Somatic Mutation Discovery

Background:

Castleman disease (CD) is a heterogeneous group of disorders involving systemic inflammation and polyclonal lymphoproliferation. Of note, there are no clonal cell populations that are visible microscopically and no evidence of spreading or “metastasis” which is often the case with somatically-mutated/clonal malignancies. Nevertheless, given the clinico-pathologic similarities between iMCD and disorders like Hodgkin lymphoma and angioimmunoblastic T cell lymphoma, the field has long hypothesized that a rare population of somatically mutated clonal cells may be involved in UCD and iMCD pathogenesis. Recently, somatic mutations have been described in a couple studies of unclear/poor quality in patients with unicentric CD (UCD) and idiopathic multicentric CD (iMCD). suggesting a potential role for somatically mutated cells in pathogenesis. Given that the lymph node is the site of histopathologic changes required to diagnose CD, the lymph node tissue has been considered the most likely site where somatically mutated cells may be if present in CD.

Project Plan:

Extracted DNA from FFPE slides from 84 patients including multiple CD subtypes, positive disease controls, and healthy individuals as well as extracted DNA from PBMC samples which will be used to screen out potential germline mutation.

Research Questions:

  1. QC: Are there somatic mutations identified in the 14 healthy controls between DNA from the lymph node tissue and the spleen (negative control)? Hypothesize no.

  2. QC: Are there somatic mutations identified in the 5 ulcerative colitis lymph node samples (negative control)? Hypothesize no.

  3. QC: Are there somatic mutations identified in the DLBCL samples that have been previously reported in DLBCL (positive control)? Hypothesize yes.

  4. Are there multiple, recurrent somatic mutations in the same gene (and/or same locus) in lymph node tissue across multiple patients in our CD cohort? 

  5. Are there multiple somatic mutations in different genes in the same pathway in lymph node tissue across multiple patients in our CD cohort?

  6. Are there any single somatic mutations that may be involved in CD and require further functional studies?