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Published OnlineFirst November 7, 2013; DOI: 10.1158/2159-8290.CD-RW2013-244

RESEARCH WATCH

Mutations

Major finding: Most chondroblastomas Concept: Giant cell tumor H3F3A Impact: Histone H3.3 genes and muta- have H3F3B mutations, but giant cell mutations are distinct from those tions may have distinct roles in devel- tumors only have mutations in H3F3A. observed in pediatric brain tumors. opment and tumorigenesis.

HISTONE H3.3 MUTATIONS ARE CANCER TYPE-SPECIFIC Chondroblastoma is a rare benign tumor type 48 tumors) or leucine (Gly34Leu; 1 tumor). Inter- that affects the cartilaginous growth plates of estingly, these mutations are distinct from the long bones in children and young adults. To gain recurring H3F3A mutations recently identifi ed insight into the etiology of chondroblastoma, in pediatric gliomas, which result in Gly34Arg, Behjati and colleagues sequenced the genomes of Gly34Val, or Lys27Met. The mutual exclusivity of six chondroblastomas and matched normal DNA. histone H3.3 mutations in different tumor types Strikingly, all six tumors had somatic mutations in derived from different lineages is surprising given either of the genes encoding histone H3.3, H3F3A that H3F3A and H3F3B encode proteins with an (one tumor) or H3F3B (fi ve tumors), each of which affected identical amino acid sequence, and suggests that H3F3A and lysine 36 (Lys36Met). Sequencing of H3F3A and H3F3B in H3F3B are unlikely to have redundant roles in development an additional 71 chondroblastomas identifi ed histone H3.3 and tumorigenesis. Although the roles of histone H3.3 muta- Lys36Met mutations in a total of 73 of 77 tumors (95%), tions in the pathogenesis of giant cell tumor of bone and predominantly in H3F3B (68 of 73 tumors; 93%). The authors chondroblastoma remain to be determined, these fi ndings screened seven other types of bone and cartilage tumors for also suggest that H3F3A and H3F3B mutations may be useful H3F3A and H3F3B mutations and found that 49 of 53 giant diagnostic markers for these tumors. ■ cell tumors of bone (92%) harbored mutations in H3F3A, whereas few, if any, mutations affecting histone H3.3 or other Behjati S, Tarpey PS, Presneau N, Scheipl S, Pillay N, Van Loo P, related histone H3 genes were found in other tumor types. et al. Distinct H3F3A and H3F3B driver mutations defi ne chondro- Each giant cell tumor H3F3A mutation affected glycine 34, blastoma and giant cell tumor of bone. Nat Genet 2013 Oct 27 [Epub resulting in either a substitution to tryptophan (Gly34Trp; ahead of print].

Lung Cancer

Major finding: Gene fusions involving Concept: TRKA inhibitors block TRKA Impact: Patients with NTRK1-rearranged NTRK1 (which encodes TRKA) were iden- autophosphorylation and proliferation NSCLC may benefit from treatment with tified in 3.3% of patients with NSCLC. in cells expressing NTRK1 fusions. TRKA-selective inhibitors.

ACTIONABLE NTRK1 REARRANGEMENTS OCCUR IN NSCLC Selective kinase inhibitors have shown activity in a subset MPRIP–NTRK1 and CD74–NTRK1 led to TRKA autophos- of patients with non–small cell lung cancers (NSCLC) that phorylation and induced cytokine-independent growth, harbor activating mutations or rearrangements in EGFR, anchorage-independent growth, and tumor formation in ALK, ROS1, and RET, but many patients with NSCLC nude mice, suggesting that these fusions are oncogenic. lack these genetic alterations and are not candidates for Treatment of NTRK1 fusion-expressing cells with the TRKA- the corresponding targeted therapies. Vaishnavi and col- selective inhibitor ARRY-470 or less specifi c inhibitors such leagues performed next-generation sequencing on 36 as lestaurtinib or crizotinib blocked TRKA autophospho- NSCLCs without mutations in genes known to be muta ted rylation, suppressed proliferation, and inhibited colony or rearranged in lung cancer and found two in-frame formation in soft agar. Based on these fi ndings, the patient fusion events involving the kinase domain of neurotrophic with the MPRIP–NTRK1 fusion, for whom no standard tyrosine kinase receptor type 1 (NTRK1), which encodes therapies were available, was treated with crizotinib. The the nerve growth factor receptor transforming tyrosine patient experienced a minor radiologic response although kinase protein A (TRKA). NTRK1 was fused to myosin her disease progressed after approximately 3 months. These phosphatase Rho interacting protein (MPRIP) in one case results provide a rationale for clinical evaluation of TRKA- and the major histocompatibility complex class II invari- selective inhibitors for NTRK1-rearranged NSCLC. ■ ant chain gene, CD74, in another. A third fusion involving NTRK1 and an unknown locus was identifi ed among 56 Vaishnavi A, Capelletti M, Le AT, Kako S, Butaney M, Ercan D, additional NSCLCs by fl uorescent in situ hybridization, et al. Oncogenic and drug-sensitive NTRK1 rearrangements in lung for an overall frequency of 3.3%. Forced expression of cancer. Nat Med 2013;19:1469–72.

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.

DECEMBER 2013CANCER DISCOVERY | 1329

Actionable NTRK1 Rearrangements Occur in NSCLC

Cancer Discovery 2013;3:1329. Published OnlineFirst November 7, 2013.

Updated version Access the most recent version of this article at: doi:10.1158/2159-8290.CD-RW2013-244

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