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  • Primary research
  • Open Access

The mitochondrial C16069T polymorphism, not mitochondrial D310 (D-loop) mononucleotide sequence variations, is associated with bladder cancer

  • 1,
  • 2, 4Email author,
  • 3,
  • 4,
  • 1,
  • 4,
  • 4,
  • 5 and
  • 3
Cancer Cell International201313:120

https://doi.org/10.1186/1475-2867-13-120

  • Received: 19 June 2013
  • Accepted: 27 November 2013
  • Published:

Abstract

Background

Bladder cancer is a relatively common and potentially life-threatening neoplasm that ranks ninth in terms of worldwide cancer incidence. The aim of this study was to determine deletions and sequence variations in the mitochondrial displacement loop (D-loop) region from the blood specimens and tumoral tissues of patients with bladder cancer, compared to adjacent non-tumoral tissues.

Methods

The DNA from blood, tumoral tissues and adjacent non-tumoral tissues of twenty-six patients with bladder cancer and DNA from blood of 504 healthy controls from different ethnicities were investigated to determine sequence variation in the mitochondrial D-loop region using multiplex polymerase chain reaction (PCR), DNA sequencing and southern blotting analysis.

Results

From a total of 110 variations, 48 were reported as new mutations. No deletions were detected in tumoral tissues, adjacent non-tumoral tissues and blood samples from patients. Although the polymorphisms at loci 16189, 16261 and 16311 were not significantly correlated with bladder cancer, the C16069T variation was significantly present in patient samples compared to control samples (p < 0.05). Interestingly, there was no significant difference (p > 0.05) of C variations, including C7TC6, C8TC6, C9TC6 and C10TC6, in D310 mitochondrial DNA between patients and control samples.

Conclusion

Our study suggests that 16069 mitochondrial DNA D-Loop mutations may play a significant role in the etiology of bladder cancer and facilitate the definition of carcinogenesis-related mutations in human cancer.

Keywords

  • Mitochondrial DNA displacement loop
  • 16069 D-Loop mutation
  • Urinary bladder neoplasm

Introduction

Human mitochondrial DNA (mtDNA) is a 16569-bp closed circular, double-stranded molecule approximately 1000 copies per cell. mtDNA contains 37 genes, including 13 subunits involved in the electron transport chain, 22 tRNAs, the 12S and 16S rRNAs, and a non-coding region (D-loop) located at nucleotide position 16024–576 (MITOMAP, 2011) [1]. The D-loop region regulates the replication and transcription of mtDNA, where mutations in this region might lead to copy number and/or change in mtDNA gene expression [2].

Bladder cancer is the ninth most common cancer worldwide [3]. According to the latest American Cancer Society statistics, bladder cancer accounts for 7% of all cancers and 3% of all cancer deaths [4, 5]. In Iran, bladder cancer accounts for 7.04% of all cancers [6].

Many attempts have been made to develop an urothelial cancer biomarker test to complement or replace urine cytology, including NMP22, BTA stat, BTA TRAK, and FISH. Most studies on the molecular genetics of the bladder cancer focus on changes in genomic DNA, including oncogenes and tumor suppressor genes, such as HRAS, ERBB2, TP53 and RB, and subsequent cellular events [7, 8].

Mitochondrial function and DNA attract less interest in studies on bladder carcinoma. Mitochondrial dysfunction has been linked to a wide range of degenerative and metabolic diseases, cancer, and even aging. mtDNA, which has a very high mutation rate, results in three classes of clinically relevant phenotypes: deleterious germline mtDNA mutations, which are linked to mitochondrial diseases; mtDNA polymorphisms, which are related to environmental adaptation in human evolution; and mtDNA somatic mutations, which are associated with aging and cancer. Mitochondrial defects were first associated with carcinogenesis several decades before, when Warburg reported “injury of the respiratory chain” and high glycolytic rate as typical of cancer [912].

