Disentangling oncogenic amplicons in esophageal adenocarcinoma.

Esophageal adenocarcinoma is a prominent example of cancer characterized by frequent amplifications in oncogenes. However, the mechanisms leading to amplicons that involve breakage-fusion-bridge cycles and extrachromosomal DNA are poorly understood. Here, we use 710 esophageal adenocarcinoma cases with matched samples and patient-derived organoids to disentangle complex amplicons and their associated mechanisms.

Preferential hypermethylation in SDH-deficient wild-type GIST.

Aims: Wild-type gastrointestinal stromal tumours (wtGIST) are frequently caused by inherited pathogenic variants, or somatic alterations in the succinate dehydrogenase subunit genes (). Succinate dehydrogenase is a key enzyme in the citric acid cycle. SDH deficiency caused by inactivation leads to an accumulation of succinate, which inhibits DNA and histone demethylase enzymes, resulting in global hypermethylation.

Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells.

Cellular DNA damage caused by reactive oxygen species is repaired by the base excision repair (BER) pathway which includes the DNA glycosylase MUTYH. Inherited biallelic MUTYH mutations cause predisposition to colorectal adenomas and carcinoma. However, the mechanistic progression from germline MUTYH mutations to MUTYH-Associated Polyposis (MAP) is incompletely understood.

Breast cancer in multiple endocrine neoplasia type 1 (MEN1).

Summary: A 38-year-old female was identified as carrying a heterozygous pathogenic MEN1 variant (c.1304delG) through predictive genetic testing, following a diagnosis of familial hyperparathyroidism. Routine screening for parathyroid and pituitary disease was negative.

A Diffusion-like Process Accommodates New Crypts During Clonal Expansion in Human Colonic Epithelium.

Background & Aims: Colorectal cancer (CRC) is thought to arise when the cumulative mutational burden within colonic crypts exceeds a certain threshold that leads to clonal expansion and ultimately neoplastic transformation. Therefore, quantification of the fixation and subsequent expansion of somatic mutations in normal epithelium is key to understanding colorectal cancer initiation. The aim of the present study was to determine how advantaged expansions can be accommodated in the human colon.

The role of [ Ga]Ga-DOTATATE PET/CT in wild-type KIT/PDGFRA gastrointestinal stromal tumours (GIST).

Background: [ Ga]Ga-DOTATATE PET/CT is now recognised as the most sensitive functional imaging modality for the diagnosis of well-differentiated neuroendocrine tumours (NET) and can inform treatment with peptide receptor radionuclide therapy with [Lu]Lu-DOTATATE. However, somatostatin receptor (SSTR) expression is not unique to NET, and therefore, [ Ga]Ga-DOTATATE PET/CT may have oncological application in other tumours. Molecular profiling of gastrointestinal stromal tumours that lack activating somatic mutations in KIT or PDGFRA or so-called 'wild-type' GIST (wtGIST) has demonstrated that wtGIST and NET have overlapping molecular features and has encouraged exploration of shared therapeutic targets, due to a lack of effective therapies currently available for metastatic wtGIST.

Next-generation sequencing demonstrates the rarity of short kinase variants specific to quadruple wild-type gastrointestinal stromal tumours.

Aim: There is no known specific biomarker or genetic signal for quadruple wild-type (qWT) gastrointestinal stromal tumours (GISTs). By next-generation sequencing (NGS) of different GIST subgroups, this study aimed to characterise such a biomarker especially as a potential therapeutic target.

Methods And Results: An NGS panel of 672 kinase genes was applied to DNA extracted from 11 wild-type GISTs (including three qWT GISTs) and 5 mutated GISTs.

SDHC epi-mutation testing in gastrointestinal stromal tumours and related tumours in clinical practice.

The enzyme succinate dehydrogenase (SDH) functions in the citric acid cycle and loss of function predisposes to the development of phaeochromocytoma/paraganglioma (PPGL), wild type gastrointestinal stromal tumour (wtGIST) and renal cell carcinoma. SDH-deficient tumours are most commonly associated with a germline SDH subunit gene (SDHA/B/C/D) mutation but can also be associated with epigenetic silencing of the SDHC gene. However, clinical diagnostic testing for an SDHC epimutation is not widely available.

Translating metabolomic analysis of succinate dehydrogenase deficient tumours into clinical utility.

