On the other hand, 95% of FNMTC is non-syndromic and the culprit genes are yet to be identified (Yang and Ngeow, 2016). Therefore, genetic screening isn’t available.
The genes implicated in FNMTC have not been identified, with that being said several candidate loci involved in FNMTC associated with other familial syndromes have not been found to have an effect in the much more common isolated cases of FNMTC (Moses, Weng and Kebebew, 2011).
Some of the most common somatic mutations in genes associated with sporadic thyroid cancers, such as BRAF, RET, RET/PTC, MET, MEK1, MEK2, RAS, and NTRK, have been excluded by several germline mutation analyses as candidate genes for FNMTC (Lee et al., 2014).
To date, six potential regions for harboring of an FNMTC have been identified; MNG1 (14q32), thyroid carcinoma with oxyphilia (TCO; 19p13.2), fPTC/papillary renal neoplasia (PRN; 1q21), NMTC1 (2q21), FTEN (8p23.1– p22), and the telomere-telomerase complex. While
The HABP2, FOXE1, TTF-1/NKX2, and SRGAP1 genes were recently identified as candidate susceptibility genes (Guilmette and Nosé, 2018). The validity of these genes is still under investigation.
On the other hand, germline mutations in the following tumor suppressor genes are associated with the syndromic form of NMTC; PTEN with Cowden Syndrome and WRN with Werner Syndrome (Yu et al., 2015). Thus, instead of relying on classical linkage analysis, to predict genetoc suscesptibility to FNMT, a better strategy would be to screen for rare gerline mutations in some of the most important tumor suppresspr genes (Yu et al., 2015).
However, there is one major challenge when it comes to screening for rare germline mutations on known important tumor suppressor genes. Whole exons have to be sequenced because most loss of function mutations do not indicate any hot spot patterns. Therefore, massive parallel sequencing technology (NGS) will be of advantage over conventional sequencing technologies e.g Sanger sequencing (Yu et al., 2015).
4.4 Subtypes of FNMTC
Familial Thyroid Cancer comprises of two main subtypes; Familial Medullary Thyroid Cancer (FMTC) and Familial Non-Medullary Thyroid Cancer (FNMTC). FNMTC comprises of syndromic and non-syndromic forms.
FMTC is inherited autosomal dominant way, while FNMTC is suggested to have an autosomal dominant mode of inheritance with incomplete penetrance with variable expressivity (Nixon et al., 2016). It is also worth noting that, FNMTCs display the phenomenon of anticipation (earlier age at disease onset and increased severity in successive generations) (Prazeres et al., 2010).
5. Current challenges – Molecular/genetic diagnosis
Since FNMTC constitutes 3-9% of all thyroid cancers, several clinical features remain controversial and unknown. The first challenge is to identify molecular markers that will diagnose FNMTC more accurately than the clinical definition (Nosé, 2008). The underlying genetic causes of most of FNMTC cases are poorly understood. Several candidate genes and loci have been identified, but they are still being validated.
Only a small percentage of FNMTC can be explained by syndromic germline mutations. These syndromes include Cowden syndrome, familial adenomatous polyposis, Gardner syndrome, Carney complex type 1, Werner syndrome and DICER1 syndrome. For the first time in Cyprus, we will use sequencing technologies to try and identify the underlying genetic causes of FNMTC using Sanger sequencing and Next Generation Sequencing (NGS).