PAPILLARY THYROID CARCINOMA (PTC)
Genetic susceptibility to PTC can be seen in familial adenomatous polyposis syndrome (FAP), Cowden syndrome (CS), possibly Carney complex (CNC), and in a familial site-specific syndrome. Thyroid cancers can be detected in 2–25 % of FAP patients. It should be noted that there is evidence that what is commonly referred to as “PTC” in FAP is not identical to classic PTC (cPTC) nor its follicular variant of PTC (FvPTC). FAP-related thyroid cancer is of a distinct cribriform subtype, currently referred to as cribriform-morular variant (cmv) of PTC (Harach et al. 1994; Ito et al. 2011). In contrast to classic PTC, FAP- related thyroid cancers do not show the typical fir tree branching papillary pattern, and psammoma bodies are rare or nonexistent. This distinct architecture seen in APC-related thyroid carcinomas is very unusual in sporadic PTC (Harach et al. 1994). FAP-related cmv-PTC is often multifocal compared to the rare sporadic cmv-PTC (Ito et al. 2011). Recent studies suggest that FAP-related cmv-PTC patients are predominantly female, and the great majority of the germline APC mutations occurred in exon 15, especially the 5′ portion of this exon (Cetta et al. 2000; Jarrar et al. 2011).
Unlike the general population, PTC is underrepresented in CS-related thyroid carcinomas, especially in those with germline PTEN mutations (Harach et al. 1999). In contrast, however, pilot data suggest that PTC is overrepresented in individuals with CS who carry germline SDHB/SDHD variants of germline KLLN epimutation compared to those with germline PTEN mutations (Ni et al. 2008; Bennett et al. 2010). While thyroid Tumours, for example, PTC, have been reported in CNC, it is currently unclear if PTC is true component cancers of CNC.
Several putative loci, but no genes, have been identified for non- syndromic familial PTC and are summarized in the Table 4.1. It is believed that the 14q31-related multinodular goiter gene is DICER1 although it is unclear whether PTC is part of this newly described syndrome that most likely comprises multinodular goiter, Sertoli-Leydig cell Tumours, and perhaps Wilms’ Tumours (Rio Frio et al. 2011). Previously, DICER1 germline mutations are associated with the rare phenotypes of pleuropulmonary blastoma and familial cystic nephroma. Various low-penetrance germline variants, notably in pre-miR-146a (odds ratio = 1.6), have been reported (Jadziewski et al. 2009).
Table (1) Familial PTC
|PTC with cell oxyphilia||TCO, 19p13.2||Oncocytic PTC|
|PTC without oxyphilia||19p13.2|
|Multinodular goiter (MNG)||MNG1, 14q31||MNG and PTC|
|MNG2, Xp22||MNG only|
|PTC and renal Tumours||1q21||PTC, thyroid nodular disease, papillary renal cell carcinoma|
|PTC and clear cell renal cancer||t(3;8)(p14.2;q24.1)|
|FNMTC||NMTC1, 2q21||Follicular variant of PTC|
Reviewed in Eng (2000a, b, c)
Sporadic PTC are characterized by somatic translocations between one of several genes and the intracellular domain of RET (at intron 11) termed RET/PTCn. The precise frequency is unknown but could range from 10 to 60 %. Typically, the 5′-translocation partner encodes a protein which can force dimerization of the kinase domain of RET, for example, leucine zippers (Lanzi et al. 1992; Sozzi et al. 1992; Bongarzone et al. 1993). It would appear that PTC Tumours without RET/PTC translocations harbor a relatively high frequency of somatic gain-of-function BRAF mutations (Kimura et al. 2003; Soares et al. 2003). As somatic BRAF mutations and the presence of the RET/PTC translocation or RAS mutations are mutually exclusive, it is suggested that activation of the RAS-RAF-MAP kinase pathway is important in PTC development but that two insults to this pathway are not necessary.