An NCI-designated Comprehensive Cancer Center
By City of Hope | March 18, 2020
Steven Smith Steven Smith, Ph.D.
One of the worst facts about cancer is that it most often occurs spontaneously. Most prostate, breast and blood cancers have no known cause, and are not linked to any particular gene or group of genes. 
 
Cancers do have defining genetic characteristics once they emerge, but the underlying cause of the mutations they have acquired is largely unknown. Understanding the origin of the spontaneous mutagenesis that accompanies aging and tumorigenesis, is a key area of research at City of Hope and around the world.
 
“One clue has been the discovery of DNA sequences that can spontaneously form strange structures in DNA,” said Steven Smith, Ph.D., professor of molecular science emeritus with City of Hope’s Beckman Research Institute and Department of Hematological Malignancies and Translational Science Biomedical Research Center. “These sequences have been thought to be candidates for what is called “replication stress” in the field. They can pop into what amount to speed bumps that slow or effectively halt the process of copying DNA when cells try to divide.”
 
This in turn can cause chromosomes to delete certain sequences or break in ways known to occur in cancer. Sites with this potential often possess what is called a G-quadruplex motif. More than 700,000 such sites have been identified in the human genome.
  
In collaboration with a labs led by Zoë Waller, Ph.D., in England and Flavia Pichiorri, Ph.D., at City of Hope, along with the help of Joyce Muratta-Collins, Ph.D., of City of Hope’s cytology core facility, City of Hope scientists have developed an approach to detecting sites of replication stress linked to the failure of suppression systems in human cancer and aging that normally take these strange structures apart. A study about that approach published this month in Cancer Genomics and Proteomics.
 
The approach should supplement in vitro sequencing efforts using G4-seq, a whole genome sequencing method that uses potassium ion or a chemical compound called PDS to draw single-stranded genomic DNA into these structures. That method identifies sequences that can form these strange structures.  The method described in the new study takes a snapshot that identifies a subset those sequences that are actively generating structural replication impediments in vivo
 
The team is also currently exploring tissue and age-linked nature of this phenomenon, which often results in site-specific deletion damage within genes that can play a role in tumorigenesis, e.g. RACK7, ABL1, BCR, and PLAG2. The team is studying these effects in prostate cancer and multiple myeloma specimens. Many labs including the collaborating lab headed by Dr. Waller are looking at the possibility that compounds they have developed that stabilize these structures may provide a new approach to cancer therapy by selectively blocking cancer cells from dividing.
 
Smith was the study’s lead author and other authors include Waller, Pichiorri, Murrata-Collins, Camille Amparo, Jarrod Clark, Victoria Bedell, Marianna Martella, Emily F. Warner and Mahmoud A.S. Abdelhamid.