Characterize the Effect of Risk Variant in SMAD6 (Rs12438941, G>A) On Langerhans Cell Histiocytosis Disease Pathogenesis
Background
Langerhans cell histiocytosis (LCH), the most common histiocytic disorder, is a rare form of cancer that occurs mostly in children. The incidence of LCH is 4 to 8 cases per million children, similar to that observed in Hodgkin Lymphoma or acute myeloid leukemia; however, it remains a poorly understood disease. Rationale for treatment is largely empiric, resulting in an upfront chemotherapy failure rate of 50%, leading to disease progression that results in considerable short-term morbidity and significant late effects. Moreover, there are no biomarkers available to assist with difficult clinical decisions to initiate potentially toxic therapies that are essential for certain LCH patients. Despite advances to elucidate the somatic mutational landscape underlying LCH pathogenesis, germline risk factors remain unknown, even though there are significant differences in LCH prevalence across different ethnic groups. We therefore conducted the first genome-wide association study of LCH and identified a risk variant in SMAD6 (rs12438941, G>A) associated with increased LCH risk. SMAD6 protein normally functions to keep in check bone morphogenetic protein (BMP) and transforming growth factor-beta (TGF-beta) signaling pathways, whose activation is an underlying phenomenon in Langerhans cell differentiation.
Project Goal
Hence, the overall objective of the current study is to characterize the role of SMAD6 variant on LCH susceptibility and pathogenesis. Interestingly, we observed that the SMAD6 risk variant disrupted SMAD6 protein expression, but not messenger RNA. Whether a gene is "on" or "off" is controlled at two different levels, first by reading the gene's DNA into a slightly different chemical copy called messenger RNA and second by using molecular machines called ribosomes to read the information in the messenger RNA and make the protein product, which is the actual functional manifestation of the gene within the cell. Given that it is SMAD6 protein, and not RNA, production that seems to be affected by the SMAD6 variant, we hypothesize that the SMAD6 (rs12438941, G>A) variant is leading to inhibition of SMAD6 protein production by generating alternate RNA forms that can either not use the protein synthesis machinery or are making proteins that are actively getting degraded. Hence as part of ALSF's POST Program, Ms. Hahne's goals will be to test this hypothesis by determining the alternate SMAD6 RNA isoforms resulting due to the risk variant and how they negatively impact SMAD6 protein production. This will potentially lay the platform for improved genetic testing and counseling strategies in LCH patients and their families.
Mentored by Dr. Rikhia Chakraborty
Baylor College of Medicine, Houston, TX
