Gene-level consequences of chromosomal rearrangements

Cytogenetic and molecular genetic research on benign and malignant neoplastic cells during the last more than 50 years has shown that the acquired chromosomal aberrations are distinctly nonrandom, with some aberration patterns being specific for some phenotypic diagnostic entities.

During the last three decades, furthermore, the mentioned specific aberrations have been shown to generate gene-level changes that contribute to tumorigenesis. One of the main mechanisms whereby this is achieved is through generation of qualitatively altered (i.e., their primary structure is changed) fusion genes that activate the oncogenic properties of proto-oncogenes. Because the generation of oncogenic fusion genes in neoplastic cells by acquired clonal chromosomal rearrangements is a main mechanism of pathogenesis in leukemias, lymphomas, and solid tumors, knowledge about them is essential if one aims to understand tumorigenesis in any fundamental way.

Different tumor types are characterized by specific translocations, which lead to fusion genes of equal specificity, and the discovery of which fusions correspond to which translocations contributes also diagnostically toward the goal of creating an alternative classification system of neoplasms based on pathogenesis rather than phenotype [1]. This opens up for the long-term possibility of personalized medicine in which each cancer patient has the underlying pathogenetic mechanism of his/her tumor determined as part of the diagnostic proceedings, whereupon the patient can be treated with drugs generated to counteract that tumor's particular molecular genetic rearrangement in a completely specific manner.

Aim of the research

We aim for a classification of tumors based on knowledge of the tumor's phenotype (= how things look) at the cell and tissue level as well as genotype (= the totality of the tumor cells' genetic material) to improve diagnostic precision and prognosis while simultaneously knowledge about the pathogenesis (= how the tumor came into being). We want to increase the knowledge on diagnosis, prognosis, and possibly reach the goal of personalized therapy in some subgroups of hematologic tumors and sarcomas. Although much is already known about these tumors, new genetic subgroups are still being detected that make it challenging and difficult for clinicians and pathologists to diagnose, classify, and treat their patients optimally. Among the challenges that clinicians and pathologists are facing every day we mention three issues that will be the main focus for our future research.

  1. Tumors that have the same phenotypes (they look alike) but have different genotypes (they are different at the genomic level).
  2. Tumors that have the same genotype (show the same acquired genetic aberrations) but are different at the phenotypic level .
  3. Rare tumors about which very little is known at the genotypic level


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