A Comprehensive Characterization of Mitochondrial Genome in Papillary Thyroid Cancer

Abstract

Nuclear genetic alterations have been widely investigated in papillary thyroid cancer (PTC), however, the characteristics of the mitochondrial genome remain uncertain. We sequenced the entire mitochondrial genome of 66 PTCs, 16 normal thyroid tissues and 376 blood samples of healthy individuals. There were 2508 variations (543 sites) detected in PTCs, among which 33 variations were novel. Nearly half of the PTCs (31/66) had heteroplasmic variations. Among the 31 PTCs, 28 specimens harbored a total of 52 somatic mutations distributed in 44 sites. Thirty-three variations including seven nonsense, 11 frameshift and 15 non-synonymous variations selected by bioinformatic software were regarded as pathogenic. These 33 pathogenic mutations were associated with older age (p = 0.0176) and advanced tumor stage (p = 0.0218). In addition, they tended to be novel (p = 0.0003), heteroplasmic (p = 0.0343) and somatic (p = 0.0018). The mtDNA copy number increased in more than two-third (46/66) of PTCs, and the average content in tumors was nearly four times higher than that in adjacent normal tissues (p < 0.0001). Three sub-haplogroups of N (A4, B4a and B4g) and eight single-nucleotide polymorphisms (mtSNPs) (A16164G, C16266T, G5460A, T6680C, G9123A, A14587G, T16362C, and G709A) were associated with the occurrence of PTC. Here we report a comprehensive characterization of the mitochondrial genome and demonstrate its significance in pathogenesis and progression of PTC. This can help to clarify the molecular mechanisms underlying PTC and offer potential biomarkers or therapeutic targets for future clinical practice.

The Mitochondrial DNA Control Region might have useful Diagnostic and Prognostic Biomarkers for Thyroid Tumors

“…Besides, G16129A was located in the extended termination association sequence 1 (ETAS1) and T16304C was located in the ETAS2 which take place in mitochondrial replication (Sbisa et al, 1997). Amongst these SNPs, T16362C was found associated with PTC occurrence in Chinese population previously (Su et al, 2016). In this study, the prevalence of T16362C was detected higher in CTNs than HTN, PTC and NC (12.3% vs 1.5, 4.2 and 3.8%, respectively).…”

“…The number of studies related to the effects of mtDNA haplogroups on susceptibility to thyroid cancers is rather limited in the literature. However, in a study of 66 PTC cases in the Chinese population, Su et al, (2016) reported that A4, B4a and B4g mtDNA haplogroups were associated with PTC development. In spite of this, in a study conducted in 100 thyroid cancer cases, Fang H et al (2010) reported that the D4a haplogroup had a higher risk of thyroid cancer in Chinese population.…”

“…This metabolic reprogramming is known as Warburg effect (Lee and Wei, 2009). Although advantages conferred to cancer cells of the Warburg effect have not been clearly understood, it is suggested that they may relate to the ability to proliferate in the lack of oxygen, to decreased susceptibility to mitochondrial apoptosis, or to the need of the tumor cell to accumulate nutrients for increased proliferation (Lee and Wei, 2009;Nicholls and Ferguson, 2013;Su et al, 2016).…”

“…However, a few studies are interested in genomic changes of the mtDNA D-Loop region at thyroid tumors, especially PTC (Lohrer et al, 2002). Majority of the studies have been focused on mtDNA microsatellite instabilities (mtMSIs) either D310 alone or D310, D514 and np 16183-16192 altogether Lohrer et al, 2002;Maximo et al, 2005;Su et al, 2016). Also, these studies have some sample size limitations.…”

“…So, they did not considered any influence of the other SNPs rather than mtMSIs at CR of the mtDNA. But only one study in literature includes all mitochondrial genome investigation at PTC samples but the study did not have any benign thyroid tumor samples to demonstrate the influence of the mitochondrial genome in thyroid tumorigenesis (Su et al, 2016). In addition to that, Cocos et al (2017) reported that mtDNA haplogroup K has a protective role for thyroid cancer and suggested that investigating mtDNA haplogroups is a candidate susceptibility marker for the patients with thyroid nodules.…”