Thyroid Cancer: Is It All in the Genes?
JNCI J Natl Cancer Inst (
Thyroid Cancer: Is It All in the Genes?
Electron Kebebew 0
0 Affiliations of authors: Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda , MD; Department of Surgery, The George Washington University, School of Medicine and Health Sciences , Washington, DC , USA
Thyroid cancer represents one of the most biologically and
clinically diverse solid malignancies. While most thyroid cancers
originate from the follicular cells, the genetic alterations that
drive these cancers are unique to each histologic subtype (
Further, the behavior of thyroid cancer has a wide spectrum,
from the commonly indolent and widespread papillary thyroid
microcarcinoma (present in up to 35.6% of individuals at
autopsy) to the uniformly rare and lethal undifferentiated thyroid
). Our understanding of the genetic events involved
in thyroid cancer initiation and progression has grown, with
some having translational implications for predicting thyroid
cancer behavior and as therapeutic targets for advanced thyroid
In this issue of the Journal, two independent groups report
interesting studies on the genetic alterations associated with
radiation exposure–associated thyroid cancer in patients who had
exposure to 131I from the Chernobyl meltdown, and a second
study reports on the prognostic utility of BRAF V600E mutation
status—the most prevalent somatic oncogenic mutation in
thyroid cancer—in patients with solitary isolated papillary thyroid
cancer, which accounts for up to 80% of all thyroid cancer cases
A well-established risk factor for thyroid cancer is radiation
exposure. While previous studies have established that certain
recurrent genetic alterations occur in radiation exposure–
associated thyroid cancer, the study by Efanov and colleagues
provides a comprehensive analysis of gene mutations in a
cohort in which thyroid radiation dose was measured (
report that 96.9% of 65 papillary thyroid cancers in patients from
the Ukrainian-American cohort with a measurement of 131 I
thyroid doses have somatic gene mutations (26.2% with point
mutations and 70.8% with gene fusions). The type of gene
mutation was also associated with the thyroid radiation dose. Gene
fusions occurred at a higher frequency with a higher thyroid
radiation dose (mean 1.4 Gy), and point mutations had a higher
frequency in a lower thyroid radiation dose (mean 0.2 Gy). In a
univariate analysis, cases with gene fusions had a lower mean
age at exposure and surgery for papillary thyroid cancer and
higher rates of histologic features of solid-trabecular and
follicular growth pattern and extrathyroidal invasion. In a
multivariable analysis, the association between the type of gene
mutations and thyroid radiation dose was statistically
significant. Some of the gene fusions identified (POR-BRAF, MBP-BRAF,
ZBTB8A-BRAF, SQSTM1-RET, and BANP-NTRK1) were novel, and
functional characterization of one of the gene fusions
(PORBRAF) showed oncogenic function in in vitro assays and
activation of the MAPK pathway. This study in radiation-associated
thyroid cancer provides new evidence on the pathobiology on
how radiation leads to thyroid cancer. It may have therapeutic
relevance given that most of the point mutations and gene
fusions are known or likely to activate the MAPK pathway,
which now can be targeted with various kinase inhibitors
already approved for radioiodine-refractory thyroid cancer or
that are currently being tested in clinical trials.
Huang and associates, in their multinational and -center
study, characterized the association of somatic BRAF V600E
mutations in thyroid cancer, building on their prior reports
showing that BRAF mutation status is a prognostic factor for
recurrence-free survival and thyroid cancer–specific mortality
). In the current study, they focused on solitary intrathyroidal
papillary thyroid cancer (>1 cm and 4 cm)—which accounted
for 29% of the entire study cohort—and the implications of BRAF
mutations’ status to address a clinically important and
controversial question on the extent of thyroidectomy alternatives
(hemithyroidectomy, total, or near total thyroidectomy)
currently recommended in such patients (
). The surgical
treatment options are controversial because there is no level 1
clinical evidence that shows the superiority of any of the
approaches relative to the risk of recurrent/persistent disease
and, understandably, disease-specific mortality given the low
rate of such an event in patients with low-risk papillary thyroid
cancer. The primary end point in this retrospective study was
disease recurrence as defined by serum thyroglobulin,
structural recurrence on ultrasound imaging, and/or pathology.
Huang and associates report a higher rate of locoregional
thyroid cancer recurrence in tumors with BRAF V600E mutations as
Published by Oxford University Press 2017. This work is written by a US Government employee and is in the public domain in the US.
compared with wild-type tumors in patients who all had total
thyroidectomy with or without lymph node dissection and
postoperative 131I. Interestingly, in comparison with high-risk
papillary thyroid cancer, solitary intrathyroidal papillary thyroid
cancer with BRAF V600E mutation had similar rates of
recurrence. Further, the association between BRAF V600E mutation
and higher recurrence was seen in all tumor size increments
analyzed. A high negative predictive value of 97% to 100% was
observed for recurrence when there was no BRAF V600E
mutation. Based on their findings, Huang and colleagues concluded
that a personalized or tailored treatment approach could be
undertaken based on BRAF V600E mutation testing in patients
with solitary intrathyroidal papillary thyroid cancer. Given that
the entire cohort in this retrospective study had a total
thyroidectomy, it is difficult to propose that individuals with no
mutation can have a hemithyroidectomy and be sure their risk of
recurrence would be low or nil based on the negative predictive
value. Similarly, given the locoregional recurrences in both the
thyroid bed and lymph node (it was not specified whether in
the central neck and/or lateral neck), how does one then use
this information to perform prophylactic lymph node dissection
in individuals with solitary intrathyroidal papillary thyroid
cancer that is positive for BRAF V600E mutation, expect a lower
recurrence rate as a result of aggressive treatment (or vice versa,
not perform lymph node dissection in BRAF wild-type cases),
and be certain that patients will have similar locoregional
recurrence as in this study? The same can be said for selecting
patients who would require radioiodine ablation with 131I.
In summary, both studies provide new, important
information on the pathobiology and clinical relevance of gene
mutations that may impact patient care—if future well-designed
studies validate these findings and exploit these genetic
changes for prognostication and as treatment targets.
The author has no conflicts of interest to disclose.
1. Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma . Cell . 2014 ; 159 ( 3 ): 676 - 690 .
2. Harach HR , Franssila KO , Wasenius VM . Occult papillary carcinoma of the thyroid. A “normal” finding in Finland. A systematic autopsy study . Cancer . 1985 ; 56 ( 3 ): 531 - 538 .
3. Kebebew E , Greenspan FS , Clark OH , Woeber KA , McMillan A . Anaplastic thyroid carcinoma. Treatment outcome and prognostic factors . Cancer . 2005 ; 103 ( 7 ): 1330 - 1335 .
4. Fagin JA , Wells SA Jr. Biologic and clinical perspectives on thyroid cancer . N Engl J Med . 2016 ; 375 ( 23 ): 2307 .
5. Efanov AA BA , Bogdanova TI , Kelly LM , et al. Genomic profiling of postChernobyl thyroid cancer reveals correlation between radiation dose and gene fusions . J Natl Cancer Inst . 2018 ; 110 ( 4 ): 371 - 378 .
6. Huang Y QS , Zhu G , Wang F , et al. BRAF V600E mutation-assisted risk stratification of solitary intrathyroidal papillary thyroid cancer for precision treatment . J Natl Cancer Inst . 2018 ; 110 ( 4 ): 362 - 370 .
7. Haugen BR , Alexander EK , Bible KC , et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer . Thyroid . 2016 ; 26 ( 1 ): 1 - 133 .