title: Single nucleotide polymorphism rs17849071 G/T in the PIK3CA gene is inversely associated with follicular thyroid cancer and PIK3CA amplification.
abstract: The proto-oncogene PIK3CA has been well studied for its activating mutations and genomic amplifications but not single nucleotide polymorphism (SNP) in thyroid cancer. We investigated SNP rs17849071 (minor allele G and major allele T) in PIK3CA in thyroid tumors in 503 subjects by PCR and sequencing of a region of intron 9 carrying this SNP. This SNP was found in both normal and thyroid tumor tissues as well as in different generations of a studied family, confirming it to be a germline genetic event in thyroid tumor patients. In comparison with normal subjects, a dramatically lower prevalence of the heterozygous genotype G/T at rs17849071 was found in patients with follicular thyroid cancer (FTC). Specifically, rs17849071G/T was found in 15% (18/117) normal subjects vs. 1.3% (1/77) FTC patients, with an odds ratio of 0.07 (95% CI 0.01-0.55; P = 0.001). This represents a 93% risk reduction for FTC with this SNP. In contrast, no difference was seen with benign thyroid neoplasms in which the prevalence of rs17849071G/T was 13.1% (17/130), with an odds ratio of 0.83 (95% CI 0.40-1.69; P = 0.72). There was a trend of lower prevalences of rs17849071G/T and odds ratio in other types of thyroid cancer without statistical significance. We also found an interesting inverse relationship of rs17849071G/T with PIK3CA amplification. With copy number ≥4 defined as copy gain, 2.9% (1/34) rs17849071G/T vs. 19.0% (67/352) rs17849071T/T cases displayed PIK3CA amplification (P = 0.01). Conversely, 1.5% (1/68) cases with PIK3CA amplification vs. 10.4% (33/318) cases without PIK3CA amplification harbored rs17849071G/T (P = 0.01). This provides an explanation for the reciprocal relationship of rs17849071G/T with FTC, since PIK3CA amplification is an important oncogenic mechanism in thyroid cancer, particularly FTC. Thus, the present study uncovers an interesting phenomenon that rs17849071G/T is protective against FTC possibly through preventing PIK3CA amplifications.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Xing
authors.forename: Ralph P
authors.initials: RP
authors.lastname: Tufano
authors.forename: Avaniyapuram Kannan
authors.initials: AK
authors.lastname: Murugan
authors.forename: Dingxie
authors.initials: D
authors.lastname: Liu
authors.forename: Gary
authors.initials: G
authors.lastname: Wand
authors.forename: Paul W
authors.initials: PW
authors.lastname: Ladenson
authors.forename: Mingzhao
authors.initials: M
authors.lastname: Xing
authors.forename: Barry
authors.initials: B
authors.lastname: Trink
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000201:enzymology* / Q000235:genetics*; D001483:Base Sequence; D058534:Class I Phosphatidylinositol 3-Kinases; D005784:Gene Amplification; D020022:Genetic Predisposition to Disease; D005854:Germ Cells / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D007438:Introns / Q000235:genetics; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D000090063:Proto-Oncogene Mas
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D000090063:Proto-Oncogene Mas; C000715470:MAS1 protein, human; C484760:PIK3CA protein, human