Mitochondrial DNA is thought to accumulate more mutations than nuclear DNA (nDNA) to some extent, because the protective histones as well as the highly efficient DNA repair mechanisms do not exist in the mitochondrial nucleus. Certain tumors have been shown to result from mutations in nDNA-encoded mitochondrial proteins, which may result in increased reactive oxygen species (ROS) production. Mitochondrial dysfunction does appear to be a factor in cancer etiology. Alterations in mitochondrial DNA (mtDNA), including point mutations, deletions, insertions and genome copy number changes, are believed to be responsible for carcinogenesis [1315]. For example, many reports have identified a mtDNA 4977-bp deletion in lung [16], breast [17] and endometrial carcinomas [18].

The use of mtDNA mutation and/or polymorphism patterns as a biomarker is rapidly expanding in disciplines, ranging from rare metabolic diseases and aging to cancer and the tracing of human migration patterns, population characterization and human identification in forensic science. In this study, we examined the presence of mutations in the mitochondrial D-Loop sequences of tumoral tissues as compared with adjacent non-tumoral tissues from Iranian patients with bladder cancer.

Materials and Methods

Twenty-six men with primary urothelial bladder cancer with a mean age of 62.5 years were enrolled in this study (Table 1). The patients’ written consent was obtained and the institutional review board approved this study. Tumoral tissues were obtained from transurethral resection of the bladder tumor (TURBT) or radical cystectomy specimens. Tumoral tissues and adjacent non-tumoral tissues were immediately frozen in liquid nitrogen and kept at -80°C, while blood samples from patients were obtained before surgery.
Table 1

Age and histological type of primary urothelial bladder neoplasm sybtypes

No. of Male patients

Age

Histological type

1

62

Carcinoma in situ+

2

60

Papilloma

3

58

Papillary Urothelial carcinoma- low grade

4

63

Neoplasm of low malignant potential Papillary urothelial

5

73

Carcinoma in situ+

6

80

Papillary urothelial carcinoma – high grade

7

69

Papillary Urothelial carcinoma- low grade

8

68

Neoplasm of low malignant potential Papillary urothelial

9

53

Non-papillary urothelial carcinoma –high grade

10

55

Papillary urothelial carcinoma – high grade

11

75

Non-papillary urothelial carcinoma –high grade

12

78

Papillary Urothelial carcinoma- low grade

13

73

Neoplasm of low malignant potential Papillary urothelial

14

69

Papillary Urothelial carcinoma- low grade

15

68

Non-papillary urothelial carcinoma –high grade

16

57

Neoplasm of low malignant potential Papillary urothelial

17

53

Non-papillary urothelial carcinoma –high grade

18

50

Papillary urothelial carcinoma – high grade

19

49

Papillary Urothelial carcinoma- low grade

20

45

Non-papillary urothelial carcinoma –high grade

21

29

Papillary urothelial carcinoma – high grade

22

70

Papillary Urothelial carcinoma- low grade

23

66

Non-papillary urothelial carcinoma –high grade

24

58

Papillary urothelial carcinoma – high grade

25

59

Papillary Urothelial carcinoma- low grade

26

74

Neoplasm of low malignant potential Papillary urothelial

Urothelial bladder cancer diagnosis was done via histological analysis. Blood samples from healthy controls with a mean age of 57.5 years were obtained from 404 individuals of 17 ethnicities and 100 random individuals, all from the Tehran Special Medical Center. The exclusion criterion for the control group was any history of cancer, metabolic diseases and mitochondrial DNA related diseases that may affect the mtDNA. Ethics approval and patient informed consent including consent to participate in the study and consent to publish was obtained for the present study in accordance to the Tehran Special Medical Center and Medical Ethics Committee (Approval No. MS-16-2007).

DNA extraction and sequencing

Genomic DNA (DNA fast, QIAGEN, Cat. No. 51204) was isolated from the tumoral tissues, adjacent non-tumoral tissues and blood samples of patients, as well as from the blood samples of controls, according to the manufacturer’s protocol. Two pairs of primers designed to amplify the mtDNA D-loop region are as follows: ONP 98 F )1579-15810(: 5′-ATC ATT GGA CAA GTA GCA TC -3′ and ONP 79R )780-761(: 5′-GAG CTG CAT TGC TGC GTG CT-3′. Polymerase chain reaction (PCR) was carried out with the following protocol: pre-denaturation at 95°C for 5 min, then 35 cycles of 94°C for 30 sec, 60°C for 45 sec and 72°C for 1 min, and a final extension step of 72°C for 6 min. Each amplified fragment was purified using a Agarose Gel DNA Fragment Recovery Kit, Ver.2.0 (TaKaRa, Japan) and subsequently sequenced using a ABI PRISM 3730 sequence analyzer (gene Fanavaran, Macrogene Seoul, Korea). The quality of the obtained chromatograms was assessed by FinchTV® software Version 1.4.0 (Geospiza, Inc., USA).

Multiplex PCR

The PCR reactions were performed for 35 cycles of the following steps: 94°C for 10 min, 55°C for 10 min, and 72°C for 35 sec. Using the primers ONP 86, ONP 89, ONP 10, ONP 74, ONP 25 and ONP 99, the deletion-prone region between 5461 nt of the light strand and 15000 nt of the heavy strand was investigated in all the patients. The distances between the primers were long enough to allow amplification only if a part of the DNA between each respective primers was deleted. As a control in PCR analysis, a normal internal mtDNA fragment in a region which is seldom affected by deletions was amplified using the primer pair of ONP 86 and ONP 89 (Table 2). Polymerase chain reaction products were separated on 2% agarose gels and run in 0.5× Tris/Borate/EDTA buffer at 110 V for 50 min, stained in 0.002 μg/mL ethidium bromide, and visualized by means of an ultraviolet light.
Table 2

Primers used for detection of four deletions

Forward Start point of primer

Reversed End point of primer

Length of deletion, kb

ONP 86: 5461–5480

ONP 74: 15260–15241

8.7

5′-CCCTTACCACGCTACTCCTA -3′

5′-TGTCTACTGAGTAGCCTCCT-3′

ONP 86: 5461–5480

ONP 10: 13640–13621

7.5

5′-CCCTTACCACGCTACTCCTA -3′

5′-GTTGACCTGTTAGGGTGAG-3′

ONP 25: 8161–8180

ONP 10: 13640–13621

5

5′-CTACGGTCAATGCTCTGAAA-3′

5′-GTTGACCTGTTAGGGTGAG-3′

ONP 25: 8161–8180

ONP 99: 16150–16131

7.5

5′-CTACGGTCAATGCTCTGAAA-3′

5′-GTGGTCAAGTATTTATGGTA-3′

ONP 86: 5461–5480

ONP 89: 5740–5721

Internal Control

5′-CCCTTACCACGCTACTCCTA -3′

5′-GGCGGGAGAAGTAGATTGAA-3′

Southern blot analysis

Extracted mtDNA was eletrophoresed on 1% agarose gel. After electrophoresis, the DNA were denatured, neutralized and transferred to nylon membrane. Meanwhile, the ONP98 primer (5′-ATCATTGGACAAGTAGCATC-3′), located at 15791–15810 bp, and the ONP79 primer (5′-GAGCTGCATTGCTGCGTGCT-3′), located at 780–761 bp of the mtDNA, were used to amplify a 1558-bp fragment from the D-loop region. This fragment was used as a mtDNA probe. Southern blot analysis was performed using the DIG DNA Labeling and Detection Kit (Cat. #11093657910, Roche).

Statistical analysis

Sequences were edited and aligned using ClustalX. The revised Cambridge Reference Sequence was used as a reference (GI: 251831106) (MITOMAP, 2009). The Chi-square test was used with SPSS (Statistical Package for the Social Sciences, version: 13) to examine the association of variations with control and patient samples. P-values < 0.05 were regarded as statistically significant.

Results

Samples from a total of 26 patients with sporadic bladder cancer were screened for mitochondrial deletions and variations. Sequence analysis found a total of 110 variations (Cambridge Mitochondrial Sequences), of which 62 mutations were previously reported (MITOMAP). However, 48 of these mutations were reported as new mutations, which are summarized in Table 3. In this study, almost all of the variations were homoplasmic, but in 6 (16.6%) cases, a C nucleotide insertion was seen in locus 16194. No mitochondrial deletions were found in the patient samples (Figures 1 and 2), as confirmed by Southern blotting (Figure 3).
Table 3

List of variations in both healthy controls and bladder cancer patients

NO.

Variations

Controls

Patients

1

15968

  

2

15969

  

3

15996

  

4

16004

  

5

16017

*

 

6

16021

  

7

16026

  

8

16033

 

*

9

16051

 

*

10

16067

 

*

11

16069

  

12

16071

  

13

16075

  

14

16082

  

15

16085

  

16

16086

  

17

16092

 

*

18

16093

  

19

16095

  

20

16111

 

*

21

16114

  

22

16124

  

23

16126

  

24

16129

*

 

25

16140

  

26

16145

  

27

16147

*

 

28

16148

  

29

16150

*

 

30

16153

  

31

16155

  

32

16162

  

33

16163

  

34

16167

  

35

16169

  

36

16172

  

37

16173

  

38

16174

*

 

39

16176

*

 

40

16179

  

41

16183

 

*

42

16184

  

43

16187

 

*

44

16188

 

*

45

16189

  

46

16192

  

47

16193

  

48

16201

*

 

49

16203

  

50

16207

*

 

51

16209

  

52

16213

  

53

16217

 

*

54

16220

  

55

16222

  

56

16223

  

57

16224

 

*

58

16227

*

 

59

16230

 

*

60

16234

 

*

61

16239

*

 

62

16242

*

 

63

16243

  

64

16245

  

65

16247

 

*

66

16248

 

*

67

16249

  

68

16256

*

 

69

16261

  

70

16263

  

71

16264

  

72

16265

*

 

73

16266

  

74

16270

*

 

75

16274

*

 

76

16278

*

 

77

16286

  

78

16287

*

 

79

16288

  

80

16290

 

*

81

16292

  

82

16294

  

83

16295

  

84

16296

  

85

16298

*

 

86

16304

*

 

87

16309

  

88

16311

  

89

16318

 

*

90

16318

  

91

16319

  

92

16320

 

*

93

16324

*

 

94

16325

*

 

95

16327

 

*

96

16342

  

97

16343

  

98

16352

*

 

99

16354

  

100

16355

*

 

101

16356

 

*

102

16362

  

103

16390

*

 

104

16391

*

 

105

16399

*

 

106

16413

  

107

16468

  

108

16482

*

 

109

16497

*

 

110

16527

 

*

*Indicates novel mutation has not been reported before.

Figure 1
Figure 1

Multiplex-PCR amplification. Lanes 1, 2, 3 and 5 show the internal control (279 bp), lane 4 is the negative control and lane M is a 100 bp DNA size marker. No other bands were observed. Amplification only takes place if deletions occur in the DNA between the PCR primers.

Figure 2
Figure 2

Long range PCR amplification of mtDNA using Phusion Flash high-fidelity PCR Master Mix, Thermo Scientific. A two-step long-range PCR was carried out on the major arc of the mitochondrial genome using the Expand Long Template PCR System to detect mitochondrial deletions. DNA products were separated using a 0.7% agarose gel containing ethidium bromide and viewed under UV light. Lanes 1 and 3: negative control; Lanes 2 and 4: an amplified 11 Kb fragment, indicating no deletions were observed in mtDNA; lane M: 1 kb DNA ladder marker.

Figure 3
Figure 3

Southern blot analysis of mitochondrial DNA (mtDNA) digested with the restriction enzyme BamH1 (nt14258), and hybridized with a DIG-labeled probe. Lanes 1–5 shows intact mtDNA (~16.6 Kb).

Four common variations, 16069, 16189, 16261 and 16311, were found in the tumoral tissues, adjacent non-tumoral tissues and blood samples of both patients and controls from different ethnicities. The polymorphisms at 16189, 16261 and 16311 were not significantly correlated with bladder cancer. However, the D-loop C16069T polymorphism (Figure 4) was significantly correlated with bladder cancer (P < 0.05). Analysis of control samples by ethnicities for these 4 variations is summarized in Table 4. No significant difference (p > 0.05) in D310 C variations was observed between the patient and control samples (Table 5).
Figure 4
Figure 4

Chromatogram showing homoplasmy at position 16069 of the mitochondrial DNA D-loop in a normal sequence (Figure4-A) and a variation (Figure4-B). The arrow marks the sequence variations.

