The Role of Epigenetic Modification in Tumorigenesis and Progression of Pituitary Adenomas: A Systematic Review of the Literature

<div><p>Background</p><p>Pituitary adenomas (PAs) are commonly occurring neoplasms with diverse endocrine and neurological effects. Although somatic gene mutations are uncommon in sporadic PAs, recent studies lend support to epigenetic modification as a potential cause of tumorigenesis and tumor progression.</p> <p>Methods</p><p>A systematic literature review of the PubMed and Google Scholar databases was conducted to identify abstracts (n=1,082) pertaining to key targets and mechanisms implicated in epigenetic dysregulation of PAs published between 1993-2013. Data regarding histopathological subtype, target genes, mode of epigenetic modification, and clinical correlation were recorded and analyzed.</p> <p>Results</p><p>Of the 47 that studies met inclusion criteria and focused on epigenomic assessment of PAs, only 2 were genome-scale analyses. Current evidence supports epigenetic alteration in at least 24 PA genes, which were categorized into four groups based on function and epigenetic alteration: 1) Sixteen tumor suppressor genes silenced via DNA methylation; 2) Two oncogenes overexpressed via histone acetylation and hypomethylation; 3) Three imprinted genes with selective allelic silencing; and 4) One epigenome writer inducing abnormal genome-scale activity and 5) Two transcription regulators indirectly modifying the genome. Of these, 5 genes (<i>CDKN2A, GADD45y, FGFR2</i>, caspase-8, and <i>PTAG</i>) showed particular susceptibility to epigenetic modification, with abnormal DNA methylation in >50% of PA samples. Several genes displayed correlations between epigenetic modification and clinically relevant parameters, including invasiveness (<i>CDKN2A; DAPK; Rb1</i>), sex (<i>MAGE-A3</i>), tumor size (<i>GNAS1</i>), and histopathological subtype (<i>CDKN2A; MEG3; p27; RASSF1A; Rb1</i>).</p> <p>Conclusions</p><p>Epigenetic modification of selected PA genes may play a key role in tumorigenesis and progression, which may translate into important diagnostic and therapeutic applications.</p> </div

Flow diagram depicting systematic review search results according to phases.

<p>Flow diagram depicting systematic review search results according to phases.</p

A Pathway-Centric Survey of Somatic Mutations in Chinese Patients with Colorectal Carcinomas

<div><p>Previous genetic studies on colorectal carcinomas (CRC) have identified multiple somatic mutations in four candidate pathways (<i>TGF-β, Wnt, P53</i> and <i>RTK-RAS</i> pathways) on populations of European ancestry. However, it is under-studied whether other populations harbor different sets of hot-spot somatic mutations in these pathways and other oncogenes. In this study, to evaluate the mutational spectrum of novel somatic mutations, we assessed 41 pairs of tumor-stroma tissues from Chinese patients with CRC, including 29 colon carcinomas and 12 rectal carcinomas. We designed Illumina Custom Amplicon panel to target 43 genes, including genes in the four candidate pathways, as well as several known oncogenes for other cancers. Candidate mutations were validated by Sanger sequencing, and we further used SIFT and PolyPhen-2 to assess potentially functional mutations. We discovered 3 new somatic mutations in gene <i>APC, TCF7L2,</i> and <i>PIK3CA</i> that had never been reported in the COSMIC or NCI-60 databases. Additionally, we confirmed 6 known somatic mutations in gene <i>SMAD4, APC, FBXW7, BRAF</i> and <i>PTEN</i> in Chinese CRC patients. While most were previously reported in CRC, one mutation in <i>PTEN</i> was reported only in malignant endometrium cancer. Our study confirmed the existence of known somatic mutations in the four candidate pathways for CRC in Chinese patients. We also discovered a number of novel somatic mutations in these pathways, which may have implications for the pathogenesis of CRC.</p></div

Flowchart of the data analysis strategy.

<p>Flowchart of the data analysis strategy.</p

Genes examined in this study.

<p>Genes examined in this study.</p

Diagram of the four major pathways evaluated in this study.

<p>Diagram of the four major pathways evaluated in this study.</p

Sanger sequencing validated somatic mutations.

<p>A, somatic mutations which had been reported in CRC or other cancers. B, novel somatic mutations that discovered in our CRC patients.</p

Patients with CRCs enrolled in this study.

<p>Gender: M, male; F, female. Y: Year.</p><p>TNM: Tis, carcinoma in situ; T1, tumor invades submucosa; T2, tumor invades muscularispropria; T3, tumor invades through the muscularispropria into the pericolorectal tissues; T4a, tumor penetrates to the surface of the visceral peritoneum; T4b, tumor directly invades or is adherent to other organs or structures.</p><p>Patients with CRCs enrolled in this study.</p

A Pilot Genome-Scale Profiling of DNA Methylation in Sporadic Pituitary Macroadenomas: Association with Tumor Invasion and Histopathological Subtype

<div><p>Pituitary adenomas (PAs) are neoplasms that may cause a variety of neurological and endocrine effects. Although known causal contributors include heredity, hormonal influence and somatic mutations, the pathophysiologic mechanisms driving tumorigenesis and invasion of sporadic PAs remain unknown. We hypothesized that alterations in DNA methylation are associated with PA invasion and histopathology subtype, and that genome-scale methylation analysis may complement current classification methods for sporadic PAs. Twenty-four surgically-resected sporadic PAs with varying histopathological subtypes were assigned dichotomized Knosp invasion scores and examined using genome-wide DNA methylation profiling and RNA sequencing. PA samples clustered into subgroups according to functional status. Compared with hormonally-active PAs, nonfunctional PAs exhibited global DNA hypermethylation (mean beta-value 0.47 versus 0.42, <i>P</i> = 0.005); the most significant site of differential DNA methylation was within the promoter region of the potassium voltage-gated channel <i>KCNAB2</i> (FDR = 5.11×10⁻¹⁰). Pathway analysis of promoter-associated CpGs showed that nonfunctional PAs are potentially associated with the ion-channel activity signal pathway. DNA hypermethylation tended to be negatively correlated with gene expression. DNA methylation analysis may be used to identify candidate genes involved in PA function and may potentially complement current standard immunostaining classification in sporadic PAs. DNA hypermethylation of <i>KCNAB2</i> and downstream ion-channel activity signal pathways may contribute to the endocrine-inactive status of nonfunctional PAs.</p></div

Top 30 significant genes with differential DNA methylation between NFAs and FAs.

a<p>Probe_CpG: the Illumina HM450 probe ID.</p>b<p>SD: standard deviation.</p>c<p>NFA-FA: the mean beta value subtractive difference between NFA tumors and FA tumors.</p>d<p>FDR: False Discovery Rate.</p>e<p>TSS200: 200 bp within transcription start site.</p>f<p>TSS1500: 1500 bp within the transcription start site.</p><p>* Promoter Associated.</p><p>Link to the whole information of the Probe_CpG: <a href="http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GPL13534" target="_blank">http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GPL13534</a>.</p