Studying the heterogeneity of brain tumors using medium throughput LOH analysis.

Abstract

The theory of tumor progression by clonal evolutionposits that a succession of increasingly malignant clonesarise, in turn, driven by the step-wise accumulation ofmutations (1). At each point in this process it is thoughtthat one cell in the currently dominant clone acquires anew mutation, allowing it to outcompete its siblings. As aresult, its descendants enjoy a higher rate of net growth,making them the new dominant clone whose growtheclipses that of preceding clones, until it too is left behindin the wake of the next mutation. Some direct evidencefor this model exists, for example, from analyzing the roleof TP53 in brain tumors. In an elegant study of primaryand recurrent glioma, it was possible to find the mutationprevalent in recurrent tumors represented in some cells ofthe primary lesion, suggesting that this molecular defectmarked the dominant clone about to emerge (2).In the strictest interpretation of the clonal evolutionmodel, a single clone makes up the bulk of the tumor at agiven stage (Fig. 1a). Any observed tumor heterogeneity isconsidered to be due to the remains of ancestral clones,whose sidelined descendants may persist but do not de-fine the clinical course of the disease. This view fits thedata from many studies where tumors are considered tobe, to a first approximation, homogeneous entities, and allof a tumor’s cells are combined in one sample and ana-lyzed using molecular markers of progression. This inter-pretation also is reassuring in its implication that effectivetreatment will result from targeting the dominant clone.The validity of the inherent assumptions that a tumor canbe treated as a single entity is an increasingly importantconcern, particularly as new therapies based on the per-ceived biological characteristics of an individual patient’stumor, become available.Although what may be termed the dominant cloneinterpretation of the theory of clonal evolution may verywell describe many tumor types, particularly those char-acterized by extreme changes in growth rate and invasive-ness with concomitant well-defined histologic stages, itmay not explain all cancers. Here we discuss data fromanalyses of loss of heterozygosity (LOH), which measuresclonally inherited genetic damage associated with the in-activation of tumor suppressor genes (3). Therefore LOHrelates directly to cancer progression and also serves as atool for following clonal patterns. Our data suggest thatother views of the theory of clonal evolution besides thedominant clone interpretation may need to be consideredin some tumor types.