While mutations in BRCA genes are well known to increase breast cancer risk, researchers from the 黑料网 Lineberger Comprehensive Cancer Center have uncovered a different series of genes they believe might be contributing to breast cancer through a lesser-known mechanism.
While mutations in聽BRCA聽genes are well known to increase breast cancer risk, researchers from the University of North Carolina Lineberger Comprehensive Cancer Center have uncovered a different series of genes they believe might be contributing to breast cancer through a lesser-known mechanism.
Mutations in聽BRCA聽cause cells to lose the ability to repair errors in DNA through a common repair mechanism, which can lead to an increase in cancer risk., 黑料网 Lineberger鈥檚聽, and colleagues report they discovered a different set of genes that could cause cells to hyper activate a more error-prone DNA repair mechanism and result in additional errors in the code.
Their findings reveal insights as to what is driving certain types of breast cancers and provide a potential road map for future therapeutic strategies for cancers that have this hyper-activation.
鈥淭hrough our genetic screen, we were able to identify a set of genes that when altered in cells, make them highly dependent on this alternative DNA repair pathway for survival,鈥� said Gupta, assistant professor in the 黑料网 Department of Radiation Oncology and Department of Biochemistry & Biophysics. 鈥淔uture work will explore whether targeting this pathway will lead to novel therapeutic strategies.鈥�
DNA repair and breast cancer
Mutations in聽BRCA聽genes can disrupt 鈥� and inactivate 鈥� a mechanism that cells use to fix breaks in their DNA. The loss of this repair mechanism can lead to cancer. Women who inherit mutations in these genes have increased risk for breast cancer.
More recently, researchers uncovered a lesser-known mechanism of DNA repair called theta-mediated end-joining. This is a repair mechanism that researchers believe cells normally use only when they cannot use more reliable repair mechanisms. It is more error-prone, Gupta said, meaning it can lead to errors in the DNA sequence.
鈥淯苍濒颈办别听BRCA, which can be inactivated in certain breast cancers, we think this pathway gets hyper-activated in tumors,鈥� Gupta said. 鈥淚t鈥檚 a more mutation-prone pathway that may confer advantages to tumors as they develop.鈥�
New study findings
In their study, Gupta and his colleagues found a series of genetic alterations they believe cause cells to become 鈥渁ddicted鈥� to the more error-prone DNA repair pathway in order to survive.
When they analyzed breast cancer samples from The Cancer Genome Atlas, they found about 30 percent of breast cancers in that patient group had alterations in those genes, and that these cancers had evidence, or 鈥渟cars,鈥� that indicated high levels of theta-mediated end-joining.
鈥淥ur work raises the possibility that these genomic scars might be useful as predictors of addiction to this polymerase theta-dependent pathway,鈥� Gupta said.
Potential treatment implications
Inhibitors of the polymerase theta protein that drives this form of DNA repair are in development, Gupta said.
Given the possibility that some breast cancer cells may be relying on this error-prone pathway to fix their DNA, some scientists think the newly discovered genes could help identify which cancers might be susceptible to potential treatments that block this repair mechanism.
鈥淭here is an open question in terms of: What are the clinical contexts in which polymerase theta inhibitors would be most effective?鈥� Gupta said. 鈥淥ur work begins to address this topic by identifying a set of gene mutations that may confer greater dependence on this pathway.鈥�
In addition to Gupta, other authors included Wanjuan Feng, Dennis A. Simpson, Juan Carvajal-Garcia, Brandon A. Price, Rashmi J. Kumar, Lisle E. Mose, Richard D. Wood, Naim Rashid, Jeremy E. Purvis, Joel S. Parker and Dale A. Ramsden.
The study was funded in part by聽the National Cancer Institute, the Burroughs Wellcome Fund. the University Cancer Research Fund and the U.S. Department of Defense.
Story courtesy of 黑料网 Healthcare.