RESEARCH HIGHLIGHTS Nature Reviews Clinical Oncology advance online publication 11 November 2014; doi:10.1038/nrclinonc.2014.193
GENETICS
T
he most-common form of thyroid cancer is papillary thyroid carcinoma (PTC), the incidence of which is increasing. Although PTC generally has a good prognosis, with 5-year survival often exceeding 95%, some cases dedifferentiate into more-aggressive tumours. The Cancer Genome Atlas (TCGA) Research Network have turned their attention to this disease, and have published new data that improve our understanding of the biology of PTC. The TCGA researchers used their multiplatform ‘omics’ methodology, comprising next-generation DNA and RNA sequencing, copy-number analysis, and transcriptomic, methylomic and proteomic assays, to comprehensively characterize 496 PTCs at the molecular level. These data were combined with clinicopathological data to correlate the molecular findings with factors such as histopathological subtype, and risk of recurrence and mortality. Clinically aggressive tumours were excluded to focus on the categorization of driver mutations. At the most basic level, this study expands the landscape of somatic mutations underlying PTC. A number of almost mutually exclusive, recurrent mutations were identified, some of which are well-known drivers of PTC development (such as BRAF and the RAS genes). However, “we also found entirely new driving mutations (EIF1AX), as well as new variants of the previously known oncogenes,” says Tom Giordano, one of the leaders of the project. In addition, mutually exclusive gene fusions, some previously known (such as RET, NTRK1 and recently described ALK fusions) and some novel, were identified. “We found nine different fusions involving BRAF, which nicely illustrated how promiscuous BRAF can be and, together with some small deletions and BRAFV600E hotspot mutations, also illustrate the many ways that BRAF can be activated to create an oncogene,” Giordano explains.
These discoveries by the TCGA reduced the proportion of PTCs with unknown driver mutations from 25% to 70% of the tall-cell variant tumours, which were typically BRAFV600E‑mutated, had the lowest BRS and TDS values, and were associated with more-advanced stage, high-risk disease. “We think this paper justifies a reclassification of thyroid cancer by the pathology community,” concludes Giordano. Thus, the BRS and TDS scoring systems, and the associated reclassification of PTC subtypes could have important ramifications for patient stratification. David Killock Original article The Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell 159, 676–690 (2014)
ADVANCE ONLINE PUBLICATION © 2014 Macmillan Publishers Limited. All rights reserved
GENETICS
T
he most-common form of thyroid cancer is papillary thyroid carcinoma (PTC), the incidence of which is increasing. Although PTC generally has a good prognosis, with 5-year survival often exceeding 95%, some cases dedifferentiate into more-aggressive tumours. The Cancer Genome Atlas (TCGA) Research Network have turned their attention to this disease, and have published new data that improve our understanding of the biology of PTC. The TCGA researchers used their multiplatform ‘omics’ methodology, comprising next-generation DNA and RNA sequencing, copy-number analysis, and transcriptomic, methylomic and proteomic assays, to comprehensively characterize 496 PTCs at the molecular level. These data were combined with clinicopathological data to correlate the molecular findings with factors such as histopathological subtype, and risk of recurrence and mortality. Clinically aggressive tumours were excluded to focus on the categorization of driver mutations. At the most basic level, this study expands the landscape of somatic mutations underlying PTC. A number of almost mutually exclusive, recurrent mutations were identified, some of which are well-known drivers of PTC development (such as BRAF and the RAS genes). However, “we also found entirely new driving mutations (EIF1AX), as well as new variants of the previously known oncogenes,” says Tom Giordano, one of the leaders of the project. In addition, mutually exclusive gene fusions, some previously known (such as RET, NTRK1 and recently described ALK fusions) and some novel, were identified. “We found nine different fusions involving BRAF, which nicely illustrated how promiscuous BRAF can be and, together with some small deletions and BRAFV600E hotspot mutations, also illustrate the many ways that BRAF can be activated to create an oncogene,” Giordano explains.
These discoveries by the TCGA reduced the proportion of PTCs with unknown driver mutations from 25% to 70% of the tall-cell variant tumours, which were typically BRAFV600E‑mutated, had the lowest BRS and TDS values, and were associated with more-advanced stage, high-risk disease. “We think this paper justifies a reclassification of thyroid cancer by the pathology community,” concludes Giordano. Thus, the BRS and TDS scoring systems, and the associated reclassification of PTC subtypes could have important ramifications for patient stratification. David Killock Original article The Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell 159, 676–690 (2014)
ADVANCE ONLINE PUBLICATION © 2014 Macmillan Publishers Limited. All rights reserved
