Hui AB, Lin A, Xu W, Waldron L, Perez-Ordonez B, Weinreb I, et al. Potentially prognostic miRNAs in HPV-associated oropharyngeal carcinoma. Clin Cancer Res; Published OnlineFirst March 4, 2013; doi:10.1158/1078-0432.CCR-12-3572.Oropharyngeal carcinoma consists of at least 2 distinct diseases distinguished by human papillomavirus (HPV) status. In contrast with HPV-negative disease, HPV-positive oropharyngeal carcinoma is not associated with tobacco use, and these patients have a less aggressive course clinically. The molecular aberrations that distinguish HPV-positive from HPV-negative oropharyngeal carcinoma tumors are poorly understood. Hui and colleagues examined microRNAs (miRNA) expressed in oropharyngeal carcinoma tumors, identified how the miRNAs differ based on HPV status, and reported the associations between these characteristics and clinical outcomes. In a set of miRNAs associated with oropharyngeal carcinoma they found mir-21 (MIR21), an miRNA implicated in a number of cancers, to be consistently upregulated relative to normal tonsil tissues. Among miRNAs differentially expressed in oropharyngeal carcinoma, the authors then identified a set of 9 miRNAs correlated with both HPV status and p16 (CDKN2A) status, the latter a surrogate marker for HPV. Correlation of miRNA profiles with 3 different measures of clinical outcome (overall survival, diseasefree survival, and distant metastasis) revealed 5 additional miRNAs that were significantly associated with clinical outcomes. Consistent with the outcome correlation based onHPVstatus, they observed some overlap between HPV-associated and clinical outcome–associated miRNAs; however, their gene sets remained significant predictors even after adjustment for HPV status in multivariate analysis. In a comparison of measures of clinical outcome, only miR-151 (MIR151A) remained statistically significant in all 3 gene lists. Interestingly, miR-151 is located on chromosome 8q24.3, a region frequently amplified in oropharyngeal carcinoma and other human cancers. Prior data have shown that overexpression of miR-151 promotes invasion and metastasis in cancer cells. Overall, this study highlights biologic differences between HPV-positive and HPV-negative oropharyngeal carcinoma and points to prognostic factors that stratify outcome groups (in addition to HPV status) in patients.Huang FW, Hodis E, Xu MJ, Kryukov GV, Chin L, Garraway LA. Highly recurrent TERT promoter mutations in human melanoma. Science 2013;339:957–9.Horn S, Figl A, Rachakonda PS, Fischer C, Sucker A, Gast A, et al. TERT promoter mutations in familial and sporadic melanoma. Science 2013;339:959–61.Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA Jr, et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci U S A 2013;110:6021–6.Telomere length shortens with each cell division, yet maintenance of telomere length is essential for preservation of chromosomal integrity. Because cancer cells undergo repeated cell divisions, a number of mechanisms are in place to retain the cells' telomere length. In melanoma, up to 89% of tumors may have increased telomerase reverse transcriptase (TERT) expression due to mutations in the promoter region of the gene (see Huang et al. and Horn et al., below). In the present study, Killela and colleagues came up with the intriguing hypothesis that the mechanisms by which tumor cells maintain telomere length are determined by tissue-specific characteristics. They hypothesized that tumors derived from tissues that rapidly divide leverage epigenetic mechanisms used by stem and progenitor cells to regulate telomerase activity. In contrast, tumors derived fromtissues with a low rate of self-renewal and a low level of telomerase activity require somatic mutations to activate these pathways. To test this hypothesis, they evaluated TERT promoter mutations in 60 tumor types. Most striking was the very high frequency of TERT promoter mutations in certain cancers, including 79% of myxoid liposarcomas, 67% of urothelial carcinomas of the bladder, 51.1% of gliomas, 44.2% of hepatocellular carcinomas, 20.8% of medulloblastomas, and 17% of squamous cells carcinomas of the head and neck. Furthermore, TERT promoter mutations were enriched in select subgroups of tumors, including oral squamous cell carcinomas of the tongue, medulloblastomas in older patients, glioblastomas withamplification of EGFR, and oligodendrogliomas. Although some tumors with a high frequency of TERT promoter mutations were from tissues with low rates of self-renewal, this finding was not universal. Thus, multiple factors likely contribute to the importance of TERT promoter mutations in oncogenesis. Furthermore, in a given tissue, multiple cell types with different renewal capacities may be able to sustain tumor formation. These data, however, clearly support the argument that maintenance of telomere length via somatic mutation is fundamental to specific tumor types. Understanding this dependence will have implications for the biology of these tumors and may reveal novel therapeutic targets and biomarkers of disease.Dawson SJ, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin SF, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med 2013;368:1199–1209.Biomarkers that can reliably monitor treatment response are urgently