Table 4

Comparison of 4 common variations in bladder cancer patients and controls

Ethnicity

NO.

16069

16189

16261

16311

Arab

23

0 (0%)

7 (30.4%)

4 (17.4%)

4 (17.4%)

Armenian

18

0 (0%)

5 (27.7%)

2 (11%)

3 (16.7%)

Asurian

19

1 (5.2%)

7 (36.8%)

3 (15.8%)

1 (5.3%)

Azari

22

0 (0%)

6 (27.3%)

0 (0%)

4 (18.2%)

Turkmen

37

1 (2.7%)

5 (13.5%)

1(2.7%)

6 (16.2%)

Baluch

13

0 (0%)

2 (15.4%)

1 (7.7%)

0 (0%)

Bandari

31

0 (0%)

13 (42%)

2 (6.5%)

5 (13.5%)

Guilani

24

0 (0%)

2 (8.3%)

3 (12.5%)

3 (12.5%)

Jews

37

1 (2.7%)

6 (16.2%)

4 (10.8%)

4 (10.8%)

Kurd

24

2 (8.3%)

3 (12.5%)

4 (16.7%)

6 (25%)

Lur

22

0 (0%)

1 (4.5%)

8 (36.4%)

8 (36.4%)

Mazani

23

0 (0%)

4 (17.4%)

4 (17.4%)

1 (4.3%)

Persian Isfahan

16

0 (0%)

6 (37.5%)

2 (12.5%)

5 (31.2%)

Persian Kerman

25

0 (0%)

7 (28%)

1 (4%)

5 (20%)

Persian Mashhad

23

0 (0%)

5 (21.7%)

2 (8.7%)

2 (8.7%)

Persian Shiraz

23

0 (0%)

4 (17.4%)

2 (8.7%)

3 (3.2%)

Persian Yazd

24

0 (0%)

5 (20.8%)

1 (4.1%)

2 (8.3%)

Mixed Tehran

100

8 (8%)

9 (9%)

9 (9%)

12 (12%)

Total (controls)

504

13 (2.6%)

95 (18.8%)

53 (10.5%)

78 (15.5%)

Patients

26

5 (19%)*

4 (15.4%)

4 (15.4%)

8 (31%)

*Shows statistically significant, p < 0.05.

Table 5

Association of the mtDNA D310 variation in bladder cancer patients and controls

Ethnicity

NO.

C 7TC6

C 8TC6

C 9TC6

C 10TC6

Arab

23

12 (52.2%)

8 (34.7%)

2 (8.7%)

1 (4.3%)

Armenian

18

7 (38.9%)

11 (61.1%)

0 (0%)

0 (0%)

Azari

22

8 (36.4%)

12 (54.5%)

2 (9%)

0 (0%)

Turkmen

37

17 (45.9%)

16 (43%)

4 (10.8%)

0 (0%)

Bandari

31

10 (32%)

15 (48.4%)

6 (19.4%)

0 (0%)

Persian Isfahan

16

5 (31.3%)

9 (56.3%)

2 (6.5%)

0 (0%)

Persian Mashhad

23

14 (60.9%)

8 (34.8%)

1 (4.3%)

0 (0%)

Persian Shiraz

23

6 (26%)

16 (69.6)

1 (4.3%)

0 (0%)

Persian Yazd

24

9 (37.5%)

9 (37.5%)

5 (20.8%)

1 (4.1%)

Guilani

24

8 (33%)

12 (50%)

4 (16.6%)

0 (0%)

Jews

37

16 (43%)

17 (45.9)

4 (10.8%)

0 (0%)

Kurd

24

3 (12.5%)

14 (58%)

7 (29%)

0 (0%)

Lur

22

9 (41%)

9 (41%)

4 (18%)

0 (0%)

Total (controls)

324

124 (38.3)

156 (48.1%)

42 (13%)

2 (0.6%)

Patients

21

9 (42.9%)

10 (47.6%)

2 (9.5%)

0 (0%)

The D310 sequence variations of mtDNA in patients and controls were not significantly different (p > 0.05).

