Paraneoplastic Cerebellar Degeneration (PCD) associated with PCA-1 antibodies in established cancer patients

Introduction Paraneoplastic cerebellar degeneration (PCD) is a rare set of neurological disorders arising from tumor-associated autoimmunity against antigens within the cerebellum. Anti-Purkinje cell cytoplasmic antibody 1 (PCA-1), or anti-Yo, is the most commonly linked antibody and is classically associated with breast and ovarian cancers. Methods Medical records of patients at our institution who developed PCA-1 associated PCD were reviewed. Clinical information, including cancer history, cancer-directed treatment, and serum and CSF titers of PCA-1 antibody were extracted. Cases We report a series of cases of PCA-1 associated PCD in patients with known breast or ovarian cancer diagnosis not receiving immunotherapy. These cases highlight aspects of PCA-1 paraneoplastic syndrome such as triggering by cytotoxic chemotherapy or surgery, the possibility of tumor recurrence and the association with development of a second cancer. Discussion Diagnosis of the syndrome requires neurological workup with lumbar puncture (LP) with cerebrospinal fluids (CSF) studies, serum and CSF paraneoplastic antibody panel, and neuroimaging. Inpatient admission for prompt workup and initiation of treatment is recommended. Treatment most commonly includes immunosuppression with corticosteroids, plasmapheresis, and/or intravenous immune globulin (IVIG); however, we postulate that other immune modulating treatments may warrant consideration. Conclusion These cases highlight the need for early recognition of the syndrome in patients receiving nonimmune based chemotherapy, for prompt workup and treatment

Protein-lysine methyltransferases G9a and GLP1 promote responses to DNA damage

Abstract Upon induction of DNA breaks, ATM activation leads to a cascade of local chromatin modifications that promote efficient recruitment of DNA repair proteins. Errors in this DNA repair pathway lead to genomic instability and cancer predisposition. Here, we show that the protein lysine methyltransferase G9a (also known as EHMT2) and GLP1 (also known as EHMT1) are critical components of the DNA repair pathway. G9a and GLP1 rapidly localizes to DNA breaks, with GLP1 localization being dependent on G9a. ATM phosphorylation of G9a on serine 569 is required for its recruitment to DNA breaks. G9a catalytic activity is required for the early recruitment of DNA repair factors including 53BP and BRCA1 to DNA breaks. Inhibition of G9a catalytic activity disrupts DNA repair pathways and increases sensitivity to ionizing radiation. Thus, G9a is a potential therapeutic target in the DNA repair pathway

Widespread alternative exon usage in clinically distinct subtypes of Invasive Ductal Carcinoma

Cancer cells can have different patterns of exon usage of individual genes when compared to normal tissue, suggesting that alternative splicing may play a role in shaping the tumor phenotype. The discovery and identification of gene variants has increased dramatically with the introduction of RNA-sequencing technology, which enables whole transcriptome analysis of known, as well as novel isoforms. Here we report alternative splicing and transcriptional events among subtypes of invasive ductal carcinoma in The Cancer Genome Atlas (TCGA) Breast Invasive Carcinoma (BRCA) cohort. Alternative exon usage was widespread, and although common events were shared among three subtypes, ER+ HER2−, ER− HER2−, and HER2+, many events on the exon level were subtype specific. Additional RNA-seq analysis was carried out in an independent cohort of 43 ER+ HER2− and ER− HER2− primary breast tumors, confirming many of the exon events identified in the TCGA cohort. Alternative splicing and transcriptional events detected in five genes, MYO6, EPB41L1, TPD52, IQCG, and ACOX2 were validated by qRT-PCR in a third cohort of 40 ER+ HER2− and ER− HER2− patients, showing that these events were truly subtype specific

Development of Peptide Nucleic Acid Probes for Detection of the <i>HER2</i> Oncogene

<div><p>Peptide nucleic acids (PNAs) have gained much interest as molecular recognition tools in biology, medicine and chemistry. This is due to high hybridization efficiency to complimentary oligonucleotides and stability of the duplexes with RNA or DNA. We have synthesized 15/16-mer PNA probes to detect the <i>HER2</i> mRNA. The performance of these probes to detect the <i>HER2</i> target was evaluated by fluorescence imaging and fluorescence bead assays. The PNA probes have sufficiently discriminated between the wild type <i>HER2</i> target and the mutant target with single base mismatches. Furthermore, the probes exhibited excellent linear concentration dependence between 0.4 to 400 fmol for the target gene. The results demonstrate potential application of PNAs as diagnostic probes with high specificity for quantitative measurements of amplifications or over-expressions of oncogenes.</p> </div

Automated synthetic scheme of PNA probes from 3′ to 5′-amino end.

<p>Automated synthetic scheme of PNA probes from 3′ to 5′-amino end.</p

Hybridization on gold surface (a) or glass surface (b).

<p>PNA probe P1 was conjugated to the gold or glass surface at circled area. Hybridization was performed with either 50 pmol T1 (perfect match wild type target, green circles), mT (single mismatch on only glass surface, black circles,or <i>m</i>T1 (two bases mismatch, black circles) DNA targets tagged with FITC. Image was acquired after washing the targets off the surface.</p

Fluorescence bead assay of T1 and <i>m</i>T1 <i>HER2</i> targets with extraneous RNA background using P1 probe.

<p>Fluorescence bead assay of T1 and <i>m</i>T1 <i>HER2</i> targets with extraneous RNA background using P1 probe.</p

<i>HER2</i> PNA probes and targets.

<p><i>HER2</i> PNA probes and targets.</p