title: Papillary Thyroid Carcinoma: Association Between Germline DNA Variant Markers and Clinical Parameters.
abstract: Papillary thyroid cancer (PTC) is reported to be highly heritable in epidemiological studies. Genome-wide association studies (GWAS) have uncovered several variants associated with PTC predisposition. It remains unknown whether these variants might contribute to better clinical stratification of PTC patients.
  
  
  
  In order to assess the usefulness of germline genetic analyses in the management of PTC patients, the genotypes of five variants (rs965513, rs944289, rs116909374, rs2439302, and rs966423) were determined in 1216 PTC patients and 1416 controls. Additionally, the expression of seven genes located close to GWAS variants (PTCSC3, MBIP, NKX2-1, FOXE1, DIRC3, PTCSC2, and NRG1) were measured in 73 PTC paired tumor/normal tissues, respectively. Next, the association was analyzed between the genotypes of the germline variants and the levels of gene expression with clinical/pathological features such as age, sex, TNM staging, multifocality status, extrathyroidal expansion, and MACIS score.
  
  
  
  The risk allele of rs965513 was associated with larger tumor size (p = 0.025) and extrathyroidal expansion (odd ratio [OR] = 1.29, p = 0.045). The variant rs2439302 showed association with lymph node metastasis (OR = 1.24, p = 0.016), and multifocality status of the tumor (OR = 1.24, p = 0.012). The expression of MBIP was associated with T stage (p = 0.010). MBIP and PTCSC3 displayed lower expression in PTC tissue in males than in females (p = 0.025 and p = 0.036, respectively). NKX2-1 displayed lower expression in patients with N1 stage (p = 0.040).
  
  
  
  The studied germline risk alleles predisposing to PTC were associated with a more aggressive course of the disease reflected by larger tumor diameter, higher multifocality rate, and more advanced N stage at the time of diagnosis. These results show that germline variants not only predispose to PTC but also might impact its clinical course. However, these associations were only moderate, and further large multi-ethnic studies are required to evaluate the usefulness of these germline variants in the clinical stratification of PTC patients.
authors.affiliation: 1 Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University , Columbus, Ohio.|2 Department of Endocrinology and Internal Medicine, Medical University of Gdansk , Gdansk, Poland .
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Jendrzejewski
authors.affiliation: 1 Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University , Columbus, Ohio.
authors.forename: Sandya
authors.initials: S
authors.lastname: Liyanarachchi
authors.affiliation: 1 Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University , Columbus, Ohio.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Nagy
authors.affiliation: 1 Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University , Columbus, Ohio.
authors.forename: Leigha
authors.initials: L
authors.lastname: Senter
authors.affiliation: 3 Department of Pathology, The Ohio State University , Columbus, Ohio.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Wakely
authors.affiliation: 1 Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University , Columbus, Ohio.
authors.forename: Andrew
authors.initials: A
authors.lastname: Thomas
authors.affiliation: 4 Division of Endocrinology, Diabetes and Metabolism, The Ohio State University , Columbus, Ohio.
authors.forename: Fadi
authors.initials: F
authors.lastname: Nabhan
authors.affiliation: 1 Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University , Columbus, Ohio.
authors.forename: Huiling
authors.initials: H
authors.lastname: He
authors.affiliation: 1 Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University , Columbus, Ohio.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: 2 Department of Endocrinology and Internal Medicine, Medical University of Gdansk , Gdansk, Poland .
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Sworczak
authors.affiliation: 4 Division of Endocrinology, Diabetes and Metabolism, The Ohio State University , Columbus, Ohio.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Ringel
authors.affiliation: 4 Division of Endocrinology, Diabetes and Metabolism, The Ohio State University , Columbus, Ohio.
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Kirschner
authors.affiliation: 1 Human Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University , Columbus, Ohio.
authors.forename: Albert
authors.initials: A
authors.lastname: de la Chapelle
mesh_terms: D000328:Adult; D000483:Alleles; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008207:Lymphatic Metastasis / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020890:Neuregulin-1 / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D022661:RNA, Untranslated / Q000235:genetics; D012737:Sex Factors; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology; D000074482:Thyroid Nuclear Factor 1 / Q000235:genetics
chemical_list: C106894:FOXE1 protein, human; D051858:Forkhead Transcription Factors; D005819:Genetic Markers; D047908:Intracellular Signaling Peptides and Proteins; C411875:MBIP protein, human; C000614412:NKX2-1 protein, human; D020890:Neuregulin-1; C000603517:Ptcsc3 untranslated RNA, human; D022661:RNA, Untranslated; D000074482:Thyroid Nuclear Factor 1