagnosed with advanced disease, leading to a 5-year survival rate of less than 15%. Early (n = 50) and middle-advanced (n = 50) esophageal squamous cell carcinoma (ESCC) patients, as well as 71 healthy individuals, underwent 5-hydroxymethylcytosine (5hmC) sequencing on their plasma cell-free DNA (cfDNA). A Northern Chinese cohort of cfDNA 5hmC dataset of 150 ESCC patients and 183 healthy individuals were downloaded for validation. A diagnostic model was developed using cfDNA 5hmC signatures and then improved by low-pass whole genome sequencing (WGS) features of cfDNA. Conserved cfDNA 5hmC modification motifs were observed in the two independent ESCC cohorts. The diagnostic model with 5hmC features achieved an AUC of 0.810 and 0.862 in the Southern and Northern cohorts, respectively, with sensitivities of 69.3–74.3% and specificities of 82.4–90.7%. The performance was well maintained in Stage I to Stage IV, with accuracy of 70–100%, but low in Stage 0, 33.3%. Low-pass WGS of cfDNA improved the AUC to 0.934 with a sensitivity of 82.4%, a specificity of 88.2%, and an accuracy of 84.3%, particularly significantly in Stage 0, with an accuracy up to 80%. 5hmC and WGS could efficiently differentiate very early ESCC from healthy individuals. These findings imply a non-invasive and convenient method for ESCC detection when clinical treatments are available and may eventually prolong survival