Discussion

Our sequencing analysis focused on the mtDNA D-loop region, which is highly polymorphic and contains two hypervariable regions, HV1 (16024–16383) and HV2 (57–333), that was considered as a somatic mutation “hot spot” in many types of cancer [19]. In this study, no deletions were seen in the mitochondrial genome. One hundred and sixteen variations were observed in the D-Loop region, where 48 of them were not previously reported. Wada et al.[20] also reported that the majority of somatic mutations were homoplasmic, suggesting that the mutant mtDNA became dominant in tumor cells. Fliss et al.[21] screened 14 urinary bladder cancers for somatic mutations in the D-loop region, and found mutations in 4 (29%) samples.

Polymorphism 16189, which is highly polymorphic, was the previous focus of oncological research because carriers with the T16189C polymorphism were apparently more susceptible to breast cancer and ganglioma development. Interestingly, the T16189C polymorphism was found in 14% of endometrial cancers [22] and type II diabetes mellitus [23, 24].

In this study, in contrast to 16189, 16194, 16261 and 16311 variations, the C16069T polymorphism of the D-loop indicated significant correlation with bladder cancer (P < 0.05), which has not been studied in bladder cancer before. However, the C16069T polymorphism has been reported in prostate cancer [25], pancreatic cancer [26], endometrial cancer [27], breast cancer [28, 29], repeated pregnancy loss [30] and age-related macular degeneration [31]. This result supports our hypothesis, which shows the potential of specific mitochondrial 16069 polymorphism involvement in carcinogenesis.

Many studies reported that the C150T polymorphism is correlated with longevity (MITOMAP, 2009). The possible function of the C150T transition was investigated in a previous study [32], suggesting that the C150T transition functions in remodeling mtDNA replication. However, in our study, no significant differences were found between C150T mutations in patients and control samples from different ethnicities.

Large-scale mtDNA deletions have been demonstrated in several cancers. Kamalidehghan et al.[33] found that the common mtDNA4977 deletion was less frequent in gastric cancer tissues compared to the normal adjacent tissues. While in another study, a deletion of approximately 8.9 kb was more frequent in gastric carcinoma tissues than adjacent normal tissue samples [34]. However, in the present study, no deletions were detected in bladder carcinoma tissues nor adjacent non-tumoral tissues. Therefore, the pattern of mitochondrial deletions may differ among different carcinomas.

Marchington et al.[35] first used the term D310 to describe a highly polymorphic mononucleotide tract of poly (C) that varies from 12 to 18 Cs, located between nucleotide positions 303 and 318 in CSB II, that forms a RNA–DNA hybrid known as an R-loop. This poly(C) region is interrupted at nucleotide position 310 by a T (CCCCCCCTCCCCC), in which the number of Cs before the T can vary between 7 to 9 in normal polymorphic variants [35]. D310 has been reported as a mutational hot-spot in a large panel of tumors including gastric, head and neck, breast, colorectal, lung and bladder cancers, where head and neck cancer has the highest rate of D310 variants (37%), followed by breast (29%) and colorectal (28%) cancers. However, no D310 alterations were detected in prostate and ovarian cancers [36, 37].

The D310 region of mtDNA plays an important role in mitochondrial biogenesis, where somatic insertions or deletions of one or two base pairs in this region are thought to have negligible effects on cancers. However, major deletions or insertions of up to ten bases in the D310 region could interfere with mtDNA biogenesis [38]. Mutations in the D-loop, mostly at D310, have been found in 21% of all head and neck squamous cell carcinomas [39]. However, in our study, the D310 mtDNA sequence variations, including C7TC6, C8TC6, C9TC6 and C10TC6, were not significantly different (p > 0.05) between bladder cancer patients and controls of different ethnicities.

