Abstract
Papillary thyroid carcinoma (PTC) represents a heterogeneous disease with diverse clinical outcomes highlighting a need to identify robust biomarkers with clinical relevance. We applied non-negative matrix factorization-based deconvolution to publicly available gene expression profiles of thyroid cancers in the Cancer Genome Atlas (TCGA) consortium. Among three metagene signatures identified, two signatures were enriched in canonical BRAF-like and RAS-like thyroid cancers with up-regulation of genes involved in oxidative phosphorylation and cell adhesions, respectively. The third metagene signature representing up-regulation of immune-related genes further segregated BRAF-like and RAS-like PTCs into their respective subgroups of immunoreactive (IR) and immunodeficient (ID), respectively. BRAF-IR PTCs showed enrichment of tumor infiltrating immune cells, tall cell variant PTC, and shorter recurrence-free survival compared to BRAF-ID PTCs. RAS-IR and RAS-ID PTC subtypes included majority of normal thyroid tissues and follicular variant PTC, respectively. Immunopathological features of PTC subtypes such as immune cell fraction, repertoire of T cell receptors, cytolytic activity, and expression level of immune checkpoints such as and PD-L1 and CTLA-4 were consistently observed in two different cohorts. Taken together, an immune-related metagene signature can classify PTCs into four molecular subtypes, featuring the distinct histologic type, genetic and transcriptional alterations, and potential clinical significance.
Highlights
The incidence of thyroid cancer has been rapidly increasing worldwide, especially in Korea (15 times of increase) over the past few decades [1]
These trends are mainly driven by an increase in the detection of papillary thyroid carcinoma (PTC) which represents more than 80 percent of all thyroid cancers [1,2]
We evaluated the clinical utility of PTC clusters by correlative analyses with clinicopathological features including recurrence-free survival
Summary
The incidence of thyroid cancer has been rapidly increasing worldwide, especially in Korea (15 times of increase) over the past few decades [1]. These trends are mainly driven by an increase in the detection of papillary thyroid carcinoma (PTC) which represents more than 80 percent of all thyroid cancers [1,2]. Most patients with PTC have excellent prognosis after surgery. They are more likely to die from other diseases. Recurrence and death can occur more than 30 years after initial diagnosis of PTC [3]
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