needed in oncology so as to discontinue ineffective therapies early on and to determine the benefit of new treatments. For patients with breast cancer, cancer antigen 15-3 (CA 15-3; derived from MUC1) can be used but has a sensitivity of 60% to 70%. Enumeration of circulating tumor cells is emerging as a promising biomarker but has a similar sensitivity using the CellSearch System, currently the only test approved by the U.S. Food and Drug Administration. Dawson and colleagues investigated whether circulating tumor DNA (found in the cell-free fraction of blood) carrying tumor-specific sequence alterations can be used for noninvasive monitoring of patients with metastatic breast cancer. This prospective, single-center study included 30 women undergoing active treatment who had genomic alterations identified by sequencing. In these cases, DNA extracted from archival tumor tissue (screened for point mutations in PIK3CA and TP53 and subjected to whole-genome sequencing) was found to be suitable for quantifying circulating tumor DNA in serially collected plasma samples. Data comparing CA 15-3 values, circulating tumor cells, and circulating tumor DNA showed improved sensitivity of circulating tumor DNA as compared with CA 15-3 (85% vs. 59%) and as compared with circulating tumor cells (90% vs. 67%). When circulating biomarkers were compared with computed tomography imaging to assess tumor response, increases in circulating tumor DNA levels reflected progressive disease in 89% of the women, circulating tumor cells increased in 37%, and CA 15-3 levels increased in 50%. Notably, levels of circulating tumor DNA increased on average 5 months before the establishment of progressive disease by imaging. Additionally, increasing levels of circulating tumor DNA were associated with inferior overall survival (P < 0.001), as were circulating tumor cells (P = 0.03) but not levels of CA 15-3. These findings suggest that circulating tumor DNA, which requires the identification of somatic alterations in individual patients, is a biomarker that can be used in serial monitoring and early detection of treatment failure in patients with metastatic breast cancer.Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol 2013;31:860–7.A prominent infiltrate of lymphocytes, especially CD8+ T cells in tumor biopsies, is associated with a good prognosis in several different malignancies. In this clinical study Loi and colleagues asked if increased numbers of tumor-infiltrating lymphocytes in breast cancers would affect prognosis and response to chemotherapy. The authors investigated the relationship among the quantity and location of lymphocytic infiltrate in diagnostic biopsies and clinical outcome in over 2,000 node-positive breast cancer patients. The patients had been recruited into a phase III adjuvant randomized clinical trial of different chemotherapy regimens with a median follow-up of 8 years. In estrogen receptor–negative/HER2-negative breast cancer, each 10% increase in intratumoral and stromal lymphocytic infiltration was associated with a 17% and 15% reduced risk of relapse, respectively, and a 27% and 17% reduced risk of death regardless of the chemotherapy regimen received during the trial. In contrast, in HER2-positive breast cancer, a significant interaction was observed correlating increasing stromal lymphocytic infiltration with benefit from anthracycline-only chemotherapy that was not seen with other chemotherapy regimens. The results of this large study suggest that a host immune response may influence outcomes in certain subtypes of breast cancer. These patients may benefit from immunotherapy, especially after chemotherapy. Pathologic evaluation of tumor-infiltrating lymphocytes is not routinely carried out during cancer diagnoses, but maybe it should be.Bjerke L, Mackay A, Nandhabalan M, Burford A, Jury A, Popov S, et al. Histone H3.3 mutations drive pediatric glioblastoma through upregulation of MYCN. Cancer Discov; Published OnlineFirst March 28, 2013; doi:10.1158/2159-8290.CD-12-0426..Brain tumors represent the most common solid tumors of childhood, with pediatric glioblastoma tumors recently demonstrated to carry mutations in the histone 3 variant H3.3 (H3F3A). These mutations occur at 2 distinct residues, either K27 (midline tumors, younger children) or G34 (hemispheric localization, older children). Bjerke and colleagues performed ChIP-Seq for trimethylation of K36, which resides close to G34, in a G34-mutant pediatric glioblastoma cell line. The proto-oncogene MYCN, a known contributor in pediatric cancers such as neuroblastoma, medulloblastoma, retinoblastoma, and rhabdomyosarcoma, was the most significant differentially bound gene. To validate this result, the authors misexpressed mutant G34 in normal human astrocytes and transformed human fetal glial cells and observed increased expression of MYCN. They went on to demonstrate that inhibitors of Aurora kinase A showed activity preclinically (blocking viability and decreasing levels of MYCN) in G34-mutant glioblastoma cells. This study implicates MYCN as an oncogenic driver in H3F3A-G34 mutant pediatric glioblastoma.Note: Breaking Advances are written by Cancer Research Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.
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