2-AIN-506 a 2-AIN-252: Seminár z bioinformatiky (2) a (4)
Leto 2019

Erez Persi, Yuri I. Wolf, Mark D. M. Leiserson, Eugene V. Koonin, Eytan Ruppin. Criticality in tumor evolution and clinical outcome. Proceedings of the National Academy of Sciences of the United States of America, 115(47):E11101-E11110. 2018.

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How mutation and selection determine the fitness landscape of tumors and hence
clinical outcome is an open fundamental question in cancer biology, crucial for
the assessment of therapeutic strategies and resistance to treatment. Here we
explore the mutation-selection phase diagram of 6,721 tumors representing 23
cancer types by quantifying the overall somatic point mutation load (ML) and
selection (dN/dS) in the entire proteome of each tumor. We show that ML strongly 
correlates with patient survival, revealing two opposing regimes around a
critical point. In low-ML cancers, a high number of mutations indicates poor
prognosis, whereas high-ML cancers show the opposite trend, presumably due to
mutational meltdown. Although the majority of cancers evolve near neutrality,
deviations are observed at extreme MLs. Melanoma, with the highest ML, evolves
under purifying selection, whereas in low-ML cancers, signatures of positive
selection are observed, demonstrating how selection affects tumor fitness.
Moreover, different cancers occupy specific positions on the ML-dN/dS plane,
revealing a diversity of evolutionary trajectories. These results support and
expand the theory of tumor evolution and its nonlinear effects on survival.