A discovery has allowed researchers to attribute two types of tumor almost entirely to specific mutations that lie in two related genes. These mutations are found in nearly 100 percent of patients suffering from two rare bone tumors; chondroblastoma and giant cell tumor of the bone.

Chondroblastoma and giant cell tumor of bone are benign bone tumors that primarily affect adolescents and young adults, respectively. They can be extremely debilitating tumors and recur despite surgery. Occasionally, these tumors can be difficult to differentiate from highly malignant bone cancers. The mutations found in this study may be used for diagnosis of chondroblastoma and giant cell tumor. In addition, the mutations offer a starting point into research for a specific treatment against these tumors. 


The team sequenced the full genomes of six chondroblastoma tumors and found that all six tumors had mutations in one of two related genes, H3F3A and H3F3B, which produce an identical protein, called histone 3.3.

"This is an exceptional, if not a once in a lifetime discovery for the team," says Dr. Peter Campbell, co-lead author of the study from the Wellcome Trust Sanger Institute.
"What we normally see is that the same mutations occur in many different types of tumor. These mutations, however, are highly specific to these tumors. Moreover, our findings suggest that these mutations are the key, if not the sole, driving force behind these tumors."

Extending the study to more chondroblastoma tumors and to other bone tumors, they were able to verify that this mutation was found in almost all cases of chondroblastoma. Interestingly, the team also observed that most cases of a different type of bone tumor, giant cell tumor of bone, have a mutation in the H3F3A gene, albeit in a different position in the gene. A pattern emerged where both tumor types, chondroblastoma and giant cell tumor of bone, are defined by specific histone 3.3 mutations.

The team pinpointed the specificity of these mutations to affecting a single amino acid residue on the histone 3.3 protein; G34W amino acid residue underlies giant cell tumor of the bone and K36M amino acid residue underlies chondroblastoma.

"The high prevalence of these mutations in each tumor type is striking, but what's most remarkable is the unprecedented specificity of these mutations," says Dr Sam Behjati, first author from the Wellcome trust Sanger Institute. "The specificity of the mutations not only informs us about how these tumors develop, but also points to some fundamental function of these genes in normal bone development."

"Our findings will be highly beneficial to clinicians as we now have a diagnostic marker to differentiate chondroblastoma and giant cell tumor of bones from other bone tumors," says Professor Adrienne Flanagan, co-lead author from the Royal National Orthopaedic Hospital, and UCL Cancer Institute. "This study highlights the importance of continuing to sequence all types of human cancer."

"We are also extremely grateful to our patients and collaborators, without their help we would not have been able to study these extremely rare diseases," adds Professor Flanagan.