Blohmer, M. | bioRxiv Science

bioRxiv2025

Age distinguishes selection from causation in cancer genomes

Cancer genome sequencing efforts have revealed hundreds of genes under positive selection, many of which are now being developed as therapeutic targets. However, positively selected mutations also populate our aging tissues in the absence of cancer. For most mutations, it is currently unknown whether they are recurrently found in cancer genomes because they cause cancer or because they expand during normal tissue evolution and are passively inherited. Here, we develop a mathematical and statistical framework that distinguishes these two factors. We discover - across thousands of cancer and normal tissue genomes - that mutations that most strongly increase cancer risk are enriched in younger patients cancers, whereas mutations that are positively selected in normal tissue without causing cancer are enriched in older patients. Focusing on a particularly data-rich cancer type, acute myeloid leukemia, we show that genetic differences between young- and adult-onset cancers can largely be explained by the cumulative effects of normal tissue evolution, contradicting the long-standing notion that childhood cancers require a distinct set of causal mutations. Our framework establishes patient age as a powerful resource for clarifying whether positively selected mutations in cancer genomes are truly disease-promoting.

cancer biology↗

bioRxiv2024

A unique interplay of access and selection shapes peritoneal metastasis evolution in colorectal cancer

Whether metastasis in humans can be accomplished by most primary tumor cells or requires the evolution of a specialized trait remains an open question. To evaluate whether metastases are founded by non-random subsets of primary tumor lineages requires extensive, difficult-to-implement sampling. We have realized an unusually dense multi-region sampling scheme in a cohort of 26 colorectal cancer patients with peritoneal metastases, reconstructing the evolutionary history of on average 28.8 tissue samples per patient with a microsatellite-based fingerprinting assay. To assess metastatic randomness, we evaluate inter- and intra-metastatic heterogeneity relative to the primary tumor and find that peritoneal metastases are more heterogeneous than liver metastases but less diverse than locoregional metastases. Metachronous peritoneal metastases exposed to systemic chemotherapy show significantly higher inter-lesion diversity than synchronous, untreated metastases. Projection of peritoneal metastasis origins onto a spatial map of the primary tumor reveals that they often originate at the deep-invading edge, in contrast to liver and lymph node metastases which exhibit no such preference. Furthermore, peritoneal metastases typically do not share a common subclonal origin with distant metastases in more remote organs. Synthesizing these insights into an evolutionary portrait of peritoneal metastases, we conclude that the peritoneal-metastatic process imposes milder selective pressures onto disseminating cancer cells than the liver-metastatic process. Peritoneal metastases unique evolutionary features have potential implications for staging and treatment.

genetics↗