Gene expression profiling of sarcomas.

Sarcomas represent a heterogeneous group of disorders, with over 70 distinct histological subtypes. They are also rare, and comprise approximately 1–3% of all cancers. For these reasons, histopathological agreement regarding their diagnosis has been a constant subject for debate. Nor is this debate confined to the rarest and most esoteric of sarcoma subtypes. The best example of such debate revolves around arguably the single most commonly diagnosed entity, malignant fibrous histiocytoma (MFH). These facts alone make attempts at molecular profiling both enticing and challenging. There is probably no area of pathology which would benefit as greatly by the identification of molecular markers to aid the pathologist as sarcomas. We realise, of course, that the search for robust molecular markers has been around for some time. Sarcomas have obliged with an almost haematological range of pathognomonic genetic signatures, from Ewing’s family tumours to synovial sarcoma to the clinically important mutations found in gastrointestinal stromal tumours. However, for the most common subtypes of sarcomas, namely MFH, liposarcomas and leiomyosarcomas, such signatures have been less readily apparent. Moreover, molecular profiling promises much more than simple classification tools: this fascinating methodology can potentially link specific profiles to treatment response, metastatic potential, and even suggest suitable candidate pathways which may be amenable to new classes of molecularly targeted therapy. In all cases, linking the complex molecular signatures to existing pathological and clinical information is absolutely critical to progress in understanding the sarcomas. This places the pathologist in a position of central importance in integrating molecular biology into a clinically useful context. This fact is reflected in the increasing numbers of publications containing microarray data in top-ranked pathology journals here and overseas. Of course, the very scarcity of sarcomas means that molecular profiling is apparently more challenging in sarcomas than in more common and homogeneous cancer types. These present extraordinary challenges in collecting samples in a form that lends itself to extraction of the vital nucleic acids required for the experiments. However, in our view liposarcoma is of especial interest for cancer biologists using microarray technologies, for several reasons. First, liposarcoma is probably the most common of the undisputed classes of sarcomas. Although MFH is often more frequently diagnosed, Fletcher et al. have argued that two thirds of MFH can be re-classified as poorly differentiated but recognisable forms of other subtypes. While some argue that these distinctions have little clinical relevance, Fletcher et al. reported that sarcomas with myogenic features have poorer outcomes, while liposarcomas have been reported to be more sensitive to chemotherapy. Perhaps more importantly, the advent of targeted therapies means that we need to be more precise about our diagnoses, because one day it will matter. That day is closer than we think, as it becomes apparent that targeted therapies have meaningful responses in molecular subsets of cancers, as illustrated powerfully by the use of epidermal growth factor receptor (EGFR) blockers in nonsmall cell lung cancer. We wonder if we could as readily pick up a similar subset in sarcomas. Although relatively common, liposarcomas are curiously understudied cancers. Perhaps this is best illustrated by comparing the results of PubMed searches for scientific reports on liposarcomas compared to osteosarcoma. Although the incidence of these tumours is comparable, there are six times as many publications in PubMed (18 416 versus 3436), and most of these are case reports. This is despite the fact that liposarcomas are extremely interesting biologically. Well-differentiated liposarcoma is characterised by cytogenetic lesions including ring and marker chromosomes frequently containing amplified regions on 12q13–15. These regions contain classical oncogenes, including MDM2, SAS, CDK4 and HMGIC. Myxoid or round cell liposarcoma is characterised by a translocation event involving chromosomes 12 and 16, resulting in a fusion protein comprising parts of the FUS and CHOP genes. Perhaps even more interestingly, liposarcoma represents a fascinating paradigm for tumour progression, a feature which presents excellent opportunities for understanding how cancers evolve. Well-differentiated liposarcoma is a slow growing cancer, often arising in the abdominal cavity. After an indolent course over many years, approximately 20% of these cancers undergo a transformation into a high grade, de-differentiated tumour resembling MFH. This transformation, described in the article by Kim et al. in this issue of Pathology, is associated with a radical acceleration of the aggressiveness of the tumour, which may rapidly recur following surgical resection and is capable of metastasis. Unfortunately, we do not have curative systemic therapies at this time. Although the article by Kim et al. in this issue is a case report, the approach taken by the authors is potentially powerful. Most studies present cross-sectional data from a large number of tumours. It is axiomatic in clinical research that longitudinal studies, in which the effect of an intervention is evaluated before and after treatment, present a powerful way of measuring outcomes. The same is true in molecular studies. Much more information can be Pathology (April 2006) 38(2), pp. 101–102