Clinical Utility of Tumor-Naïve Presurgical Circulating Tumor DNA Detection in Early-Stage NSCLC.

Objectives: The use of tumor-informed circulating tumor DNA (ctDNA) testing in patients with early-stage disease before surgery is limited, mainly owing to restricted tissue access and extended turnaround times. This study aimed to evaluate the clinical value of a tumor-naïve, methylation-based cell-free DNA assay in a large cohort of patients with resected NSCLC.

Method: We analyzed presurgical plasma samples from 895 patients with EGFR and anaplastic lymphoma kinase-wild-type, clinical stage I or II NSCLC.

Prognostic implication of methylation-based circulating tumor DNA detection prior to surgery in stage I non-small cell lung cancer.

Background: Circulating tumor DNA (ctDNA) positivity at diagnosis, which is associated with worse outcomes in multiple solid tumors including stage I-III non-small cell lung cancer (NSCLC), may have utility to guide (neo)adjuvant therapy.

Methods: In this retrospective study, 260 patients with clinical stage I NSCLC (180 adenocarcinoma, 80 squamous cell carcinoma) were allocated (2:1) to high- and low-risk groups based on relapse versus disease-free status ≤5 years post-surgery. We evaluated the association of preoperative ctDNA detection by a plasma-only targeted methylation-based multi-cancer early detection (MCED) test with NSCLC relapse ≤5 years post-surgery in the overall population, followed by histology-specific subgroup analyses.

Pre- and post-treatment blood-based genomic landscape of patients with ROS1 or NTRK fusion-positive solid tumours treated with entrectinib.

Genomic tumour profiling informs targeted treatment options. Entrectinib is a tyrosine kinase inhibitor with efficacy in NTRK fusion-positive (-fp) solid tumours and ROS1-fp non-small cell lung cancer. FoundationOne® Liquid CDx (F1L CDx), a non-invasive in vitro next-generation sequencing (NGS)-based diagnostic, detects genomic alterations in plasma circulating tumour DNA (ctDNA).

Periodontitis and diabetes mellitus co-morbidity: A molecular dialogue.

Background: Type 2 diabetes mellitus (T2DM) and periodontitis are two biologically linked diseases that often coexist in complex interaction. While periodontitis may lead to insulin receptor desensitization, diabetes may increase the expression of inflammatory cytokines, such as Tumor Necrosis Factor-α (TNF-α) and Interleukin 6 (IL-6), in the gingival crevicular fluid and activate osteoclasts via Receptor activator of nuclear factor kappa-Β ligand (RANK-L) production, leading to bone resorption. However, the association between the two diseases processes, where one may exacerbate the progression of the other, is unclear.

Establishing community reference samples, data and call sets for benchmarking cancer mutation detection using whole-genome sequencing.

The lack of samples for generating standardized DNA datasets for setting up a sequencing pipeline or benchmarking the performance of different algorithms limits the implementation and uptake of cancer genomics. Here, we describe reference call sets obtained from paired tumor-normal genomic DNA (gDNA) samples derived from a breast cancer cell line-which is highly heterogeneous, with an aneuploid genome, and enriched in somatic alterations-and a matched lymphoblastoid cell line. We partially validated both somatic mutations and germline variants in these call sets via whole-exome sequencing (WES) with different sequencing platforms and targeted sequencing with >2,000-fold coverage, spanning 82% of genomic regions with high confidence.

Toward best practice in cancer mutation detection with whole-genome and whole-exome sequencing.

Clinical applications of precision oncology require accurate tests that can distinguish true cancer-specific mutations from errors introduced at each step of next-generation sequencing (NGS). To date, no bulk sequencing study has addressed the effects of cross-site reproducibility, nor the biological, technical and computational factors that influence variant identification. Here we report a systematic interrogation of somatic mutations in paired tumor-normal cell lines to identify factors affecting detection reproducibility and accuracy at six different centers.

Let Nature Take Its Course: Cultural Adaptation and Pilot Test of Taoist Cognitive Therapy for Chinese American Immigrants With Generalized Anxiety Disorder.

