Cancer is an evolutionary process involving the accumulation of diverse somatic mutations and clonal evolution over time. Phylogenetic inference from samples obtained from an individual patient offers a powerful approach to unraveling the intricate evolutionary history of cancer and provides insights that can inform cancer treatment. Somatic copy number alterations (CNAs) are important in cancer evolution and are often used as markers, alone or with other somatic mutations, for phylogenetic inferences, particularly in low-coverage DNA sequencing data. Many phylogenetic inference methods using CNAs detected from bulk or single-cell DNA sequencing data have been developed over the years. However, there have been no systematic reviews on these methods. To summarize the state-of-the-art of the field and inform future development, this review presents a comprehensive survey on the major challenges in inference, different types of methods, and applications of these methods. The challenges are discussed from the aspects of input data, models of evolution, and inference algorithms. The different methods are grouped according to the markers used for inference and the types of the reconstructed trees. The applications include using phylogenetic inference to understand intra-tumor heterogeneity, metastasis, treatment resistance, and early cancer development. This review also sheds light on future directions of cancer phylogenetic inference using CNAs, including the improvement of scalability, the utilization of new types of data, and the development of more realistic models of evolution.

Hypoxia, a hallmark of the tumor microenvironment (TME), drives cancer progression through immune modulation, angiogenesis promotion, metabolic reprogramming, and uncontrolled cell proliferation. This review explores the diverse functions of hypoxia-inducible factor (HIF) signaling in cancer development and progression, providing a comprehensive overview of the molecular pathways. HIFs, particularly HIF-1α and HIF-2α, regulate several genes related to cancer hallmarks such as invasion, metabolic reprogramming, angiogenesis, and therapy resistance, thus mediating a significant portion of the hypoxic response. Oxygen-dependent hydroxylation of proline and asparagine residues in HIF-α subunits is a key regulator of their stability and transcriptional activity. Notably, this complex interaction is regulated by multiple signaling pathways, including the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK), phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/Akt/mTOR), and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways. In cancer, HIF signaling affects several aspects of tumor cell biology that contribute to the cancerous characteristics, including angiogenesis induction through the upregulation of vascular endothelial growth factor (VEGF) expression, metabolic reprogramming through the enhancement of the Warburg effect, facilitation of cancer invasion and metastasis by driving epithelial-to-mesenchymal transition (EMT) and matrix remodeling patterns, and mediation of therapeutic resistance partly due to the effects on drug efflux pumps and DNA damage repair. Direct and indirect HIF inhibitors—including small molecules, peptidomimetics, antibodies, and proteolysis-targeting chimeras (PROTACs)—are under preclinical and clinical evaluation for their therapeutic efficacy. Preclinical and early clinical trials have demonstrated significant synergistic effects in inhibiting tumor development when HIF inhibition is combined with traditional therapies (chemotherapy or radiation) or immunotherapies, emphasizing major clinical implications and the potential for improving patient outcomes. Although challenges exist, particularly regarding drug resistance, further research to improve therapeutic efficacy and prolong survival for patients is warranted.