Comprehensive Genetic Analysis of Follicular Thyroid Carcinoma Predicts Prognosis Independent of Histology.

Nicolson NG1, Murtha TD1, Dong W2, Paulsson JO3, Choi J2, Barbieri AL4, Brown TC1, Kunstman JW1, Larsson C3, Prasad ML4, Korah R1, Lifton RP2, Juhlin CC3, Carling T1.

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Abstract

CONTEXT:

Follicular thyroid cancer (FTC) is classified into minimally invasive (miFTC), encapsulated angioinvasive (eaFTC), and widely invasive (wiFTC) subtypes, according to the 2017 World Health Organization (WHO) guidelines. The genetic signatures of these subtypes may be crucial for diagnosis, prognosis, and treatment, but have not been described.

OBJECTIVE:

Identify and describe the genetic underpinnings of subtypes of follicular thyroid cancer.

METHODS:

Thirty-nine tumors, comprising 12 miFTCs, 17 eaFTCs, and 10 wiFTCs were whole-exome sequenced and analyzed. Somatic mutations, constitutional sequence variants, somatic copy number alterations, and mutational signatures were described. Clinicopathologic parameters and mutational profiles were assessed for associations with patient outcomes.

RESULTS:

Total mutation burden was consistent across FTC subtypes, with a median of 10 (range 1-44) non-synonymous somatic mutations per tumor. Overall, 20.5% of specimens had a mutation in the RAS subfamily (HRAS, KRAS, or NRAS), with no significant difference between subtypes. Mutations in TSHR, DICER1, EIF1AX, KDM5C, NF1, PTEN, and TP53 were also noted to be recurrent across the cohort. Clonality analysis demonstrated more sub-clones in wiFTC. Survival analysis demonstrated worse disease-specific survival in the eaFTC and wiFTC cohorts, with no recurrences or deaths for patients with miFTC. Mutation burden was associated with worse prognosis, independent of histopathological classification.

CONCLUSIONS:

Though the number and variety of somatic variants are similar in the different histopathological subtypes of FTC in our study, mutational burden was an independent predictor of mortality and recurrence.