Consecutive seeding and transfer of genetic diversity in metastasis

• Published in: Proceedings of the National Academy of Sciences - PNAS 2019-07, Vol.116 (28), p.14129-14137
• Main Authors: Heyde, Alexander, Reiter, Johannes G., Naxerova, Kamila, Nowak, Martin A.
• Format: Article
• Language: English
• Subjects: Biological Sciences; Branching (mathematics); Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer; Carcinogenesis - genetics; Clonal Evolution - genetics; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Computer Simulation; Female; Genetic diversity; Genetic Heterogeneity; Genetic Variation - genetics; Growth conditions; Humans; Markov processes; Mathematical analysis; Metastases; Metastasis; Models, Theoretical; Mutation; Mutation - genetics; Neoplasm Metastasis; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Physical Sciences; PNAS Plus; Seeding rate; Tumors
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1819408116

During metastasis, only a fraction of genetic diversity in a primary tumor is passed on to metastases. We calculate this fraction of transferred diversity as a function of the seeding rate between tumors. At one extreme, if a metastasis is seeded by a single cell, then it inherits only the somatic mutations present in the founding cell, so that none of the diversity in the primary tumor is transmitted to the metastasis. In contrast, if a metastasis is seeded by multiple cells, then some genetic diversity in the primary tumor can be transmitted. We study a multitype branching process of metastasis growth that originates from a single cell but over time receives additional cells. We derive a surprisingly simple formula that relates the expected diversity of a metastasis to the diversity in the pool of seeding cells. We calculate the probability that a metastasis is polyclonal. We apply our framework to published datasets for which polyclonality has been previously reported, analyzing 68 ovarian cancer samples, 31 breast cancer samples, and 8 colorectal cancer samples from 15 patients. For these clonally diverse metastases, under typical metastasis growth conditions, we find that 10 to 150 cells seeded each metastasis and left surviving lineages between initial formation and clinical detection.