Kathleen Burns, M.D., Ph.D. is a physician-scientist and practicing hematopathologist. Her research laboratory studies roles that repetitive DNAs and transposable elements play in human disease.
Specific types of transposons are active in modern humans, and the Burns lab was one of the first to develop strategies to map insertion sites of these elements in the human genome. Their observations underscored that transposons are major sources of genetic structural variation in human populations. Over the next decade, catalogs of commonly-occurring mobile element insertion alleles grew, and the group led efforts to identify those variants that may be relevant to disease risk by integrating information about these insertions with findings of genome wide association studies (GWAS). Using experimental systems, the lab has shown that inherited transposable element insertion alleles can affect gene transcription and mRNA splicing, demonstrating molecular mechanisms for how transposons may impact phenotypes. Together, these avenues of investigation have shown that we each inherit a unique compliment of transposon insertions – thousands of LINE-1, Alu, SVA, and ERV alleles – and that a specific subset of these sequences potentially affects our likelihood to develop disease.
The laboratory has also had a long-standing interest in transposable element expression in human malignancies. Many cancers undergo epigenetic changes that permit the expression of otherwise silenced transposable elements. Here, the Burns lab is best known for their research on Long INterspersed Element-1 (LINE-1, L1), the only protein-coding retrotransposon active in modern humans. They were the first to develop and commercialize a monoclonal antibody to detect the LINE-1-encoded RNA-binding protein, open reading frame 1 protein (ORF1p). Using this reagent, they showed that LINE-1 expression is a hallmark of human cancers, including many of the most lethal of these diseases – lung, prostate, breast, colon, pancreatic, and ovarian cancers. The lab is now exploring whether ORF1p has utility as a marker for cancer detection. The Burns lab has also shown that ORF1p expression is an indicator of LINE-1 activity as a mobile genetic element – cancers that express ORF1p have somatically-acquired insertions of genomic LINE-1 sequences that distinguish tumor genomes from a patient’s constitutional genetic make-up. Finally, the lab is beginning to study LINE-1 insertion mechanisms and the roles replication-coupled DNA repair pathways have in resolving retrotransposition intermediates. As part of these investigations, the group is testing whether DNA damage incited by LINE-1 retrotransposition can be enhanced in cancers as a therapeutic strategy.
Kathy is a Professor of Pathology at Harvard Medical School and Chair of the Pathology Department at the Dana-Farber Cancer Institute.