What do Students Really Understand? Secondary Education Students’ Conceptions of Genetics

Individuals with a secondary education should have a knowledge level sufficient to make sense of what they read or hear about genetics, and they should be able to think scientifically in evaluation and decision-making processes. The purpose of this study is to identify the basic understanding of secondary education students about genetic concepts and the reasons for the difficulty of learning and teaching genetics. Semi-structured interviews that include student drawings have been conducted with 24 students to gain a comprehensive perspective on secondary education students’ understanding of the basic concepts of genetics. The answers given by the students to the interview questions and their drawings have been analyzed with content analysis. Qualitative data analyzed with a holistic point of view were collected and evaluated under the categories of ‘DNA, gene and chromosome’ and ‘Cell divisions and heredity relationship.’ As a general result, it has been found that students have inaccurate and inconsistent information about the basic concepts of genetics, have difficulties in establishing relationships between these concepts, and cannot fully understand and explain the processes underlying genetic events. It has been observed that various factors have an effect on this result. It will be possible to support students to develop a more accurate understanding of genetic concepts and issues by working on the weaknesses in genetics teaching, providing an enriched teaching environment with current teaching methods and materials, and moving away from rote learning.

Changes in Clonal Architecture Inform MPN Disease Course in Advance of Phenotypic Manifestations

Background Disease progression of chronic phase myeloproliferative neoplasms (MPNs) to myelofibrosis (MF) and acute myeloid leukaemia (AML) occurs in 5-10% of patients and is associated with poor prognosis. Disease classification currently uses histology, clinical and laboratory parameters and does not incorporate genomic parameters. Whilst disease evolution can be associated with genetic events , little is known about the timing of additional genetic events or clonal dynamics prior to phenotypic change. Here, we studied the longitudinal clonal dynamics and genomic architecture of MPN and related these to clinical parameters and disease status. Method Longitudinal whole-genome sequencing (WGS) was undertaken in 31 MPN patients with a median interval between WGS of 10.5 years. Tools to identify somatic mutations despite the presence of tumour-in-normal contamination were developed. Clonal trajectories of disease were mapped by reconstructing the subclonal genomic architecture at each timepoint. Mutation burden within individual clones was used to infer the timing of acquisition of clones. Laboratory and clinical information including serial blood count parameters were used to correlate changes in underlying clonal architecture with clinically apparent changes in disease phenotype. Results Disease transformation to MF or AML occurred in 18 patients between sequencing timepoints. In all patients that progressed to AML, clonal evolution was observed with the emergence and expansion of subclones that dominated the clonal landscape at the time of AML. Two patients developed JAK2-negative AML with the genomic features of de novo AML arising independently of the MPN clone. In contrast, progression to MF was not always associated with genomic evolution between sequencing timepoints. Twelve patients had clinically stable disease between sequencing timepoints (median sampling interval 11 years), Stable MPN clones with no evidence of clonal evolution were observed in 6 patients, and these patients remained clinically stable during extended follow up (median 8 years) beyond the last sequencing timepoint. In contrast, the remaining 6 patients had evidence of clonal evolution with a new clonal expansion by the second WGS timepoint despite still having a chronic phase MPN diagnosis. All 6 of these patients subsequently progressed during extended follow up (median 30 months, range 17-55 months), suggesting that genomic progression predates clinical progression by several years. Blood count changes were found to be a late manifestation of clonal evolution. One patient with WHO-defined MPN was not found to have evidence of a clear clonal expansion harbouring a driver mutation. WGS of single cell derived haematopoietic colonies was used to reconstruct the phylogenetic tree of haematopoiesis and did not reveal evidence of an underlying clonal disorder. Using the burden of somatic mutations, we found that in the majority of patients, we were able to time the chronic MPN clones to have been acquired within the first half of the patients' lives. In several patients, clones that had expanded at the time of progression were detectable at the first timepoint and were timed to before diagnosis of their MPN. Conclusions Changes in the underlying clonal composition of MPN predate clinical recognition of a change in disease status by many years. In such patients, the drivers of subsequent disease transformation may have already been acquired years in advance of the initial MPN diagnosis. Serial genetic monitoring of mutant clones in MPN patients could allow prediction of the future disease course of MPN patients and offer opportunities for earlier intervention prior to deterioration in clinical status. Disclosures Campbell: Mu Genomics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees.