This report describes initial results from a multi-stage project to manualize and adapt an indigenous therapy, Chinese Taoist Cognitive Psychotherapy (CTCP), for dissemination in the United States context. Study aims were to (a) integrate cultural adaptation and implementation science frameworks to manualize and adapt the original intervention and (b) explore the feasibility, acceptability, and effectiveness of the modified intervention, renamed Taoist Cognitive Therapy (TCT), in a sample of Chinese immigrants with generalized anxiety disorder (GAD). Incorporating bottom-up and top-down adaptation approaches, we involved Chinese American clinician stakeholders and experts in Taoist philosophy, cognitive-behavioral therapy, and GAD to help identify cultural and contextual barriers and solutions to enhance treatment acceptability and implementation.

An inducible long noncoding RNA amplifies DNA damage signaling.

Long noncoding RNAs (lncRNAs) are prevalent genes with frequently precise regulation but mostly unknown functions. Here we demonstrate that lncRNAs guide the organismal DNA damage response. DNA damage activated transcription of the DINO (Damage Induced Noncoding) lncRNA via p53.

Extensive and coordinated transcription of noncoding RNAs within cell-cycle promoters.

Transcription of long noncoding RNAs (lncRNAs) within gene regulatory elements can modulate gene activity in response to external stimuli, but the scope and functions of such activity are not known. Here we use an ultrahigh-density array that tiles the promoters of 56 cell-cycle genes to interrogate 108 samples representing diverse perturbations. We identify 216 transcribed regions that encode putative lncRNAs, many with RT-PCR-validated periodic expression during the cell cycle, show altered expression in human cancers and are regulated in expression by specific oncogenic stimuli, stem cell differentiation or DNA damage.

Long noncoding RNA in genome regulation: prospects and mechanisms.

Long noncoding RNAs (lncRNAs) are pervasively transcribed and critical regulators of the epigenome[1, 2]. These long, polyadenylated RNAs do not code for proteins, but function directly as RNAs, recruiting chromatin modifiers to mediate transcriptional changes in processes ranging from X-inactivation (XIST) to imprinting (H19)[3]. The recent discovery that lncRNA HOTAIR can link chromatin changes to cancer metastasis[4] furthers the relevance of lncRNAs to human disease.

Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis.

Large intervening non-coding RNAs (lincRNAs) are pervasively transcribed in the genome yet their potential involvement in human disease is not well understood. Recent studies of dosage compensation, imprinting, and homeotic gene expression suggest that individual lincRNAs can function as the interface between DNA and specific chromatin remodelling activities. Here we show that lincRNAs in the HOX loci become systematically dysregulated during breast cancer progression.

HBO1 HAT complexes target chromatin throughout gene coding regions via multiple PHD finger interactions with histone H3 tail.

The HBO1 HAT protein is the major source of histone H4 acetylation in vivo and has been shown to play critical roles in gene regulation and DNA replication. A distinctive characteristic of HBO1 HAT complexes is the presence of three PHD finger domains in two different subunits: tumor suppressor proteins ING4/5 and JADE1/2/3. Biochemical and functional analyses indicate that these domains interact with histone H3 N-terminal tail region, but with a different specificity toward its methylation status.

ING4 mediates crosstalk between histone H3 K4 trimethylation and H3 acetylation to attenuate cellular transformation.

Aberrations in chromatin dynamics play a fundamental role in tumorigenesis, yet relatively little is known of the molecular mechanisms linking histone lysine methylation to neoplastic disease. ING4 (Inhibitor of Growth 4) is a native subunit of an HBO1 histone acetyltransferase (HAT) complex and a tumor suppressor protein. Here we show a critical role for specific recognition of histone H3 trimethylated at lysine 4 (H3K4me3) by the ING4 PHD finger in mediating ING4 gene expression and tumor suppressor functions.

ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression.

Dynamic regulation of diverse nuclear processes is intimately linked to covalent modifications of chromatin. Much attention has focused on methylation at lysine 4 of histone H3 (H3K4), owing to its association with euchromatic genomic regions. H3K4 can be mono-, di- or tri-methylated.