Progress in Thyroid Cancer Genomics: A 40-Year Journey

Abstract

Background: Very little was known about the molecular pathogenesis of thyroid cancer until the late 1980s. As part of the Centennial celebration of the American Thyroid Association, we review the historical discoveries that contributed to our current understanding of the genetic underpinnings of thyroid cancer. Summary: The pace of discovery was heavily dependent on scientific breakthroughs in nucleic acid sequencing technology, cancer biology, thyroid development, thyroid cell signaling, and growth regulation. Accordingly, we attempt to link the primary observations on thyroid cancer molecular genetics with the methodological and scientific advances that made them possible. Conclusions: The major genetic drivers of the common forms of thyroid cancer are now quite well established and contribute to a significant extent to how we diagnose and treat the disease. However, many challenges remain. Future work will need to unravel the complexity of thyroid cancer ecosystems, which is likely to be a major determinant of their biological behavior and on how they respond to therapy.

Keywords: TCGA; genetics; next-generation sequencing; oncogenes; thyroid cancer; tumor suppressors.

FIG. 1.

Functional consequences of driver mutations in PTCs: RTK fusions, RAS mutants, and BRAF^V600E activate the MAPK pathway, but they do so with different intensity. RTK fusions such as RET/PTC and ETV6-NTRK3 and mutant RAS proteins signal through RAF dimers, which are subject to negative feedback by ERK, resulting in a constitutively active but dampened flux through the MAPK pathway. By contrast, BRAF^V600E signals as a monomer and is partially unresponsive to negative feedback by ERK, resulting in a higher MAPK signaling output. The expression of genes required for thyroid cell differentiation and thyroid hormone biosynthesis is inversely correlated with the transcriptional output of the MAPK pathway. MAPK, mitogen-activated protein kinase; PTC, papillary thyroid cancer; RET, REcombined during Transfection; RTK, receptor tyrosine kinase. From N Engl J Med, Fagin JA, Wells SA Jr., Biological and Clinical Perspectives on Thyroid Cancer, v375:1054–1067. Copyright © (2016) Massachusetts Medical Society. Reprinted with permission.

FIG. 2.

BRAF-like and RAS-like papillary carcinomas: The transcriptomic, microRNA, and methylome profiles of BRAF^V600E-mutant and RAS-mutant PTC are distinct. A 71-gene signature, termed the BRS, was generated by TCGA to classify tumors as either BRAF-like or RAS-like. PTCs harboring other drivers can be categorized based on this signature: for example, RET fusions tend to be BRAF-like, whereas NTRK fusions lie somewhere in between. The BRS correlates with the histological characteristics of the tumors, their differentiation state, as well as their metastatic tropism. BRS, BRAF-RAS score; TCGA, The Cancer Genome Atlas. Reprinted with permission from Cell 2014;159:676–690 (ref. 19).

FIG. 3.

Genetics of Hurthle cell carcinomas: Hurthle cell (oncocytic) tumors are driven by alterations of the nuclear and mitochondrial genomes. Mutations of mtDNA primarily involve loss-of-function complex I gene mutations. Most of these cancers also develop widespread loss of one of the two chromosome alleles leading to a near-haploid genome. Nuclear DNA mutations are present in a smaller fraction of Hurthle cell cancers, with TP53 and TERT mutations found more commonly in widely invasive cancers. mtDNA, mitochondrial DNA. Reprinted with permission from Cancer Cell 2018;34:242.e5–255.e5 (ref. 81).

FIG. 4.

Mechanisms of radiation-induced thyroid cancer: Gene fusions are genetic hallmarks of thyroid cancer associated with exposure to ionizing radiation. Radiation exposure induces a dose-dependent increase in DNA double-strand breaks, short deletions, and simple/balanced structural variants, but not in single nucleotide variants. The radiation dose-dependent generation of fusion oncogenes is favored by spatial proximity of the participating genes and carries a signature of NHEJ at the fusion points. The most prevalent fusions involve RTK genes, which are commonly activated by recombination with a gene fragment encoding a protein dimerization domain. This drives homodimerization and activation by transphosphorylation of the cytoplasmic kinase domain of the RTK. NHEJ, nonhomologous end joining.

FIG. 5.

Molecular classification of thyroid nodules. Most thyroid nodules are HN that carry no clonal genetic alterations. Follicular cell-derived thyroid tumors develop via three distinct molecular pathways initiated by BRAF^V600E-like alterations, RAS-like alterations, or mtDNA mutations and chromosomal copy number abnormalities leading to genome haploidiation-type copy number alterations (htCNA). RAS-like encapsulated follicular-patterned tumors, including FTC, invasive efvPTC, and htCNA/mtRNA-driven encapsulated HCC likely develop from benign/preinvasive precursors: that is, FA/NIFTP and HCA, respectively. BRAF-like cPTC lack a benign precursor and develop by growth of a micropapillary thyroid cancer (mPTC). Progression of RAS-like tumors to well-differentiated cancer frequently involves EIF1AX mutations and/or 22q loss, whereas conversion of cancers initiated by all three molecular pathways to PDTC and ATC involve the accumulation of additional mutations in TERT, TP53, PI3K pathway mutations, and alterations of chromatin remodeling genes. ATC, anaplastic thyroid cancer; cPTC, classic papillary thyroid carcinomas; efvPTC, encapsulated follicular variant papillary thyroid carcinoma; FA, follicular adenoma; FTC, follicular thyroid carcinoma; HCA, Hurthle cell adenoma; HCC, Hurthle cell (oncocytic) cancer; HN, hyperplastic nodules; htCNA, genome haploidiation-type copy number alterations; mPTC, micropapillary thyroid cancer; mtRNA, mitochondrial RNA; NIFTP, noninvasive follicular tumor with papillary-like nuclear features; PDTC, poorly differentiated thyroid carcinoma; PI3K, phosphatidylinositol 3-kinase.