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Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. The molecular characteristics of histologically normal appearing tissue adjacent to the tumor (NAT) from PTC patients are not well characterized. The aim of this study was to characterize the global gene expression profile of NAT and compare it with those of normal and tumor thyroid tissues. We performed total RNA sequencing with fresh frozen thyroid tissues from a cohort of three categories of samples including NAT, normal thyroid (N), and PTC tumor (T). Transcriptome analysis shows that NAT presents a unique gene expression profile, which was not associated with sex or the presence of lymphocytic thyroiditis. Among the differentially expressed genes (DEGs) of NAT vs N, 256 coding genes and 5 noncoding genes have been reported as cancer genes involved in cell proliferation, apoptosis, and/or tumorigenesis. Bioinformatics analysis with Ingenuity Pathway Analysis software revealed that “Cancer, Organismal Injury and Abnormalities, Cellular Response to Therapeutics, and Cellular Movement” were major dysregulated pathways in the NAT tissues. This study provides improved insight into the complexity of gene expression changes in the thyroid glands of patients with PTC.

Introduction: Somatic mutations of RAS- and BRAFV600E- are the most common driver mutation in thyroid cancer (TC) and in the majority of cases, these are mutually exclusive1,2. Clinical characteristics of TC with either RAS or BRAFV600E mutation is not systemically studied. Methods: This is a retrospective study at the Ohio State University (OSU) from 1/2000 to 12/2018. Data were extracted from OSU Endocrine Neoplasia Repository (ENR). Medullary thyroid cancer was excluded. The treating physician determined patient management. Statistical analysis was performed with the chi-square test for categorical values and Mann-Whitney U test for continuous unpaired values. Two-sided P values of less than 0.05 were considered statistically significant. Results: Out of 320 patients, 152 patients had a positive mutational profile. Of these, 128 patients had a BRAFV600E mutation and 14 had a RAS mutation. Details of RAS mutation were as follows; NRASQ61K (n=2), NRASQ61R (n=1), HRASQ61R (n=1), HRASQ61K (n=1), NRAS without further details (n=9). Local lymph node metastasis was significantly less in RAS mutated cancer (58% vs 16%, p Conclusion: Thyroid cancer associated with a RAS-mutation has less tendency to metastasize locally and has a higher incidence of bone metastasis compared to thyroid cancer with BRAFV600E-mutation. Individualized clinical follow up may be indicated depends on their mutational profile. References: 1. Cancer Genome Atlas Research N. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;159(3):676-690. 2. Nikiforova MN, Lynch RA, Biddinger PW, et al. RAS point mutations and PAX8-PPAR gamma rearrangement in thyroid tumors: evidence for distinct molecular pathways in thyroid follicular carcinoma. J Clin Endocrinol Metab. 2003;88(5):2318-2326.

Background: Familial adenomatous polyposis (FAP) is a condition typically caused by pathogenic germline mutations in the APC gene. In addition to colon polyps, individuals with FAP have a substantially increased risk of developing papillary thyroid cancer (PTC). Little is known about the events underlying this association, and the prevalence of somatic "second-hit" mutations in APC is controversial. Methods: Whole-genome sequencing was performed on paired thyroid tumor and normal DNA from 12 FAP patients who developed PTC. Somatic mutation profiles were compared with clinical characteristics and previously sequenced sporadic PTC cases. Germline variant profiling was performed to assess the prevalence of variants in genes previously shown to have a role in PTC predisposition. Results: All 12 patients harbored germline mutations in APC, consistent with FAP. Seven patients also had somatic mutations in APC, and seven patients harbored somatic mutations in KMT2D, which encodes a lysine methyl transferase. Mutation of these genes is extremely rare in sporadic PTCs. Notably, only two of the tumors harbored the somatic BRAF p.V600E mutation, which is the most common driver mutation found in sporadic PTCs. Six tumors displayed a cribriform-morular variant of PTC (PTC-CMV) histology, and all six had somatic mutations in APC. Additionally, nine FAP-PTC patients had rare germline variants in genes that were previously associated with thyroid carcinoma. Conclusions: Our data indicate that FAP-associated PTCs typically have distinct mutations compared with sporadic PTCs. Roughly half of the thyroid cancers that arise in FAP patients have somatic "second-hits" in APC, which is associated with PTC-CMV histology. Somatic BRAF p.V600E variants also occur in some FAP patients, a novel finding. We speculate that in carriers of heterozygous pathogenic mutations of tumor suppressor genes such as APC, a cooperating second-hit somatic variant may occur in a different gene such as KTM2D or BRAF, leading to differences in phenotypes. The role of germline variance in genes other than APC (9 of the 12 patients in this series) needs further research.