**1. Introduction**

Almost 95% of patients with malignant thyroid tumors have non-medullary thyroid cancer (NMTC), which originates from follicular cells. Most NMTC are well-differentiated and include papillary thyroid carcinoma (PTC) (80−90%) and follicular thyroid carcinoma (FTC) (10−15%) while poorly differentiated thyroid carcinoma and anaplastic carcinoma are rare. C-cell-derived medullary thyroid carcinoma (MTC) are diagnosed in approximately 5% of patients [1]. Altogether differentiated thyroid carcinoma (DTC) represents more than 90% of all thyroid cancer histological types and the most frequent malignancy of the endocrine system (**Figure 1**) [2].

DTC incidence varies considerably around the world. High incidence was reported in some Pacific islands such as Hawaii, New Caledonia, and French Polynesia [3]. Ethnic differences in incidence within the same country have

#### **Figure 1.**

*Thyroid cancer subtypes classification.*

been noted in Hawaii and New Caledonia with higher rates among Filipinos and Melanesians than in other ethnic groups [4]. The causes underlying these wide geographic and ethnic variations are still poorly understood. If this variation in incidence was attributed to screening practices, it was suggested that environment and inherited genetic risk factors may also play an important role [5]. Clinical awareness of potential risk factors, such as inherited genetic variants allows for earlier recognition of more vulnerable populations, earlier detection, proper treatment, and improved outcomes for patients and their families, justifying current efforts to identify and understand the causal factors and mechanisms of DTC so that effective interventions can be implemented.

Familial associations are often quantified in terms of familial relative risk (FRR). The FRR denotes the risk of disease when a family member is affected compared to the risk level in the general population. Specific types of familial relationships, like first-degree relatives, parent–child, or siblings are generally examined. Remarkably, thyroid cancer displays one of the strongest FRRs among cancers. Large case–control studies conducted in populations from Utah and Sweden showed that the FRR of thyroid cancer for first-degree relatives of probands was 8.5 and 12.4, respectively [6, 7]. Data from studies focusing on DTC conducted in Sweden, Iceland, and Norway showed that the standard incidence risk (SIR) of DTC was between 4.1 and 7.8 for male relatives and between 1.9 and 4.9 for female relatives of the proband [8–10]. The SIR for PTC was calculated in the Norwegian study as 5.8 and 4.1 for male and female relatives, respectively [10]. The family structures of non-medullary thyroid carcinoma (NMTC) patients in Taiwan were also studied. The prevalence of NMTC in the general population and in first-degree relatives of NMTC patients was 0.16% and 0.64%, respectively. This corresponds to a 5.5-fold increased risk of NMTC for first-degree family members [11].

Like many cancers, thyroid cancers may arise from mutations that may or may not be heritable. They can occur due to any mistake during DNA replication during cell division or may be induced due to the effect of carcinogens on DNA like ionizing radiation. Most thyroid cancers are the result of the accumulation of somatic mutations in the cancer genome, either driver mutations of oncogenesis or passenger mutations [12]. They are not present constitutionally in the individual but only in part of thyroid cells. By contrast, constitutional (germline) variants may predispose

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

to cancer susceptibility and are present in affected individuals in all the body's nucleic cells, as well as the cancer genome, and may therefore be heritable. Nonetheless, over 90% of all thyroid cancers are sporadic, *i.e.* occur in people with no family history of thyroid cancer. The remaining are familial forms of NMTC and MTC. Familial MTC is associated with well-known germline genetic alterations in the *RET* proto-oncogene [13, 14] and genotype–phenotype correlations have been described [15]. On the contrary, the genetic causes of familial NMTC (FNMTC) or follicular cell-derived carcinoma are poorly understood despite considerable effort to identify contributing loci. In this chapter, we summarize variants associated with risk of DTC in familial and sporadic settings, as well as approaches used to map them in various populations and to identify causal genes or variants, which would greatly facilitate the estimation of disease risk and prognosis.
