Research led by Roswell Park and Genome Protection Inc. zeroes in on activated retrotransposons
BUFFALO, N.Y. — Research led by Roswell Park Comprehensive Cancer Center and Genome Protection Inc. has detected activity in the “dark genome” that could help transform the diagnosis and treatment of five of the 10 most deadly cancers in the U.S.
Lung, pancreatic, ovarian, liver and esophageal cancer — which collectively claim more than 235,000 lives annually — are often called “silent killers” because typically they’re not diagnosed until symptoms appear in the late stages, when a cure is unlikely. The research team — co-led by Andrei Gudkov, PhD, DSci, Senior Vice President, Research Technology and Innovation and the Garman Family Chair in Cell Stress Biology at Roswell Park, and Katerina Andrianova, PhD, who at the time the work was done was Vice President of Research and Development Genome Protection Inc. — discovered that the immune system begins to mount an attack against these cancers even when they have advanced only to stage 1 or stage 2, producing antibodies that can be detected with an immunoassay when the disease is at a more treatable stage.
Their findings appear in “Cancer Relevance of Circulating Antibodies Against LINE-1 Antigens in Humans,” published in Cancer Research Communications, with Alexandra Vylegzhanina, PhD, Project Leader at Genome Protection Inc., as first author.
Dr. Andrei Gudkov
“Oncology research is increasingly turning its attention to the so-called ‘dark genome,’” explains Dr. Gudkov. “This is a vast array of highly repetitive, virus-like genetic elements dispersed throughout our DNA. Known as retrotransposons, these elements typically remain silent in normal cells but are commonly derepressed — or activated — in cancer.”
Dr. Gudkov and colleagues had reported previously that Long Interspersed Nucleotide Element-1 (LINE-1) retrotransposons, which comprise more than 17% of human DNA, make it possible for cancer cells to escape chemotherapy and other cancer drugs. The immune system recognizes desilencing of LINE-1 retrotransposons by producing antibodies against their proteins. When those antibodies are detected in the blood, they could serve as a red flag to indicate the presence of cancer.
The researchers developed an immunoassay to do just that, utilizing Roswell Park’s Data Bank and BioRepository to test blood samples from more than 3,000 people, including both cancer patients and healthy people. They found that antibodies against LINE-1 antigens were especially high in patients with lung, pancreatic, ovarian, liver and esophageal cancer, even those with early-stage disease.
“This discovery sets the stage for the development of diagnostics and immunotherapies for these challenging cancer types,” says Dr. Gudkov.
The study was a collaborative effort among several institutions, including the Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California; the I. V. Davydovsky Clinical City Hospital, Moscow; Yale University, New Haven, Connecticut; and the University of Chicago Comprehensive Cancer Center.
The study was supported by a contract from Genome Protection Inc. to Dr. Gudkov.