Comprehensive characterization of PTEN mutational profile in a series of 34,129 colorectal cancers

Loss of expression or activity of the tumor suppressor PTEN acts similarly to an activating mutation in the oncogene PIK3CA in elevating intracellular levels of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), inducing signaling by AKT and other pro-tumorigenic signaling proteins. Here, we analyze sequence data for 34,129 colorectal cancer (CRC) patients, capturing 3,434 PTEN mutations. We identify specific patterns of PTEN mutation associated with microsatellite stability/instability (MSS/MSI), tumor mutational burden (TMB), patient age, and tumor location. Within groups separated by MSS/MSI status, this identifies distinct profiles of nucleotide hotspots, and suggests differing profiles of protein-damaging effects of mutations. Moreover, discrete categories of PTEN mutations display non-identical patterns of co-occurrence with mutations in other genes important in CRC pathogenesis, including KRAS, APC, TP53, and PIK3CA. These data provide context for clinical targeting of proteins upstream and downstream of PTEN in distinct CRC cohorts.Loss of the tumour suppressor gene PTEN leads to the activation of pro-tumourigenic signalling pathways. Here, the authors analyse sequencing data from a large cohort of colorectal cancer patients harbouring PTEN mutations and identify distinct patterns of associations with genomic and clinical features

Interfacial Interactions of Phosphatidylglycerol with Oligonucleotide DNA Revealed by Molecular Dynamics Method

An interaction of DNA with lipids is of great interest because of their functions. As fatty acids and lipids can specifically bind to nucleic acids forming a code sequence of the genomic DNA, it is important to study the interaction of the oligonucleotide DNA (dA)20.(dT)20 with phosphatidylglycerol by the molecular dynamics method. Molecular docking has shown that these components form a stable complex with 5.8 kcal/mole binding energy, wherein the lipid is located in the DNA minor groove. This configuration marks 354 atom groups separated by a distance less than 3.4 Ǻ. The van der Waals and hydrophobic interactions play the leading part in the DNA-phospholipid complex stabilization along with hydrogen bonds.3238-324

Source, co-occurrence, and prognostic value of PTEN mutations or loss in colorectal cancer

Abstract Somatic PTEN mutations are common and have driver function in some cancer types. However, in colorectal cancers (CRCs), somatic PTEN-inactivating mutations occur at a low frequency (~8–9%), and whether these mutations are actively selected and promote tumor aggressiveness has been controversial. Analysis of genomic data from ~53,000 CRCs indicates that hotspot mutation patterns in PTEN partially reflect DNA-dependent selection pressures, but also suggests a strong selection pressure based on protein function. In microsatellite stable (MSS) tumors, PTEN alterations co-occur with mutations activating BRAF or PI3K, or with TP53 deletions, but not in CRC with microsatellite instability (MSI). Unexpectedly, PTEN deletions are associated with poor survival in MSS CRC, whereas PTEN mutations are associated with improved survival in MSI CRC. These and other data suggest use of PTEN as a prognostic marker is valid in CRC, but such use must consider driver mutation landscape, tumor subtype, and category of PTEN alteration