A challenge to answering this PQ is the inherent inability to reliably predict the future. Although small, non-invasive lesions can be biopsied and measured for a host of parameters, one can never be sure which ones are """"""""progressors"""""""" destined to metastasize and which ones are """"""""nonprogressors"""""""" that will not invade or metastasize within a lifetime. Indeed, if progression to metastasis is stochastic, there may be no way to distinguish between progressors and nonprogressor lesions because any cell can randomly become metastatic. An ideal tool to answer this PQ is a time machine, allowing one to move forward in time to see the fate of a lesion, and then back in time to biopsy the lesion and measure properties that differ between progressors and nonprogressors. Such a time machine does not exist, but it is possible to go back in time to reconstruct the past using modern molecular phylogeny. We propose that it is possible to reconstruct the smaller progenitor of a present day tumor by sampling private (subclonal) point mutations and chromosome copy number alterations from different parts of the same tumor. Earlier smaller progressor lesions can be reconstructed from metastatic tumors, and earlier smaller nonprogressor lesions can be reconstructed from benign tumors. Preliminary Data indicate that metastasis may not be stochastic but rather that tumors start out """"""""Born to Be Bad"""""""" because reconstructed progressor lesions are measurably different from reconstructed nonprogressor lesions. The primary readout of the past is the intratumoral heterogeneity in the present day tumor. Benign tumors have private mutation patches whereas cancers have private mutation polka dot topographies that indicate early abnormal cell mobility or intermixing that scatters mutations during clonal expansion. Abnormal cell mobility, a prerequisite for invasion/metastasis, appears to be a critical rate limiting step that distinguishes progressors from nonprogressors. Tumor cells in small non-invasive nonprogressor lesions have normal mobility and do not intermix. By contrast, tumor cells in small non-invasive progressor lesions have abnormal mobility, with evidence of substantial intermixing. The proposed studies are designed to reconstruct the smaller progenitors of 15 benign tumors, 10 invasive cancers, and 10 metastatic cancers. The results will demonstrate whether early cell mobility accurately distinguishes progressors from nonprogressor lesions. The impact is that measurements of private mutation topographies in small non-invasive progenitor lesions may reliably foretell their futures. A small lesion with private mutation patches has normal cell mobility and a low risk of progression (Born to Be Good), but a small lesion with private mutation polka dots has abnormal cell mobility and a higher risk of progression (Born to Be Bad).
Early non-invasive lesions that progress to metastasis likely have properties that differ from similar lesions that will never harm individuals within their lifetimes. To test this hypothesis, we will reconstruct the smaller, earlier progenitors of metastatic or benign tumors using molecular phylogeny. Specifically, abnormal cell mobility, a prerequisite for subsequent invasion or metastasis, appears to be present at the start of a malignant tumor and absent from the start of a benign tumor.
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