Prognostic and Predictive Biomarkers in Oligometastatic Disease.

Metastatic lesions are largely responsible for cancer-related deaths and are synonymous with a poor prognosis. However, this is not always true for patients with oligometastases whose disease may be amenable to curative-intent local therapies. It has been proposed that an "intermediate state" (oligometastasis) exists in between locoregional and advanced disease states; however, the clinical definition of oligometastasis varies, and there is limited understanding of how tumor biology differs between oligometastases and polymetastases. There is evidence that local therapies can extend survival in patients with oligometastases, yet patient selection for local intervention and/or systemic therapy remains a challenge. Prognostic and predictive biomarkers of oligometastatic disease are strongly needed to identify patient candidates most likely to gain survival benefit from local therapies and to aid in the incorporation of ablative treatments in the context of existing systemic therapies.

Histone H3G34R mutation causes replication stress, homologous recombination defects and genomic instability in S. pombe.

Recurrent somatic mutations of H3F3A in aggressive pediatric high-grade gliomas generate K27M or G34R/V mutant histone H3.3. H3.3-G34R/V mutants are common in tumors with mutations in p53 and ATRX, an H3.3-specific chromatin remodeler. To gain insight into the role of H3-G34R, we generated fission yeast that express only the mutant histone H3. H3-G34R specifically reduces H3K36 tri-methylation and H3K36 acetylation, and mutants show partial transcriptional overlap with set2 deletions. H3-G34R mutants exhibit genomic instability and increased replication stress, including slowed replication fork restart, although DNA replication checkpoints are functional. H3-G34R mutants are defective for DNA damage repair by homologous recombination (HR), and have altered HR protein dynamics in both damaged and untreated cells. These data suggest H3-G34R slows resolution of HR-mediated repair and that unresolved replication intermediates impair chromosome segregation. This analysis of H3-G34R mutant fission yeast provides mechanistic insight into how G34R mutation may promote genomic instability in glioma.

Molecular mechanisms involved in initiation of the DNA damage response.

DNA is subject to a wide variety of damage. In order to maintain genomic integrity, cells must respond to this damage by activating repair and cell cycle checkpoint pathways. The initiating events in the DNA damage response entail recognition of the lesion and the assembly of DNA damage response complexes at the DNA. Here, we review what is known about these processes for various DNA damage pathways.

Cell cycle regulation by checkpoints.

Cell cycle checkpoints are surveillance mechanisms that monitor the order, integrity, and fidelity of the major events of the cell cycle. These include growth to the appropriate cell size, the replication and integrity of the chromosomes, and their accurate segregation at mitosis. Many of these mechanisms are ancient in origin and highly conserved, and hence have been heavily informed by studies in simple organisms such as the yeasts. Others have evolved in higher organisms, and control alternative cell fates with significant impact on tumor suppression. Here, we consider these different checkpoint pathways and the consequences of their dysfunction on cell fate.