Abstract
Most chondroblastomas have H3F3B mutations, but giant cell tumors only have mutations in H3F3A.
Major finding: Most chondroblastomas have H3F3B mutations, but giant cell tumors only have mutations in H3F3A.
Concept: Giant cell tumor H3F3A mutations are distinct from those observed in pediatric brain tumors.
Impact: Histone H3.3 genes and mutations may have distinct roles in development and tumorigenesis.
Chondroblastoma is a rare benign tumor type that affects the cartilaginous growth plates of long bones in children and young adults. To gain insight into the etiology of chondroblastoma, Behjati and colleagues sequenced the genomes of six chondroblastomas and matched normal DNA. Strikingly, all six tumors had somatic mutations in either of the genes encoding histone H3.3, H3F3A (one tumor) or H3F3B (five tumors), each of which affected lysine 36 (Lys36Met). Sequencing of H3F3A and H3F3B in an additional 71 chondroblastomas identified histone H3.3 Lys36Met mutations in a total of 73 of 77 tumors (95%), predominantly in H3F3B (68 of 73 tumors; 93%). The authors screened seven other types of bone and cartilage tumors for H3F3A and H3F3B mutations and found that 49 of 53 giant cell tumors of bone (92%) harbored mutations in H3F3A, whereas few, if any, mutations affecting histone H3.3 or other related histone H3 genes were found in other tumor types. Each giant cell tumor H3F3A mutation affected glycine 34, resulting in either a substitution to tryptophan (Gly34Trp; 48 tumors) or leucine (Gly34Leu; 1 tumor). Interestingly, these mutations are distinct from the recurring H3F3A mutations recently identified in pediatric gliomas, which result in Gly34Arg, Gly34Val, or Lys27Met. The mutual exclusivity of histone H3.3 mutations in different tumor types derived from different lineages is surprising given that H3F3A and H3F3B encode proteins with an identical amino acid sequence, and suggests that H3F3A and H3F3B are unlikely to have redundant roles in development and tumorigenesis. Although the roles of histone H3.3 mutations in the pathogenesis of giant cell tumor of bone and chondroblastoma remain to be determined, these findings also suggest that H3F3A and H3F3B mutations may be useful diagnostic markers for these tumors.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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