The overall goal of this project is to use genetics to improve our chances of preventing, predicting, diagnosing, treating and curing papillary thyroid carcinoma (PTC), which accounts for >80% of all thyroid cancers. Thus far, traditional genetic approaches have failed to pinpoint the culpable predisposing genes. Two genome wide association studies (GWAS) identified five genetic loci associated with highly significant low penetrance predisposition with strong population impact. Two of the pinpointed SNPs reside in conventional translated genes that are pursued elsewhere. Here we focus on the three loci (one in 9q22 and two in 14q13) that are not associated with known genes. Using molecular and in silico methods we have narrowed the regions in which the culpable genomic mutations must reside. In both cases we have identified and delineated novel long intergenic noncoding RNA (lincRNA) genes. These are implicated in the genetic predisposition as shown by their dramatic loss of expression in tumor tissue. These lincRNAs genes are the focus of the first aim of this project. Much more needs to be learned about the mechanistic aspects of the lincRNAs, moreover the culpable genomic mutations must be unequivocally identified.
The second aim focuses on translational studies examining the predictive and diagnostic value of the SNPs and the culpable mutations nearby, and their possible association with other genetic/genomic changes in PTC as well as clinical factors and outcome. Our preliminary work has shown that the five available risk SNPs are additive.
; The discovery of genes predisposing to PTC and their interaction with other genetic and clinical factors will allow for more accurate genetic counseling, genotype-based risk stratification, and prognostication. Moreover, the elucidation of the genetic pathways leading to PTC will allow therapeutic drugs and preventative strategies to be designed.
|Liyanarachchi, Sandya; Li, Wei; Yan, Pearlly et al. (2016) Genome-Wide Expression Screening Discloses Long Noncoding RNAs Involved in Thyroid Carcinogenesis. J Clin Endocrinol Metab 101:4005-4013|
|Hollingsworth, Brynn; Senter, Leigha; Zhang, Xiaoli et al. (2016) Risk Factors of (131)I-Induced Salivary Gland Damage in Thyroid Cancer Patients. J Clin Endocrinol Metab 101:4085-4093|
|Justiniano, Steven E; McElroy, Joseph P; Yu, Lianbo et al. (2016) Genetic variants in thyroid cancer distant metastases. Endocr Relat Cancer 23:L33-6|
|Nabhan, Fadi; Ringel, Matthew D (2016) Thyroid nodules and cancer management guidelines: comparisons and controversies. Endocr Relat Cancer :|
|Shirley, Lawrence A; McCarty, Samantha; Yang, Ming-Chen et al. (2016) Integrin-linked kinase affects signaling pathways and migration in thyroid cancer cells and is a potential therapeutic target. Surgery 159:163-70|
|Danysh, Brian P; Rieger, Erin Y; Sinha, Deepankar K et al. (2016) Long-term vemurafenib treatment drives inhibitor resistance through a spontaneous KRAS G12D mutation in a BRAF V600E papillary thyroid carcinoma model. Oncotarget 7:30907-23|
|Nagy, Rebecca; Ringel, Matthew D (2015) Genetic predisposition for nonmedullary thyroid cancer. Horm Cancer 6:13-20|
|Tomsic, Jerneja; He, Huiling; de la Chapelle, Albert (2015) HABP2 Mutation and Nonmedullary Thyroid Cancer. N Engl J Med 373:2086|
|He, Huiling; Li, Wei; Liyanarachchi, Sandya et al. (2015) Multiple functional variants in long-range enhancer elements contribute to the risk of SNP rs965513 in thyroid cancer. Proc Natl Acad Sci U S A 112:6128-33|
|He, Huiling; Li, Wei; Liyanarachchi, Sandya et al. (2015) Genetic predisposition to papillary thyroid carcinoma: involvement of FOXE1, TSHR, and a novel lincRNA gene, PTCSC2. J Clin Endocrinol Metab 100:E164-72|
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