Comparative assessment of genes driving cancer and somatic evolution

ABSTRACTGenetic alterations of somatic cells can drive non-malignant clone formation and promote cancer initiation. However, the link between these processes remains unclear hampering our understanding of tissue homeostasis and cancer development. Here we collect a literature-based repertoire of 3355 well-known or predicted drivers of cancer and noncancer somatic evolution in 122 cancer types and 12 noncancer tissues. Mapping the alterations of these genes in 7953 pancancer samples reveals that, despite the large size, the known compendium of drivers is still incomplete and biased towards frequently occurring coding mutations. High overlap exists between drivers of cancer and noncancer somatic evolution, although significant differences emerge in their recurrence. We confirm and expand the unique properties of drivers and identify a core of evolutionarily conserved and essential genes whose germline variation is strongly counter-selected. Somatic alteration in even one of these genes is sufficient to drive clonal expansion but not malignant transformation. Our study offers a comprehensive overview of our current understanding of the genetic events initiating clone expansion and cancer revealing significant gaps and biases that still need to be addressed. The compendium of cancer and noncancer somatic drivers, their literature support and properties are accessible at http://www.network-cancer-genes.org/.

Cooperation between liver-specific mutations of pten and tp53 genetically induces hepatocarcinogenesis in zebrafish

Background Liver cancer, mainly hepatocellular carcinoma, is one of the deadliest cancers worldwide and has a poor prognosis due to insufficient understanding of hepatocarcinogenesis. Previous studies have revealed that the mutations in PTEN and TP53 are the two most common genetic events in hepatocarcinogenesis. Here, we illustrated the crosstalk between aberrant Pten and Tp53 pathways during hepatocarcinogenesis in zebrafish. Methods We used the CRISPR/Cas9 system to establish several transgenic zebrafish lines with single or double tissue-specific mutations of pten and tp53 to genetically induce liver tumorigenesis. Next, the morphological and histological determination were performed to investigate the roles of Pten and Tp53 signalling pathways in hepatocarcinogenesis in zebrafish. Results We demonstrated that Pten loss alone induces hepatocarcinogenesis with only low efficiency, whereas single mutation of tp53 failed to induce tumour formation in liver tissue in zebrafish. Moreover, zebrafish with double mutations of pten and tp53 exhibits a much higher tumour incidence, higher-grade histology, and a shorter survival time than single-mutant zebrafish, indicating that these two signalling pathways play important roles in dynamic biological events critical for the initiation and progression of hepatocarcinogenesis in zebrafish. Further histological and pathological analyses showed significant similarity between the tumours generated from liver tissues of zebrafish and humans. Furthermore, the treatment with MK-2206, a specific Akt inhibitor, effectively suppressed hepatocarcinogenesis in zebrafish. Conclusion Our findings will offer a preclinical animal model for genetically investigating hepatocarcinogenesis and provide a useful platform for high-throughput anticancer drug screening.

Multiregional genetic evolution of metastatic uveal melanoma

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults and leads to deadly metastases for which there is no approved treatment. Genetic events driving early tumor development are well-described, but those occurring later during metastatic progression remain poorly understood. We performed multiregional genomic sequencing on 22 tumors collected from two patients with widely metastatic UM who underwent rapid autopsy. We observed multiple seeding events from the primary tumors, metastasis-to-metastasis seeding, polyclonal seeding, and late driver variants in ATM, KRAS, and other genes previously unreported in UM. These findings reveal previously unrecognized temporal and anatomic complexity in the genetic evolution of metastatic uveal melanoma, and they highlight the distinction between early and late phases of UM genetic evolution with implications for novel therapeutic approaches.