In conclusion, our study suggests that the mitochondrial DNA D-Loop 16069 mutation may play a significant role in the etiology of bladder cancer and facilitate the definition of carcinogenesis-related mutations in human mtDNA.

Competing of interests

The authors declare that they have no competing of interests.

Abbreviations

mtDNA: 

mitochondrial DNA

D-Loop: 

Displacement loop

PCR: 

Polymerase chain reaction

nDNA: 

nuclear DNA

ROS: 

Reactive oxygen species

TURBT: 

Transurethral resection of the bladder tumor

SPSS: 

Statistical package for the social sciences

HV: 

Hypervariable

mtMSI: 

Mitochondrial microsatellite instability.

Declarations

Acknowledgements

We are thankful to the “Urology and Nephrology Research Center (UNRC) of Tehran” for giving the grant for this project and the “National Institute for Genetic Engineering and Biotechnology (NIGEB) of Tehran”, Project 187.

Authors’ Affiliations

(1)
Urology and Nephrology Research Center (UNRC), Shahid Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
(2)
National Institute for Genetic Engineering and Biotechnology, Tehran, Iran
(3)
Department of Pharmacy, Faculty of Medicine, University of Malaya (UM), Kuala Lumpur, 50603, Malaysia
(4)
Medical Genetics Department, Special Medical Center, Tehran, Iran
(5)
UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, UPM Serdang, Selangor, 43400, Malaysia

