Abstract
The development of cancer has been associated with the gradual acquisition of genetic alterations leading to a progressive increase in malignancy. In various cancer types this process is enabled and accelerated by genome instability. While genome sequencing-based analysis of tumor genomes becomes increasingly a standard procedure in human cancer research, the potential necessity of genome instability for tumorigenesis in Drosophila melanogaster has, to our knowledge, never been determined at DNA sequence level. Therefore, we induced formation of tumors by depletion of the Drosophila tumor suppressor Polyhomeotic and subjected them to genome sequencing. To achieve a highly resolved delineation of the genome structure we developed the Deterministic Structural Variation Detection (DSVD) algorithm, which identifies structural variations (SVs) with high accuracy and at single base resolution. The employment of long overlapping paired-end reads enables DSVD to perform a deterministic, i.e. fragment size distribution independent, identification of a large size spectrum of SVs. Application of DSVD and other algorithms to our sequencing data reveals substantial genetic variation with respect to the reference genome reflecting temporal separation of the reference and laboratory strains. The majority of SVs, constituted by small insertions/deletions, is potentially caused by erroneous replication or transposition of mobile elements. Nevertheless, the tumor did not depict a loss of genome integrity compared to the control. Altogether, our results demonstrate that genome stability is not affected inevitably during sustained tumor growth in Drosophila implying that tumorigenesis, in this model organism, can occur irrespective of genome instability and the accumulation of specific genetic alterations.
Highlights
Mechanisms maintaining genomic integrity are an essential part of the functional repertoire of any eukaryotic cell, as genome instability may have deleterious consequences for the affected cell but for the entire organism
Upon Ph depletion we observed ectopic activation of the Notch signaling pathway (Figure 1B), which contributes to tumor growth [26]
Much of the mechanistic redundancy contributing to the proliferative homeostasis in mammals is lacking in Drosophila, which has promoted the development of tumor models applicable to study different aspects of human cancer
Summary
Mechanisms maintaining genomic integrity are an essential part of the functional repertoire of any eukaryotic cell, as genome instability may have deleterious consequences for the affected cell but for the entire organism. The fruit fly Drosophila melanogaster constitutes a genetically exceptionally well-defined tumor model, serving for the identification and characterization of numerous tumor suppressor genes and tumor relevant pathways [6,7,8,9] In this model, the reduced genetic redundancy and biochemical diversity, compared to mammalian systems, facilitates the identification of cancer genes, since altering the activity of one gene is generally sufficient to initiate tumorigenesis. A recent publication [10] demonstrates that induced chromosomal instability results in tumor formation and metastasis in a very short period of time in Drosophila epithelial cells, if apoptosis is blocked This observation may indicate that a loss of genome integrity could be a general feature of overgrowth in Drosophila, which remained unnoticed so far because some of the underlying changes might be subtle and not detectable by methods of insufficient sensitivity. Karyotype changes have been observed in tumorous tissue allografts from various mutants defective in genes that control asymmetric cell division [11], but whether these changes are directly involved in tumor progression has not been determined
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