**2. Familial non-medullary thyroid cancers**

Familial NMTC (FNMTC) is clinically defined as the presence of the disease in two or more first-degree relatives of the patient. It encompasses a heterogeneous group of diseases, including diverse syndromic-associated tumors with a preponderance of non-thyroidal tumors and non-syndromic tumors with a preponderance of NMTC. Hereditary cancer syndromes associated with FNMTC account for 5% of all familial cases and include familial adenomatous polyposis (FAP) and its variant Gardner syndrome, Cowden syndrome, Carney complex, Werner syndrome, and DICER1 syndrome. Other syndromes with less established links to the development of NMTC include McCune-Albright syndrome, Ataxia-telangiectasia, Li-Fraumeni syndrome, and Peutz-Jeghers syndrome [16–20], also no epidemiological studies confirmed a significantly increased risk of NMTC for patients affected by these latter syndromes and for their relatives. Non-syndromic-associated conditions encompass pure familial PTC (fPTC) with or without oxyphilia, fPTC with papillary renal cell carcinoma, and fPTC with multinodular goiter [21–23]. The clinical characteristics of FNMTC are controversial. Several studies found an earlier age of onset, higher incidence of multifocality and lymph node metastasis, and a more aggressive outcome with more frequent relapses compared with sporadic disease [24], while other studies showed no significant increase in risk of recurrence or disease-related mortality in FNMTC cases compared to sporadic cases [25, 26]. Additionally, the second generation of parent-offspring FNMTC cases presents the disease at a younger age with more severe symptoms, indicating the presence of genetic anticipation [27].

Understanding the genetic basis of a heterogeneous disease such as FNMTC and the identification of biomarkers of disease aggressiveness can help to better stratify risk, allowing predictive screening of at-risk family members, improved surveillance guidance, and clinical management plan.

#### **2.1 Genetic variants associated with risk of syndromic-associated disorders**

Germline mutation (or "pathogenic variants") accounting for syndromic FNMTC are highly penetrant and actionable, meaning that targeted genet testing is recommended when the clinician recognizes the clinical phenotype of the syndrome. Clinical characteristics and genes involved in the predisposition to syndromic FNMTC are summarized hereafter.

**Familial adenomatous polyposis (FAP)** is inherited as an autosomal dominant trait characterized by young-onset multiple gastrointestinal adenomatous polyps, especially of the colon, with malignant potential. In about 90% of cases, FAP is caused by germline loss-of-function variants in the tumor suppressor gene *APC* (*adenomatous polyposis coli*) located on chromosome 5q21 and encoding an inhibitor of Wnt signaling pathway. Ten to 25% of germline pathogenic *APC* variants arise *de novo.* Patients with FAP or with **Gardner syndrome,** a subset of FAP in which patients also develop extra-colonic manifestations [28], have a 160-fold greater risk than unaffected individuals of developing PTC [29–31]. Two to 12% of patients with FAP develop PTC [32], and 70% to 90% of these latter are diagnosed with a cribriformmorular variant of PTC (CMV-PTC), an extremely rare variant accounting for less than 1% of all PTC in the general population [33].

**Cowden syndrome** (also called **PTEN-hamartoma tumor syndrome**) is an autosomal dominant disorder characterized by hamartomatous changes and epithelial tumors of the breast, thyroid, kidney, colon, and endometrium caused by germline pathogenic variants in the tumor suppressor gene *PTEN* (*Phosphatase and TENsin homolog*) on chromosome 10q23.3 in about 9% of tested probands [34]. Up to 60% of patients with Cowden syndrome have thyroid nodules and 25% of patients have thyroid cancer [35]. These patients develop principally PTC (55.1%), followed by follicular variants of PTC (19.5%) and FTC (10%) [35]. Germline pathogenic variants in genes *SDHB*, *SDHC,* and *SDHD* encoding the subunits of the succinate dehydrogenase have also been described, as well as an epimutation in the promoter of the *killin* (*KLLN*) gene [35]. Succinate dehydrogenase belongs to mitochondrial complex II that participates in both the electron transport chain and Krebs cycle, and *KLLN* is a p53-regulated gene located upstream of *PTEN* and sharing a bidirectional promoter region.

