Grant given to Texas Children's Hospital Histiocytosis Program of $25,000 in January 2015: LCH Sequencing Studies

Grant given to Texas Children's Hospital Histiocytosis Program of $25,000 in January 2015:  LCH Sequencing Studies

Summary of LCH Sequencing Studies:

1. Targeted sequencing of MAPK and related genes in a large patient cohort (goal=1000 cases)
2. Extended discovery strategies (whole genome sequencing, RNASeq) to identify additional genetic causes of LCH
3.  Clinical correlation between specific somatic mutations and clinical outcomes to develop therapeutic risk-stratification strategies.

We have investigated all of the regions of DNA that are used to give instructions for making RNA and proteins in LCH lesions and matched blood from the same patients, with some remarkable findings.  First, compared to classic pediatric “cancers”, there are an extremely small number of genetic changes in the LCH lesions.  However, almost every patient has a change (or mutation) in genes that encode proteins in a pathway that regulates cell growth, proliferation and development, called the Map kinase (MAPK) pathway.  Approxiately 50% of patients have a mutation in the B-RAF gene, another 25% have a mutation in a gene called MAP2K1, and other potentially significant mutations were found in other MAPK genes.

In order to fully define the mutations that may give rise to LCH, we plan to perform targeted sequencing of a limited panel of candidate genes in a much larger number of LCH samples.  In addition to discovering more rare mutations that may lead to LCH, these experiments will be linked to long-term clinical information to determine the impact of specific mutations on clinical outcomes.

For the few cases (~25%) where no mutation is discovered by targeted sequencing, we will perform more extensive studies to look at the entire genome (whole genome sequencing) as well as RNA profile (RNASeq) to identify other potential mechanisms of pathogenesis in LCH.

By the end of this study, we should be able to develop an approach to define the vast majority of mutations that cause LCH and also to interpret the clinical significance of these mutations.  In the future, this information may be used to incorporate a personalized approach to therapy for patients with LCH.  Specific mutations may determine intensity and duration of therapy for each patient, as well as potential to use specific targeted drugs.