Association between GWAS-Derived rs966423 Genetic Variant and Overall Mortality in Patients with Differentiated Thyroid Cancer.
OBJECTIVE
Five germline genetic variants (rs116909374, rs965513, rs944289, rs966423, and rs2439302) have been associated in genome-wide association studies (GWAS) with increased risk of differentiated thyroid cancer (DTC), but their role in mortality of patients has not been established. Also, no preoperative marker of the clinical outcome of thyroid cancer had yet been identified. The aim of the study was to investigate the relationship between the variants and overall mortality in patients with DTC.


METHODS
Retrospective study of 1,836 patients (1,643 women, 193 men) with median age at diagnosis of 49 years and overall median follow-up time of 8.7 years after initial treatment at a single comprehensive cancer center between 1990 and 2013.


RESULTS
Among 5 variants, rs966423 was associated with increased mortality, which was 6.4% (33 of 518) versus 3.7% (47 of 1,259) in TT carriers versus CC/CT carriers (P = 0.017). The HR of TT versus TC/CC carriers was 1.6 [95% confidence interval (CI), 1.02-2.49; P = 0.038] after adjustment for age at diagnosis and sex. Importantly, the association of rs966423 with mortality remained valid when clinicopathologic risk factors were included in the model (HR, 1.89; 95% CI, 1.14-3.13; P = 0.014). Higher rs966423-associated patient mortality of TT versus CC/CT carriers was also observed in interaction with angioinvasion (adjusted HR, 3.48; 95% CI, 1.67-7.22; P < 0.001), lymph node metastasis (adjusted HR, 3.47; 95% CI, 1.16-10.4; P = 0.018), extrathyroidal invasion (adjusted HR, 2.07; 95% CI, 1.15-3.73; P = 0.013).


CONCLUSIONS
The presence of the rs966423-TT genotype was associated with a significant increase in overall mortality of patients with DTC. Contrary to BRAF mutation and other somatic changes, the status of germline rs966423 is known before the treatment and might be used in the management of mortality risk by means of modification of therapy.
Genomic Medicine, Medical University of Warsaw, Warsaw, Poland. Centre of New Technologies, CENT, University of Warsaw, Warsaw, Poland.
Michał
M
Świerniak
Genomic Medicine, Medical University of Warsaw, Warsaw, Poland. Centre of New Technologies, CENT, University of Warsaw, Warsaw, Poland.
Anna
A
Wójcicka
Genomic Medicine, Medical University of Warsaw, Warsaw, Poland. Department of Endocrine Oncology and Nuclear Medicine, Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
Małgorzata
M
Czetwertyńska
Department of Endocrine Oncology and Nuclear Medicine, Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
Joanna
J
Długosińska
Department of Endocrine Oncology and Nuclear Medicine, Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
Elżbieta
E
Stachlewska
Genomic Medicine, Medical University of Warsaw, Warsaw, Poland.
Wojciech
W
Gierlikowski
Centre of New Technologies, CENT, University of Warsaw, Warsaw, Poland.
Adam
A
Kot
Department of Pathology, Medical University of Warsaw, Warsaw, Poland.
Barbara
B
Górnicka
Department of Pathology, Medical University of Warsaw, Warsaw, Poland.
Łukasz
Ł
Koperski
Department of Pathology, Medical University of Warsaw, Warsaw, Poland.
Magdalena
M
Bogdańska
Department of General and Endocrine Surgery, Medical University of Warsaw, Warsaw, Poland.
Wiesław
W
Wiechno
Genomic Medicine, Medical University of Warsaw, Warsaw, Poland. Centre of New Technologies, CENT, University of Warsaw, Warsaw, Poland. krystian.jazdzewski@wum.edu.pl.
Krystian
K
Jażdżewski
D000328:Adult; D000368:Aged; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012307:Risk Factors; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology
C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf