Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone

Abstract

It is recognized that some mutated cancer genes contribute to the development of many cancer types, whereas others are cancer type specific. For genes that are mutated in multiple cancer classes, mutations are usually similar in the different affected cancer types. Here, however, we report exquisite tumor type specificity for different histone H3.3 driver alterations. In 73 of 77 cases of chondroblastoma (95%), we found p.Lys36Met alterations predominantly encoded in H3F3B, which is one of two genes for histone H3.3. In contrast, in 92% (49/53) of giant cell tumors of bone, we found histone H3.3 alterations exclusively in H3F3A, leading to p.Gly34Trp or, in one case, p.Gly34Leu alterations. The mutations were restricted to the stromal cell population and were not detected in osteoclasts or their precursors. In the context of previously reported H3F3A mutations encoding p.Lys27Met and p.Gly34Arg or p.Gly34Val alterations in childhood brain tumors, a remarkable picture of tumor type specificity for histone H3.3 driver alterations emerges, indicating that histone H3.3 residues, mutations and genes have distinct functions.

Figure 1. Prevalence and distribution of histone 3.3 mutations in different tumour types

The percentage of cases in each series that harbour a specific histone 3.3 mutation is indicated: paediatric glioblastoma multiforme (light blue); paediatric diffuse intrinsic pontine glioma (dark blue); osteosarcoma (dark orange); giant cell tumour of bone (light orange); clear cell chondrosarcoma (light green); conventional chondrosarcoma (white); chondroblastoma (dark green). Circles represent amino acid residues which are identical for H3F3A and H3F3B. Black circles represent post-translational modifications that occur at residues: me = methylation; ac = acetylation; P = phosphorylation.