Chromosomal translocations in cancer

Chromosomal translocations that create gene fusions are a leading cause of malignant transformation in hemato­ logical malignancies and sarcomas [1]. Although they are less common in solid tumors, fusion genes are now also recognized as driving events in such tumors ­ for example, in prostate and thyroid cancers. Most of the cancer­causing translocations were detected by chromo­ some banding techniques [2], and they provided reward­ ing entry points for the positional cloning of oncogenes. Combined array comparative genomic hybridi zation and gene expression studies, as well as whole genome or exome sequence analysis, have now been added to the methods available to screen tumor genomes for recurrent aberrations, gene fusions or aberrant transcripts. The prototypic example of a cancer­causing chromo­ somal translocation is the Philadelphia chromosome, first identified in patients with chronic myelogenous leukemia. The Philadelphia chromosome, generated through a reci­ procal translocation between chromosomes 9 and 22 [3], results in a fusion transcript of the genes BCR and ABL1, which encodes a protein with increased tyrosine kinase activity. Patients with this translocation can be effectively treated with tyrosine kinase inhibitors, such as imatinib, which specifically targets the oncogenic fusion protein [4]. Endometrial stromal sarcoma (ESS) belongs to the group of endometrial stromal tumors, which are a category of relatively rare mesenchymal neoplasms of the uterus. The diagnostic spectrum of endometrial stromal tumors ranges from endometrial stromal nodule (ESN) through low­grade ESS (LESS) to high­grade (undifferentiated) ESS. ESNs are benign, well­circumscribed lesions, but LESS and ESS both show malignant behavior. The distinction between LESS and ESS is clinically important because the prognosis of these lesions is drastically different. LESSs are indolent tumors with a low propensity for mainly local recurrences many years after surgical treatment. In contrast, ESSs are highly malignant and often develop extra­uterine metastases. The 5­year survival rate for LESS is close to 100%, compared with 55% for ESS [5]. The histological distinc tion is based on tumor cell necrosis, mitotic index and atypical cell morphology. However, both tumor types can show unusual features, resulting in difficulties for definitive tumor classification. Surgical removal of the fallopian tubes and ovaries on both sides remains the mainstay for the treatment of early stage disease and for LESS, whereas adjuvant or neo­adjuvant chemoradio therapy is used for advanced stages and for ESS. However, a definitive benefit of chemoradiotherapy has yet to be established, highlight­ ing the importance of targeted therapies [6].