To understand the prognostic relevance of any genetic alteration, you need to understand that within the context of genetic intratumoral heterogeneity. And that’s because tumor evolution is dictated by very conserved patterns of ordering co-occurrence and mutual exclusivity of genetic driver events. And that means that the early acquisition of any given event then sets down a downstream set of tumor behavior...
To understand the prognostic relevance of any genetic alteration, you need to understand that within the context of genetic intratumoral heterogeneity. And that’s because tumor evolution is dictated by very conserved patterns of ordering co-occurrence and mutual exclusivity of genetic driver events. And that means that the early acquisition of any given event then sets down a downstream set of tumor behavior. So, some mutations will confer a fitness advantage that leads to a rapid expansion of a dominant clonal population, and that drives very aggressive tumor growth. Whereas another mutation might permit subclonal diversification downstream, and that means that you have high levels of intratumor heterogeneity. And those tumors are associated with a more indolent course for advanced disease. So using histology is a mechanism by which we can predict genetic alterations in multiple samples of the tumor in a way that is scalable and affordable because you can’t take multiple regions of the tumor for genetic sequencing. It’s too expensive, but we can do that for histology. So by using morphological surrogates of these genetic alterations, we can predict the tumor evolutionary pathway and therefore predict patient outcomes. So it’s a way of risk stratifying patients. We’ll be able to identify genetic alterations associated with a high risk of metastases and differentiate them from areas of the tumor which are likely to proceed in a more indolent manner.
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