**Carney complex** is a dominantly inherited syndrome characterized by a classic triad of spotty skin pigmentation, endocrine overactivity, and myxomas. About 5% of patients develop thyroid nodules (follicular adenoma) and cancer (PTC or FTC). Inactivating pathogenic variants in the *PRKAR1A* gene located at 17q22–24 are identified in 73% of patients and their penetrance has been estimated to be 97.5% [36]. The gene encodes the protein kinase cAMP-dependent type I regulatory subunit alpha. Phosphorylation mediated by the cAMP/protein kinase A signaling pathway is involved in the regulation of metabolism, cell proliferation, differentiation, and apoptosis [37]. Remarkably, the *PRKAR1A* gene can fuse to the RET protooncogene by gene rearrangement and form the thyroid tumor-specific chimeric oncogene known as *PTC2* [38].

**Werner syndrome** is an autosomal recessive genetic instability and progeroid ('premature aging') syndrome associated with loss-of-function variants in the *WRN* (*Werner syndrome RecQ like helicase*) gene located at 8p11–21 [39]. The *WRN* gene encodes a member of the RecQ subfamily of DNA helicase protein. This nuclear protein is involved in important functions required for the maintenance of genome stability such as replication, transcription, DNA repair, and telomere maintenance. Patients with Werner syndrome develop features reminiscent of premature aging beginning in the second decade of life, including bilateral cataracts, graying and loss of hair, scleroderma-like skin changes, diabetes mellitus, and osteoporosis. They are also at elevated risk for common, clinically important age-dependent diseases, such as cancer and atherosclerotic cardiovascular disease, which are the most common causes of death at a median age of 54 years [40]. Sixteen percent of patients with Werner syndrome develop thyroid cancer, with FTC being the most common histological subtype, followed by PTC and anaplastic thyroid cancers [40].

*Genetic Susceptibility to Differentiated Thyroid Cancer DOI: http://dx.doi.org/10.5772/intechopen.107831*

**DICER1 syndrome,** also known as **pleuropulmonary blastoma familial tumor and dysplasia syndrome**, is a rare pediatric autosomal dominant inherited disorder that predisposes individuals to various benign and malignant tumors. It is caused by germline pathogenic variants in the *DICER1* gene located at 14q32.13. The gene encodes a member of the ribonuclease III (RNaseIII) family involved in the generation of micro-RNA (miRNAs) and modulates gene expression by interfering with mRNA function. In the thyroid, germline *DICER1* loss-of-function variants disrupt the correct timing and expression of miRNA production necessary for normal thyroid differentiation and function [41, 42]. Patients with DICER1 syndrome are at higher risk of early-onset multinodular goiter and thyroid carcinomas. In particular, in DICER1 syndrome families, carriers of a *DICER1* pathogenic variant have a 16-fold increase in risk of DTC as compared to noncarriers [43].

#### **2.2 Genetic variants associated with risk of non-syndromic-associated disorders**

Initial efforts to identify DTC susceptibility genes were conducted in the late 90s − early 2000s by conducting genome-wide linkage analysis in multigenerational families with multiple affected members, usually with attempt to replicate best hits in an independent set of smaller families. Some candidate genes within the mapped regions have been subsequently screened. To date, seven loci involved in FNMTC susceptibility have been mapped (1q21, 2q21, 8p23.1-p22, 8q24, 12p14, 14q32, 19p13.2), where the causal genes remain to be identified or confirmed in independent family sets. With the introduction of massive-parallel sequencing technologies in diagnostic and research laboratories in the 2010s, some of these regions have been more extremely screened highlighting new candidates (*AK023948* at 8q24, *SRGAP1* at 12p14, *DICER1*




## *Genetic Susceptibility to Differentiated Thyroid Cancer DOI: http://dx.doi.org/10.5772/intechopen.107831*

#### *Thyroid Cancer – The Road from Genes to Successful Treatment*


*GWAS: genome-wide association study, LOH: loss of Heterozygosity, MAF: minor allele frequency, Ref.: reference, WES: whole-exome sequencing, WGS: whole-genome sequencing.*

#### **Table 1.**

*DTC susceptibility loci evidenced in family studies on non-syndromic NMTC (in chronological order of discovery).*

#### **Figure 2.**

*DTC susceptibility loci evidenced in family studies (in red) and in genome-wide association studies (GWAS) on NMTC (in blue). Only GWAS loci replicated in independent samples are shown.*

at 14q32, *MYO1F* at 19p13.2). In addition, whole-exome or whole-genome sequencing followed in most instances by functional assays allowed identification of potentially causal variants in other genes (*HABP2*, *SRRM2*, *MAP2K5*, *NOP53*, *TINF2*, *POT1*) located elsewhere in the genome. The details of these studies and clinical features of non-syndromic FNMTC families used in the discovery steps and replication steps are reported in **Table 1** and summarized in **Figure 2**.
