The present invention relates to the field of cancer. More specifically, the present invention provides methods and compositions related to certain promoter mutations in cancer. In one embodiment, a method for treating a subject having thyroid cancer comprises the steps of (a) obtaining a biological sample from the subject; (b) performing an assay on the sample obtained from the subject to identify a mutation at 1 295 228 C>T (C228T) and 1 295 250 C>T (C250T), corresponding to ?124 C>T and ?146 C>T from the translation start site in the promoter of the telomerase reverse transcriptase (TERT) gene; (c) identifying the subject as having or likely to develop aggressive thyroid cancer if the C228T and/or C250T mutation is identified; and (d) treating the subject with one or more treatment modalities appropriate for a subject having or likely to develop aggressive thyroid cancer.