Molecular Signature Expands the Landscape of Driver Negative Thyroid Cancers
by
, and
Larissa Valdemarin Bim
1, 
Thaise Nayane Ribeiro Carneiro
1,
Vanessa Candiotti Buzatto
2,
Gabriel Avelar Colozza-Gama
1,
Fernanda C. Koyama
2,
Debora Mota Dias Thomaz
1,
Ana Carolina de Jesus Paniza
1,
Eunjung Alice Lee
3,
Pedro Alexandre Favoretto Galante
2
and
Janete Maria Cerutti
1,* 1
Genetic Bases of Thyroid Tumors Laboratory, Division of Genetics, Department of Morphology and Genetics, Escola Paulista de Medicina, Universidade Federal de São Paulo, Pedro de Toledo 669, 11 Andar, São Paulo 04039-032, SP, Brazil
2
Centro de Oncologia Molecular, Hospital Sírio-Libanês, Rua Professor Daher Cutait 69, Bela Vista, São Paulo 01308-060, SP, Brazil
3
Division of Genetics and Genomics, Boston Children’s Hospital and Harvard Medical School, 3 Blackfan Circle, Boston, MA 02115, USA
*
Author to whom correspondence should be addressed.
Cancers 2021, 13(20), 5184; https://doi.org/10.3390/cancers13205184
Submission received: 29 September 2021
/
Accepted: 12 October 2021
/
Published: 15 October 2021
(This article belongs to the Special Issue New Insights on Genomics in Thyroid Cancers: Impact on Diagnosis, Prognosis and Therapy)
Simple Summary
Thyroid cancer is the most common endocrine malignancy. However, the cytological diagnosis of certain malignant thyroid tumors and their benign counterparts is a challenge for preoperative diagnosis, as nearly 20–30% of biopsied thyroid nodules are classified as having an indeterminate risk of malignancy. Although multigene panels customized for thyroid cancer include most of the known tumor driver genes, many thyroid samples have negative results for the tested genes. To expand our knowledge, driver-negative samples were profiled by RNA-sequencing. Here, we report novel gene variants that might be associated with the pathogenesis of thyroid tumors, and show that driver-negative samples have two distinct expression signatures. We believe that our findings will ultimately impact preoperative diagnosis on thyroid nodules and provide directions for further experimental validation analysis.
Abstract
Thyroid cancer is the most common endocrine malignancy. However, the cytological diagnosis of follicular thyroid carcinoma (FTC), Hürthle cell carcinoma (HCC), and follicular variant of papillary thyroid carcinoma (FVPTC) and their benign counterparts is a challenge for preoperative diagnosis. Nearly 20–30% of biopsied thyroid nodules are classified as having indeterminate risk of malignancy and incur costs to the health care system. Based on that, 120 patients were screened for the main driver mutations previously described in thyroid cancer. Subsequently, 14 mutation-negative cases that are the main source of diagnostic errors (FTC, HCC, or FVPTC) underwent RNA-Sequencing analysis. Somatic variants in candidate driver genes (ECD, NUP98,LRP1B, NCOR1, ATM, SOS1, and SPOP) and fusions were described. NCOR1 and SPOP variants underwent validation. Moreover, expression profiling of driver-negative samples was compared to 16 BRAF V600E, RAS, or PAX8-PPARg positive samples. Negative samples were separated in two clusters, following the expression pattern of the RAS/PAX8-PPARg or BRAF V600E positive samples. Both negative groups showed distinct BRS, ERK, and TDS scores, tumor mutation burden, signaling pathways and immune cell profile. Altogether, here we report novel gene variants and describe cancer-related pathways that might impact preoperative diagnosis and provide insights into thyroid tumor biology.
