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

2013; Nature Portfolio; Volume: 45; Issue: 12 Linguagem: Inglês

10.1038/ng.2814

1546-1718

Sam Behjati, Patrick Tarpey, Nadège Presneau, Susanne Scheipl, Nischalan Pillay, Peter Van Loo, David C. Wedge, Susanna L. Cooke, Gunes Gundem, Helen Davies, Serena Nik‐Zainal, Sancha Martin, Stuart McLaren, Victoria Goody, Ben Robinson, Adam Butler, Jon W. Teague, Dina Halai, Bhavisha Khatri, Ola Myklebost, Daniel Baumhoer, Gernot Jundt, Rifat Hamoudi, Roberto Tirabosco, Maria Fernanda Amary, P. Andrew Futreal, Michael R. Stratton, Peter J. Campbell, Adrienne M. Flanagan,

Cancer-related molecular mechanisms research

Adrienne Flanagan and colleagues identify distinct driver mutations in H3F3A and H3F3B in chondroblastoma and giant cell tumor of bone. The mutations occur in over 90% of tumors and exhibit a high degree of tumor type specificity. 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.