Cancer type-specific alterations in actin genes: Worth a closer look?

Actins form a strongly conserved family of proteins that are central to the functioning of the actin cytoskeleton partaking in natural processes such as cell division, adhesion, contraction and migration. These processes, however, also occur during the various phases of cancer progression. Yet, surprisingly, alterations in the six human actin genes in cancer studies have received little attention and the focus was mostly on deregulated expression levels of actins and even more so of actin-binding or regulatory proteins. Starting from the early mutation work in the 1980s, we propose based on reviewing literature and data from patient cancer genomes that alterations in actin genes are different in distinct cancer subtypes, suggesting some specificity. These actin gene alterations include (missense) mutations, gene fusions and copy number alterations (deletions and amplifications) and we illustrate their occurrence for a limited number of examples including actin mutations in lymphoid cancers and nonmelanoma skin cancer and actin gene copy number alterations for breast, prostate and liver cancers. A challenge in the future will be to further sort out the specificity per actin gene, alteration type and cancer subtype. Even more challenging is (experimentally) distinguishing between cause and consequence: which alterations are passengers and which are involved in tumor progression of particular cancer subtypes?

Prevalence of Cytoplasmic Actin Mutations in Diffuse Large B-Cell Lymphoma and Multiple Myeloma: A Functional Assessment Based on Actin Three-Dimensional Structures.

Mutations in actins have been linked to several developmental diseases. Their occurrence across different cancers has, however, not been investigated. Using the cBioPortal database we show that human actins are infrequently mutated in patient samples of various cancers types. Nevertheless, ranking these studies by mutational frequency suggest that some have a higher percentage of patients with ACTB and ACTG1 mutations. Within studies on hematological cancers, mutations in ACTB and ACTG1 are associated with lymphoid cancers since none have currently been reported in myeloid cancers. Within the different types of lymphoid cancers ACTB mutations are most frequent in diffuse large B-cell lymphoma (DLBCL) and ACTG1 mutations in multiple myeloma. We mapped the ACTB and ACTG1 mutations found in these two cancer types on the 3D-structure of actin showing they are in regions important for actin polymer formation or binding to myosin. The potential effects of the mutations on actin properties imply that mutations in cytoplasmic actins deserve dedicated research in DLBCL and multiple myeloma.

A new evolutionary model for the vertebrate actin family including two novel groups.

Database surveys in the vertebrate model organisms: chicken (Gallus gallus), western clawed frog (Xenopus tropicalis), anole lizard (Anolis carolinensis) and zebrafish (Danio rerio) indicate that in some of these species the number of actin paralogues differs from the well-established six paralogues in mouse (Mus musculus). To investigate differential functions of actins and for establishing disease models it is important to know how actins in the different model organisms relate to each other and whether the vertebrate actin family is truly limited to six groups. Primarily through synteny analyses we discovered that the vertebrate actin family consists of eight instead of six orthologous actin groups for which we propose improved gene nomenclature. We also established that α-skeletal muscle, γ-enteric smooth muscle and γ-cytoplasmic actin genes originated prior to tetrapods contradicting an earlier and widely accepted model of actin evolution. Our findings allow a more reliable predictive classification of actin paralogues in (non-mammalian) vertebrates and contribute to a better understanding of actin evolution as basis for biomedical research on actin-related diseases.

Surveillance of Myelodysplastic Syndrome via Migration Analyses of Blood Neutrophils: A Potential Prognostic Tool.

Autonomous migration is a central characteristic of immune cells, and changes in this function have been correlated to the progression and severity of diseases. Hence, the identification of pathologically altered leukocyte migration patterns might be a promising approach for disease surveillance and prognostic scoring. However, because of the lack of standardized and robust assays, migration patterns have not been clinically exploited so far. In this study, we introduce an easy-to-use and cross-laboratory, standardized two-dimensional migration assay for neutrophil granulocytes from peripheral blood. By combining time-lapse video microscopy and automated cell tracking, we calculated the average migration of neutrophils from 111 individual participants of the German Heinz Nixdorf Recall MultiGeneration study under steady-state, formyl-methionyl-leucyl-phenylalanine-, CXCL1-, and CXCL8-stimulated conditions. Comparable values were obtained in an independent laboratory from a cohort in Belgium, demonstrating the robustness and transferability of the assay. In a double-blinded retrospective clinical analysis, we found that neutrophil migration strongly correlated with the Revised International Prognostic Scoring System scoring and risk category of myelodysplastic syndrome (MDS) patients. In fact, patients suffering from high-risk subtypes MDS with excess blasts I or II displayed highly significantly reduced neutrophil migration. Hence, the determination of neutrophil migration patterns might represent a useful tool in the surveillance of MDS. Taken together, we suggest that standardized migration assays of neutrophils and other leukocyte subtypes might be broadly applicable as prognostic and surveillance tools for MDS and potentially for other diseases.