Pathophysiology of Myelodysplastic Syndromes

Ineffective hematopoiesis is the major characteristic of early myelodysplastic syndromes. Its pathophysiology relies on a diversity of mechanisms supported by genetic events that develop in aging hematopoietic stem cells. Deletion and mutations trigger epigenetic modifications, and co-transcriptional and post-transcriptional deregulations of gene expression. Epistatic interactions between mutants may aggravate the phenotype. Amplification of minor subclones containing mutations that promote their growth and suppress the others drives the clonal evolution. Aging also participates in reprogramming the immune microenvironment towards an inflammatory state, which precedes the expansion of immunosuppressive cells such as Tregs and myeloid-derived suppressive cells that alters the anti-tumor response of effector cells. Integrating biomarkers of transcription/translation deregulation and immune contexture will help the design of personalized treatments.

Biology and Management of Dedifferentiated Liposarcoma: State of the Art and Perspectives

Dedifferentiated liposarcoma (DDL) is defined as the transition from well-differentiated liposarcoma (WDL)/atypical lipomatous tumor (ALT) to non-lipogenic sarcoma, which arises mostly in the retroperitoneum and deep soft tissue of proximal extremities. It is characterized by a supernumerary ring and giant marker chromosomes, both of which contain amplified sequences of 12q13-15 including murinedouble minute 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) cell cycle oncogenes. Detection of MDM2 (and/or CDK4) amplification serves to distinguish DDL from other undifferentiated sarcomas. Recently, CTDSP1/2-DNM3OS fusion genes have been identified in a subset of DDL. However, the genetic events associated with dedifferentiation of WDL/ALT remain to be clarified. The standard treatment for localized DDL is surgery, with or without radiotherapy. In advanced disease, the standard first-line therapy is an anthracycline-based regimen, with either single-agent anthracycline or anthracycline in combination with the alkylating agent ifosfamide. Unfortunately, this regimen has not necessarily led to a satisfactory clinical outcome. Recent advances in the understanding of the pathogenesis of DDL may allow for the development of more-effective innovative therapeutic strategies. This review provides an overview of the current knowledge on the clinical presentation, pathogenesis, histopathology and treatment of DDL.

The Genetic Changes of Hepatoblastoma

Hepatoblastoma is the most common malignant liver cancer in childhood. The etiology of hepatoblastoma remains obscure. Hepatoblastoma is closely related to genetic syndromes, hinting that hepatoblastoma is a genetic predisposition disease. However, no precise exposures or genetic events are reported to hepatoblastoma occurrence. During the past decade, significant advances have been made in the understanding of etiology leading to hepatoblastoma, and several important genetic events that appear to be important for the development and progression of this tumor have been identified. Advances in our understanding of the genetic changes that underlie hepatoblastoma may translate into better patient outcomes. Single nucleotide polymorphisms (SNPs) have been generally applied in the research of etiology’s exploration, disease treatment, and prognosis assessment. Here, we reviewed and discussed the molecular epidemiology, especially SNPs progresses in hepatoblastoma, to provide references for future studies and promote the study of hepatoblastoma’s etiology.

Case Report: Two Distinct Focal Congenital Hyperinsulinism Lesions Resulting From Separate Genetic Events

Focal hyperinsulinism (HI) comprises nearly 50% of all surgically treated HI cases and is cured if the focal lesion can be completely resected. Pre-operative localization of the lesion is thus critical. Few cases of hyperinsulinism with multiple focal lesions have been reported, and assessment of the molecular mechanisms driving this rare occurrence has been limited. We present two cases of multifocal HI, each resulting from two independent, pancreatic focal lesions. 18Fluoro-dihydroxyphenylalanine positron emission tomography/computed tomography detected both lesions preoperatively in one patient, whereas identification of the second lesion was an incidental finding during surgical exploration in the other. Complete resection of the focal lesions resulted in cure of the HI in both cases. In each patient, genetic testing of the individual focal lesions revealed different regions of loss of heterozygosity for the maternal 11p15 allele, confirming that each lesion arose from independent somatic events in the setting of a paternally inherited germline ABCC8 mutation. These cases highlight the importance of a multidisciplinary and personalized approach to the management of infants with HI.