Balkan Journal of Medical Genetics

ANALYSIS OF MITOCHONDRIAL TRANSFER RNA MUTATIONS IN BREAST CANCER
Ding H.J.1, Zhao Y.P.2, Jiang Z.C.3, Zhou D.T.4, Zhu R.1* Han-Jie Ding and Ya-Ping Zhao contribute equally for this work
*Corresponding Author: Ph.D. Rui Zhu, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Binwen Road No. 548, Hangzhou, P.R. China. Phone/Fax: 0086-0571-86633133, E-mail: zhuruizjtcm@yeah.net
page: 15

RESULTS

Mutational Analysis of mt-tRNA Genes in Breast Cancer. The complete mt-tRNA genes of 80 tumor tissues and normal controls were analyzed by PCR-Sanger sequencing. The clinical and pathological data of these patients are listed in Table 1. Sanger sequencing suggested the presence of five mutations: tRNAVal G1606A, tRNAIle A4300G, tRNASer(UCN) T7505C, tRNAGlu A14693G and tRNAThr G15927A (Figure 1). Notably, the G1606A and A4300G mutations were in heteroplasmic forms, whereas the T7505C, A14693G and G15927A mutations were in homoplasmic forms. Interestingly, none of these occurred in control subjects. Moreover, the G1606A, A4300G and G15927A mutations were found in one patient with breast cancer (1.25%), while the T7505C and A14693G mutations were identified in two patients with breast cancer (2.5%), the molecular characterization of these mutations is listed in Table 2. Assessments of the Pathogenicity. The following criteria were used to evaluate the pathogenic roles of mttRNA mutations: (1) had a relative high level of CI (≥75%) [26], (2) found < 1% in control group, (3) had the ability to affect the tRNA functions, (4) affected the mitochondrial functions. As can be seen from Figure 1 and Table 2, one mutation (G1606A) was located at acceptor arm, two mutations (A4300G and G15927A) occurred at anticodon stem, one mutation (T7505C) in D-arm and one mutation (A14693G) in TΨC-loop. Four mutations (G1606A, A4300G, T7505C and G15927A) disrupted the highly conserved Watson-Crick base-pairings. Thus, it may be anticipated that these mutations will disrupt the tRNA stability level and function. We further analyzed mitochondrial functions in patients carrying these mt-tRNA mutations, as shown in Figure 2. We found that patients with putative pathogenic mt-tRNA mutations had much lower levels of mtDNA copy number and ATP, as compared with the controls (p=0.0138 and 0.0362, respectively) In addition, the classical pathogenicity scoring system [25] was then used to assess the scores of these mt-tRNA mutations. As a result, the total scores of tRNAVal G1606A, tRNAIle A4300G, tRNASer(UCN) T7505C, tRNAGlu A14693G and tRNAThr G15927A mutations were 13, 11, 13, 9 and 13 points, which belonged to “definitely pathogenic” and “possibly pathogenic” according to its standard (Table 3).

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