(PQC3) Genomic Diversity and Microenvironment as Drivers of Metastasis in DCIS

描述（由申请人提供）：导管原位癌（DCIS）是一种乳腺浸润前病变，几乎占所有乳房x光检查发现的恶性肿瘤的30% 1,2。在DCIS中，与许多恶性前病变一样，主要的临床挑战是预测哪些病变可能发展为侵袭性和转移性疾病。在缺乏可靠的预后工具的情况下，所有DCIS都被视为会进展，导致DCIS缺乏进展潜力的患者难以治疗。因此，迫切需要准确和临床可操作的DCIS预后标志物。肿瘤的发展是一个随机突变和克隆扩增的过程，导致肿瘤之间和肿瘤内部存在广泛的异质性，这使得基于特定标记物预测预后具有挑战性。此外，肿瘤内的克隆多样性覆盖在异质性微环境的背景上，这可以通过对不同肿瘤区域的不同元群体施加不同的选择压力来加速进化过程。种群的遗传多样性是自然选择的燃料，也是决定进化速度的关键因素8,9。遗传和微环境多样性越丰富，选择就越有机会推动克隆扩增，肿瘤也就越有机会适应新的选择压力。考虑到进化的随机性，我们对进化预测问题的解决方案不是测量躯体进化的产物（例如，是否存在突变），而是测量躯体进化的过程（例如，遗传多样性）。

DESCRIPTION (provided by applicant): Ductal carcinoma in situ (DCIS) is a preinvasive lesion of the breast that makes up almost 30% of all mammographically detected malignancies1,2. In DCIS, as for many pre-malignant lesions, the main clinical challenge is predicting which lesions are likely to progress to invasive and metastatic disease. In the absence of reliable prognostic tools, all DCIS is treated as if it would progress, resulting in har for those patients whose DCIS lacks potential for progression. Thus accurate and clinically actionable prognostic markers for DCIS are critically needed. Neoplasms progress through a process of random mutations and clonal expansions, leading to widespread heterogeneity both between and within neoplasms4 that makes it challenging to predict prognosis on the basis of specific markers. Moreover, the clonal diversity within a neoplasm is overlaid upon a background of heterogeneous microenvironments, which can accelerate the evolutionary process5,6 by imposing different selective pressures on different meta-populations in different tumor regions7. Genetic diversity in a population is the fuel for natural selection and is a key determinant of the rate of evolution8,9. The more genetic and microenvironmental diversity, the more opportunities for selection to drive clonal expansions and for the neoplasm to adapt to new selective pressures. Our solution to the problem of predicting progression given its stochastic nature is not to measure the products of somatic evolution (e.g., presence/absence of a mutation), but to measure the process of somatic evolution (e.g., genetic diversity).