Purpose: Mutations in the mitochondrial enzyme succinate dehydrogenase (SDH) subunit genes are associated with a wide spectrum of tumours including phaeochromocytoma and paraganglioma (PPGL) 1, 2, gastrointestinal stromal tumours (GIST) 3, renal cell carcinoma (RCC) 4 and pituitary adenomas5. SDH-related tumorigenesis is believed to be secondary to accumulation of the oncometabolite succinate. Our aim was to investigate the potential clinical applications of MRI spectroscopy (H-MRS) in a range of suspected SDH-related tumours.

Correction: Metabolite quantification of faecal extracts from colorectal cancer patients and healthy controls.

[This corrects the article DOI: 10.18632/oncotarget.26022.

Metabolite quantification of faecal extracts from colorectal cancer patients and healthy controls.

Colorectal cancer (CRC), a primary cause of morbidity and mortality worldwide is expected to rise in the coming years. A better understanding of the metabolic changes taking place during the disease progression is needed for effective improvements of screening strategies and treatments. In the present study, Nuclear Magnetic Resonance (NMR) metabolomics was used to quantify the absolute concentrations of metabolites in faecal extracts from two cohorts of CRC patients and healthy controls.

Fixation and Spread of Somatic Mutations in Adult Human Colonic Epithelium.

We investigated the means and timing by which mutations become fixed in the human colonic epithelium by visualizing somatic clones and mathematical inference. Fixation requires two sequential steps. First, one of approximately seven active stem cells residing within each colonic crypt has to be mutated.

5-hydroxymethylcytosine marks promoters in colon that resist DNA hypermethylation in cancer.

Background: The discovery of cytosine hydroxymethylation (5hmC) as a mechanism that potentially controls DNA methylation changes typical of neoplasia prompted us to investigate its behaviour in colon cancer. 5hmC is globally reduced in proliferating cells such as colon tumours and the gut crypt progenitors, from which tumours can arise.

Results: Here, we show that colorectal tumours and cancer cells express Ten-Eleven-Translocation (TET) transcripts at levels similar to normal tissues.

Spindle pole body history intrinsically links pole identity with asymmetric fate in budding yeast.

Background: Budding yeast is a unique model for exploring differential fate in a cell dividing asymmetrically. In yeast, spindle orientation begins with the old spindle pole body (SPB) (from the preceding cell cycle) contacting the bud by its existing astral microtubules (aMTs) while the new pole delays astral microtubule organization. This appears to prime the inheritance of the old pole by the bud.

Mechanism for astral microtubule capture by cortical Bud6p priming spindle polarity in S. cerevisiae.

Background: Budding yeast is a unique model to dissect spindle orientation in a cell dividing asymmetrically. In yeast, this process begins with the capture of pole-derived astral microtubules (MTs) by the polarity determinant Bud6p at the cortex of the bud in G(1). Bud6p couples MT growth and shrinkage with spindle pole movement relative to the contact site.

Ase1p phosphorylation by cyclin-dependent kinase promotes correct spindle assembly in S. cerevisiae.

Spindle morphogenesis and dynamics follow an orderly sequence of events coupled to the oscillatory activation of cyclin-dependent kinase (CDK). Using S. cerevisiae, we have addressed the requirement of CDK for phosphorylation of the spindle midzone component Ase1p and its significance to spindle assembly.

Actin-mediated delivery of astral microtubules instructs Kar9p asymmetric loading to the bud-ward spindle pole.

In Saccharomyces cerevisiae, Kar9p, one player in spindle alignment, guides the bud-ward spindle pole by linking astral microtubule plus ends to Myo2p-based transport along actin cables generated by the formins Bni1p and Bnr1p and the polarity determinant Bud6p. Initially, Kar9p labels both poles but progressively singles out the bud-ward pole. Here, we show that this polarization requires cell polarity determinants, actin cables, and microtubules.

Transient CENP-E-like kinetochore proteins in plants.

Derived from candidate sequences of a barley EST database two proteins with homology to the coiled coil region of the human kinetochore protein (KP) CENP-E were generated and classified as centromere protein E-like 1 and 2 (Cpell and Cpe12). Specific antibodies produced against recombinant Cpe11 and Cpe12 proteins labeled the centromere on mitotic chromosomes of barley and field bean and recognized specifically proteins from nuclear/chromosomal protein extracts on immunoblots. No function was predicted for homologues of Cpe11 within the databases for Arabidopsis and rice genomes.