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.

Characterization of FN1–FGFR1 and novel FN1–FGF1 fusion genes in a large series of phosphaturic mesenchymal tumors

“…Fortunately, the high prevalence of NAB2-STAT6 fusion (with nuclear STAT6 expression) in solitary fibrous tumor and H3F3A/B hotspot mutations in giant cell tumor and chondroblastoma help to distinguish them from phosphaturic mesenchymal tumors. 44,45 With those three notable exceptions, high-level expression of FGFR1 seems to be relative sensitive and specific for phosphaturic mesenchymal tumor, and may be of some value as an adjunctive test in selected cases.…”

Epigenetic modification in chromatin machinery and its deregulation in pediatric brain tumors: Insight into epigenetic therapies

“…For example, glycine 34 to tryptophan/leucine (G34W/L) mutations occur in giant cell tumors of the bone, lysine 36 to methionine (K36M) mutations have been reported in »95% of chondroblastomas, and H3K36 mutations promote sarcomagenesis. [39][40][41][42] Associated changes in DNA methylation patterns DNA methylation patterns have been extensively studied in adult GBM and have helped guide clinical trials, predicting the recurrence of tumors and resistance to radiotherapy. Indeed, CpG island methylator phenotype (G-CIMP) helped subdivide GBMs into glioma, G-CIMP-positive and G-CIMP-negative GBM subsets, partially predicting response to treatment.…”

Histone Variant H3.3: A versatile H3 variant in health and in disease

“…This spectrum also showed tumor type-specific H3.3 mutations (Behjati et al, 2013). While the K36M substitution was found predominantly in H3F3B gene in chondroblastoma, G34W/L mutation exclusively existed in H3F3A gene.…”

“…Recently, the function of H3.3 has been highlighted by recurrent somatic mutations identified in gliomas and a subset of skeletal neoplasms. These mutations include K27M, G34R/W/V/L, and K36M in both H3F3A and H3F3B genes ( Figure 2B) (Behjati et al, 2013;Schwartzentruber et al, 2012;Sturm et al, 2012;Wu et al, 2012) .…”