City of Hope researchers recently found mutations in FEN-1, a gene important to DNA repair, in human melanoma and lung, breast and esophageal cancers. They also showed that similar mutations in a mouse model promote a high incidence of lung cancer.
Binghui Shen, Ph.D., professor and director of the Department of Radiation Biology at City of Hope, and colleagues reported their findings in Nature Medicine, which published the results early on its Web site June 24.
“DNA damage is a fundamental way that cancer is initiated,” Shen said. “We have DNA repair systems to protect and fix damage caused by environmental or endogenous causes. In this study we also find that these enzymes keep the immune system in order.”
Certain proteins in the body help control cell growth, Shen explained. Over time, genes that encode these proteins can become damaged, potentially leading to cancer.
Fortunately, DNA repair enzymes usually recognize, remove and repair the genetic damage. But when a gene that encodes a DNA repair enzyme becomes mutated itself, cells are in big trouble — because potentially harmful mutations are ignored by the very cellular tools that ordinarily fix the damage.
Shen has spent over a decade analyzing how the repair enzyme known as FEN-1, short for flap endonuclease-1, helps build normal DNA and also smoothes over breaks or flaps in damaged DNA.
The group, led by first author Li Zheng, Ph.D., a postdoctoral fellow in Shen’s lab, engineered mice to produce one or two copies of mutant FEN-1. When the mice turned about a year old, cancer began to appear — mostly in the lungs, but also in the liver, kidneys and stomach.
Mice developed lung tumors proportional to the number of defective copies of FEN-1 they carried. Lung cancer arose in nearly 37 percent of mice with one defective FEN-1 gene copy, while tumors grew in more than 61 percent of mice with two defective copies of the gene.
The study also made a second, major contribution. The authors showed that before developing cancer, mutant mice showed increased autoimmune disorders and chronic inflammatory responses. “We were surprised, because FEN-1 was known as a DNA repair gene; but when we saw this inflammation effect, we re-examined work we did a couple of years ago and found that FEN-1 mutations are also involved in DNA fragmentation associated with apoptosis,” said Shen. Apoptosis is a form of cellular suicide in which DNA breaks down.
Generation of DNA fragments promotes a condition similar to the autoimmune disease lupus, Shen said. “DNA fragments floating around in the bloodstream look like foreign substances and become auto-antigens generating a lot of auto-antibodies. This is probably the cause of the inflammation,” Shen said. Toxic substances produced by inflammation could then cause DNA damage, leading to cancer, he surmised.
Study co-author Kemp Kernstine, M.D., Ph.D., professor and director of the Lung Cancer and Thoracic Oncology Program and the Department of Thoracic Surgery, notes that the study might lead not only to novel treatments, but also to earlier ways to diagnose lung cancer.
Contributing authors included City of Hope’s Qin Huang, M.D., Huifang Dai, Mian Zhou, M.D., Ph.D., Mei Li, Ph.D., Purnima Singh, Ph.D., Junzhuan Qiu, Ph.D., Walter Tsark, Ph.D., as well as Xuemei Zhang, M.D., Ph.D., and Dongxin Lin, M.D., of the Chinese Academy of Medical Sciences in Beijing. Shen also credited the Animal Resource Center and Kristine Justus, Ph.D., of Faculty and Institutional Support.
The National Institutes of Health and the Lung Cancer and Thoracic Oncology Program funded the research.