A study by Livia Casciola-Rosen, Ph.D. and Ami Shah, M.D. from the Johns Hopkins Division of Rheumatology in collaboration with Steve J. Elledge, Ph.D. and colleagues at MIT and Harvard, used cutting-edge technologies to identify a new subgroup of antibodies present in people without classical scleroderma-associated antibodies who develop cancer and scleroderma within a short period of time.
Why was this study done?
Scleroderma is an autoimmune disease in which two thirds of patients have autoantibodies against one of three different proteins (centromere, topoisomerase I and POLR3A, which will be referred to here as “CTP” antibodies). A subset of scleroderma patients (those with POLR3A antibodies, and those that lack the CTP antibodies) get cancer within an average of 3 years of scleroderma onset. In this study, we used two cutting-edge technologies to search for new antibody biomarkers within the CTP negative group of scleroderma patients to identify scleroderma patients at risk for cancer.
How was this study done?
For this study, two different approaches to autoantibody discovery were used to test blood samples from two very well-defined groups of scleroderma patients who had a short interval between receiving a diagnosis of scleroderma and cancer (the POLR3A positive and CTP negative groups). These complementary high-throughput techniques identify proteins that are specifically targeted by antibodies in the patients’ blood. This is done by mixing the serum fraction of the blood with a vast library of potential proteins and letting the antibodies bind to the precise proteins that are recognized. After that, the antibodies and their bound proteins, each marked by a unique DNA tag, are attached to magnetic beads and pulled down with a magnet. High-throughput sequencing of the mixture of DNA tags then reveals the identity of which proteins were recognized by the antibodies in the patient’s blood.
What were the major findings?
We found that antibodies targeting RNPC3, a protein found in the nucleus of all cells, are found in the blood of a group of CTP negative patients with a short interval between their scleroderma diagnosis and the detection of cancer. Our findings highlight that these new high-throughput discovery methods are effective at identifying new antibody biomarkers in patients with rheumatic diseases, especially when complementary approaches are used to study well-defined groups of patients.
What is the impact of this work?
By using powerful antigen discovery techniques to study well-defined patients in whom cancer and scleroderma are detected within a short time, a new subset of scleroderma patients marked by antibodies to RNPC3 was identified. Such approaches will be important in the evolving precision medicine era, where specific targets of the immune response in patients with autoimmunity or cancer may predict outcome or direct physicians in choosing the most effective treatment.
This research was supported by:
The Scleroderma Research Foundation and the National Institutes of Health (K23 AR061439 and R01 DE-12354).
Link to original research article:
Systematic autoantigen analysis identifies a distinct subtype of scleroderma with coincident cancer. Xu GJ, Shah AA, Li MZ, Xu Q, Rosen A, Casciola-Rosen L, Elledge SJ. Proc Natl Acad Sci U S A. 2016 Nov 22;113(47):E7526-E7534.