Previous genetic studies on the PIK3CA
gene in thyroid cancer have been mostly focused on somatic oncogenic genetic alterations, such as activating mutations and genomic amplification. Little is known about the role of polymorphism of the PIK3CA
gene in the development of thyroid cancer. The present work on rs17849071G/T represents a novel genetic study on thyroid tumors. The striking finding was the extremely low occurrence of heterozygous genotype G/T at rs17849071 in intron 9 of the PIK3CA
gene preferentially in FTC, associated with a significantly decreased odd ratio (93% reduction) for the development of FTC. Only 1.3% (1/77) cases of FTC vs. 15% (18/117) normal subjects (P
0.001) and the average 10.3% (52/503) of all subjects (P
0.005) harbored the rs17849071G/T, suggesting that presence of rs17849071G/T in an individual would greatly protect against the development of FTC.
Polymorphism, particularly SNP, is common and accounts for about 90% of sequence variations in the human genome 
. Although most SNPs seem to be functionally silent, many are associated with increased risk for the development of certain diseases or disease characteristics. Some SNPs in the coding area of a gene may affect the function of the protein product of the gene while other SNPs in regulatory regions may affect the expression of the gene 
. This latter group of SNPs usually occur in promoters, silencers, enhancers, and introns. They may affect gene expression by altering the binding properties of regulatory regions of a gene with transcription and regulatory factors, ultimately interfering with the transcription or splicing processes.
Certain SNPs have been reported to affect thyroid cancer. For example, the L769L polymorphism of the RET
gene seemed to affect the onset age of familial MTC 
. Certain RET
gene SNPs were shown to be associated with an increased risk of differentiated thyroid cancer 
. A XRCC3 18067T polymorphic allele was similarly shown to be associated with differentiated thyroid cancer 
. More extensive genome-wide association studies have recently shown the association of several SNPs with the occurrence of thyroid cancer 
. Unlike these thyroid cancer-promoting SNPs, the rs17849071G/T found in the present study decreases the risk for FTC, which represents a rare example of tumor suppressor SNP.
Because the tumor suppressor function of the rs17849071G/T was only seen in FTC, but not other types of thyroid tumors (), it seems to be true that this SNP affects an oncogenic process that is unique and critical to the tumorigenesis of FTC. Our finding of the inverse association of the rs17849071G/T with PIK3CA
amplification provides such a mechanism explaining the protective effect of this SNP. As PIK3CA
amplification plays a prominent role in the tumorigenesis of thyroid cancer, particularly FTC 
, the significant decrease in the occurrence of PIK3CA
amplification in association with rs17849071G/T may conceivably result in decreased development of FTC in the presence of this SNP. It is also possible that the rs17849071G/T may negatively affect the expression of the PIK3CA
gene, minimizing its oncogenicity and hence reducing the development of FTC. As the rs17849071G/T is in intron 9 of the PIK3CA
gene, or the middle of the gene, this SNP could affect the binding and function of the splicing machinery, thus limiting the production of normal mRNA of the PIK3CA
. Interestingly, the 5 cases of homozygous rs17849071G/G in ATC all harbored PIK3CA
amplifications. Therefore, the mutual exclusivity seems to occur only between PIK3CA
amplification and heterozygous rs17849071G/T, but not the homozygous rs17849071G/G. However, in undifferentiated ATC, the copy gain of PIK3CA
may not necessarily represent genomic amplification; it may represent chromosomal aneuploidy 
, thus not following the relationship of rs17849071with PIK3CA
amplification in differentiated thyroid tumors. It remains to be elucidated how rs17849071G/T is linked to suppression of PIK3CA
amplification. One possibility that can be speculated is that rs17849071G/T may affect the binding of DNA with an unknown regulator that plays an important role in the process of gene amplification.
The discovery of this novel FTC-suppressor SNP is interesting. If this can be confirmed in larger studies, it will add a new dimension to the currently known genetic alteration arrays in thyroid cancer and represents a novel pathway that plays a critical role in FTC tumorigenesis. Mechanistic elucidation of this phenomenon will lead to important insights into the molecular mechanisms involved in the development of FTC and to the discovery of novel therapeutic targets as well. The rs17849071G/T represents also the first genetic marker that predicts the absence of FTC with high accuracy. It may therefore be useful in excluding a diagnosis of FTC in appropriate clinical settings.