Somatic mutations of the CD95 gene in Hodgkin and Reed-Sternberg cells

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Classical Hodgkin's disease (cHD) involves Hodgkin and Reed-Sternberg (H/RS) cells, believed to originate from germinal center B cells.
• The mechanisms by which these precursor cells evade apoptosis, a critical process in germinal centers, remain largely unknown.

Purpose of the Study:

• To investigate somatic mutations in the CD95 gene within H/RS cells from cHD patients.
• To determine the role of CD95 gene mutations in the escape of H/RS cell precursors from apoptosis.

Main Methods:

• Single H/RS cells were isolated from 10 cHD cases using micromanipulation.
• The CD95 gene, including its 5' regions and the death domain-coding exon, was analyzed for somatic mutations.
• The IkappaB alpha gene was also examined for mutations.

Main Results:

• Clonal mutations within the CD95 gene were identified in H/RS cells from two cHD cases.
• Mutations included alterations in the 5' regions and the death domain, with some H/RS cells exhibiting monoallelic stop-codon or replacement mutations.
• These CD95 mutations are predicted to impair CD95 function, potentially hindering apoptosis.
• All analyzed H/RS cells also carried inactivating mutations in the IkappaB alpha gene.

Conclusions:

• Somatic mutations in the CD95 gene are present in a subset of cHD cases.
• These CD95 mutations may contribute to the survival of H/RS cell precursors by enabling escape from CD95-mediated apoptosis.
• Mutations in the IkappaB alpha gene appear to precede CD95 gene mutations in the oncogenic pathway of cHD.