Abstract
Recent genomic analyses have revealed substantial tumor heterogeneity across various cancers. However, it remains unclear whether and how genomic heterogeneity is constrained during tumor evolution. Here, we sequence a unique cohort of multiple synchronous lung cancers (MSLCs) to determine the relative diversity and uniformity of genetic drivers upon identical germline and environmental background. We find that each multicentric primary tumor harbors distinct oncogenic alterations, including novel mutations that are experimentally demonstrated to be functional and therapeutically targetable. However, functional studies show a strikingly constrained tumorigenic pathway underlying heterogeneous genetic variants. These results suggest that although the mutation-specific routes that cells take during oncogenesis are stochastic, genetic trajectories may be constrained by selection for functional convergence on key signaling pathways. Our findings highlight the robust evolutionary pressures that simultaneously shape the expansion and constraint of genomic diversity, a principle that holds important implications for understanding tumor evolution and optimizing therapeutic strategies.
Highlights
Recent genomic analyses have revealed substantial tumor heterogeneity across various cancers
To gain further insights into the genetic alterations shaping lung tumorigenesis, we sampled four patients (RJLC1-4; Table 1) with treatment-naive multiple synchronous lung cancers (MSLCs) (16 tumor samples within 11 independent lesions, all adenocarcinomas) and performed whole-exome sequencing on tumor and matched adjacent normal lung DNA (Supplementary Fig. 1), yielding a mean coverage of 244× (205×−296×)
In order to determine whether MSLC was derived from one single lesion with intra-thoracic metastases or multiple local primary tumors, non-silent mutations were mapped on the basis of their intertumoral distributions and classified as shared or private alterations
Summary
Recent genomic analyses have revealed substantial tumor heterogeneity across various cancers. Many established tumors are genetically unstable, creating a tendency to accumulate additional mutations; as a result, the constituent malignant cells within a tumor are constantly evolving[3, 4] One consequence of these forces is substantial genomic divergence that causes extensive intratumoral heterogeneity and branching phylogenies[5,6,7,8,9,10]. Four independent tumors occurring in a patient with Von Hippel Lindau syndrome exhibited functionally recurrent activation of the mTOR pathway[20] One caveat of these studies is that the tumor clones or subclones studied shared largely identical somatic alterations or well-known germline cancer-predisposition genes, which may potentially define an intrinsic boundary for evolutionary divergence. Simultaneous evolutionary expansion and constraint of genomic heterogeneity may competitively and collaboratively shape tumorigenesis of lung cancer and potentially other human malignancies
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