The incidence of thyroid cancer has more than doubled in the last 30 years with nearly 50% of this increase attributable to papillary microcarcinomas (PMC). Despite compeling evidence that cautious observation is a safe and effective alternative to immediate surgical resection, very few PMC patients in the United States are given the option of an active surveillance approach. This is in part due to reports in the literature of a small percentage of patients with PMC that develop loco-regional or distant metastases. Unfortunately, neither clinical features, nor the mutational status ofthe known thyroid cancer oncogenes reliably identify the few PMC patients destined to develop clinically significant disease progression. Since only a small minority of PMC progress to clinically significant disease, it is imperative that we critically re-evaluate the current management paradigm that indiscriminately recommends immediate surgical intervention without giving patients an option for active surveillance. We propose to use both paraffin embedded tissue samples from our pathology archives and fresh frozen PMC samples obtained after 2-5 years of observation in a prospective active surveillance trial to identify molecular events that are predictive of disease progression through a comprehensive evaluation of the PMC cancer genome using massively parallel next generation exon sequencing of 230 genes commonly mutated in cancer coupled to quantitative expression profiling using a custom-designed NanoString platform. Our goal is to identify genomic predictors of disease progression in PMC so that tumors likely to develop into clinically significant disease can be surgically removed, whereas the vast majority that are unlikely to grow or metastasize can be followed with periodic surveillance.
Aim 1 : To perform indepth genomic profiling of PMCs without metastatic disease compared to PMCs with loco-regional and/or distant metastasis.
Aim 2 : To identify genomic predictors of disease progression in a prospectively followed population of patients with PMC.
Even though most patients with papillary microcarcinoma (PMC) do not require immediate surgery, very few are given the option of active surveillance. Our goal is to identify molecular predictors of disease progression that can be used to differentiate the PMC patients that may benefit from an early surgical intervention from the remaining majority that can be followed with observation.
|Ganly, Ian; Makarov, Vladimir; Deraje, Shyamprasad et al. (2018) Integrated Genomic Analysis of Hürthle Cell Cancer Reveals Oncogenic Drivers, Recurrent Mitochondrial Mutations, and Unique Chromosomal Landscapes. Cancer Cell 34:256-270.e5|
|De Martino, Daniela; Yilmaz, Emrullah; Orlacchio, Arturo et al. (2018) PI3K blockage synergizes with PLK1 inhibition preventing endoreduplication and enhancing apoptosis in anaplastic thyroid cancer. Cancer Lett 439:56-65|
|Marlow, Laura A; Rohl, Stephen D; Miller, James L et al. (2018) Methodology, Criteria, and Characterization of Patient-Matched Thyroid Cell Lines and Patient-Derived Tumor Xenografts. J Clin Endocrinol Metab 103:3169-3182|
|Krishnamoorthy, Gnana P; Davidson, Natalie R; Leach, Steven D et al. (2018) EIF1AX and RAS mutations cooperate to drive thyroid tumorigenesis through ATF4 and c-MYC. Cancer Discov :|
|Untch, Brian R; Dos Anjos, Vanessa; Garcia-Rendueles, Maria E R et al. (2018) Tipifarnib Inhibits HRAS-Driven Dedifferentiated Thyroid Cancers. Cancer Res 78:4642-4657|
|Knauf, Jeffrey A; Luckett, Kathleen A; Chen, Kuen-Yuan et al. (2018) Hgf/Met activation mediates resistance to BRAF inhibition in murine anaplastic thyroid cancers. J Clin Invest 128:4086-4097|
|Anelli, Viviana; Villefranc, Jacques A; Chhangawala, Sagar et al. (2017) Oncogenic BRAF disrupts thyroid morphogenesis and function via twist expression. Elife 6:|
|Tuttle, R Michael; Fagin, James A; Minkowitz, Gerald et al. (2017) Natural History and Tumor Volume Kinetics of Papillary Thyroid Cancers During Active Surveillance. JAMA Otolaryngol Head Neck Surg 143:1015-1020|
|Xu, Bin; Tuttle, R Michael; Sabra, Mona M et al. (2017) Primary Thyroid Carcinoma with Low-Risk Histology and Distant Metastases: Clinicopathologic and Molecular Characteristics. Thyroid 27:632-640|
|Montero-Conde, Cristina; Leandro-Garcia, Luis J; Chen, Xu et al. (2017) Transposon mutagenesis identifies chromatin modifiers cooperating with Ras in thyroid tumorigenesis and detects ATXN7 as a cancer gene. Proc Natl Acad Sci U S A 114:E4951-E4960|
Showing the most recent 10 out of 53 publications