References

  1. Suzuki M, Toyooka S, Miyajima K, Iizasa T, Fujisawa T, Bekele NB, Gazdar AF: Alterations in the mitochondrial displacement loop in lung cancers. Clin Cancer Res. 2003, 9 (15): 5636-5641.PubMedGoogle Scholar
  2. Yu M, Zhou Y, Shi Y, Ning L, Yang Y, Wei X, Zhang N, Hao X, Niu R: Reduced mitochondrial DNA copy number is correlated with tumor progression and prognosis in Chinese breast cancer patients. IUBMB life. 2007, 59 (7): 450-457. 10.1080/15216540701509955.View ArticlePubMedGoogle Scholar
  3. Tomera KM: NMP22 BladderChek Test: point-of-care technology with life-and money-saving potential. Expert Rev Mol Diagn. 2004, 4 (6): 783-794. 10.1586/14737159.4.6.783.View ArticlePubMedGoogle Scholar
  4. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ: Cancer statistics, 2008. CA Cancer J Clin. 2008, 58 (2): 71-96. 10.3322/CA.2007.0010.View ArticlePubMedGoogle Scholar
  5. Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P: Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol. 2007, 18 (3): 581-View ArticlePubMedGoogle Scholar
  6. Shakhssalim N, Hosseini SY, Basiri A, Eshrati B, Mazaheri M, Soleimanirahbar A: Prominent bladder cancer risk factors in Iran. Asian Pac J Cancer Prev. 2010, 11: 601-606.PubMedGoogle Scholar
  7. Ørntoft TF, Wolf H: Molecular alterations in bladder cancer. Urol Res. 1998, 26 (4): 223-233. 10.1007/s002400050050.View ArticlePubMedGoogle Scholar
  8. Brandau S, Böhle A: Bladder cancer. Eur Urol. 2001, 39 (5): 491-497. 10.1159/000052494.View ArticlePubMedGoogle Scholar
  9. Warburg O: On the origin of cancer cells. Science. 1956, 123 (3191): 309-314. 10.1126/science.123.3191.309.View ArticlePubMedGoogle Scholar
  10. Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, Mey A, Taschner PEM, Rubinstein WS, Myers EN: Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science. 2000, 287 (5454): 848-10.1126/science.287.5454.848.View ArticlePubMedGoogle Scholar
  11. Gambhir SS: Molecular imaging of cancer with positron emission tomography. Nat Rev Cancer. 2002, 2 (9): 683-693. 10.1038/nrc882.View ArticlePubMedGoogle Scholar
  12. Lima J, Teixeira-Gomes J, Soares P, Máximo V, Honavar M, Williams D, Sobrinho-Simões M: Germline succinate dehydrogenase subunit D mutation segregating with familial non-RET C cell hyperplasia. J Clin Endocrinol Metab. 2003, 88 (10): 4932-10.1210/jc.2002-030008.View ArticlePubMedGoogle Scholar
  13. Clayton DA, Doda JN, Friedberg EC: The absence of a pyrimidine dimer repair mechanism in mammalian mitochondria. Proc Natl Acad Sci. 1974, 71 (7): 2777-10.1073/pnas.71.7.2777.PubMed CentralView ArticlePubMedGoogle Scholar
  14. LeDoux SP, Wilson GL, Beecham EJ, Stevnsner T, Wassermann K, Bohr VA: Repair of mitochondrial DNA after various types of DNA damage in Chinese hamster ovary cells. Carcinogenesis. 1992, 13 (11): 1967-10.1093/carcin/13.11.1967.View ArticlePubMedGoogle Scholar
  15. Croteau DL, Bohr VA: Repair of oxidative damage to nuclear and mitochondrial DNA in mammalian cells. J Biol Chem. 1997, 272 (41): 25409-25412. 10.1074/jbc.272.41.25409.View ArticlePubMedGoogle Scholar
  16. Dai JG, Xiao YB, Min JX, Zhang GQ, Yao K, Zhou RJ: Mitochondrial DNA 4977 BP deletion mutations in lung carcinoma. Indian J Cancer. 2006, 43 (1): 20-10.4103/0019-509X.25771.View ArticlePubMedGoogle Scholar
  17. Ye C, Shu XO, Wen W, Pierce L, Courtney R, Gao YT, Zheng W, Cai Q: Quantitative analysis of mitochondrial DNA 4977-bp deletion in sporadic breast cancer and benign breast diseases. Breast Cancer Res Treat. 2008, 108 (3): 427-434. 10.1007/s10549-007-9613-9.View ArticlePubMedGoogle Scholar
  18. Futyma K, Putowski L, Cybulski M, Miotla P, Rechberger T, Semczuk A: The prevalence of mtDNA4977 deletion in primary human endometrial carcinomas and matched control samples. Oncol Rep. 2008, 20 (3): 683-688.PubMedGoogle Scholar
  19. Akouchekian M, Houshmand M, Hemati S, Ansaripour M, Shafa M: High rate of mutation in mitochondrial DNA displacement loop region in human colorectal cancer. Dis Colon Rectum. 2009, 52 (3): 526-10.1007/DCR.0b013e31819acb99.View ArticlePubMedGoogle Scholar
  20. WADA T, TANJI N, OZAWA A, WANG J, SHIMAMOTO K, SAKAYAMA K, YOKOYAMA M: Mitochondrial DNA mutations and 8-hydroxy-2′-deoxyguanosine Content in Japanese patients with urinary bladder and renal cancers. Anticancer Res. 2006, 26 (5A): 3403-PubMedGoogle Scholar
  21. Fliss MS, Usadel H, Caballero OL, Wu L, Buta MR, Eleff SM, Jen J, Sidransky D: Facile detection of mitochondrial DNA mutations in tumors and bodily fluids. Science. 2000, 287 (5460): 2017-10.1126/science.287.5460.2017.View ArticlePubMedGoogle Scholar
  22. Liu VWS, Wang Y, Yang HJ, Tsang PCK, Ng TY, Wong LC, Nagley P, Ngan H: Mitochondrial DNA variant 16189 T > C is associated with susceptibility to endometrial cancer. Hum Mutat. 2003, 22 (2): 173-174. 10.1002/humu.10244.View ArticlePubMedGoogle Scholar
  23. Poulton J, Luan JA, Macaulay V, Hennings S, Mitchell J, Wareham NJ: Type 2 diabetes is associated with a common mitochondrial variant: evidence from a population-based case–control study. Hum Mol Genet. 2002, 11 (13): 1581-1583. 10.1093/hmg/11.13.1581.View ArticlePubMedGoogle Scholar
  24. Chinnery P, Elliott H, Patel S, Lambert C, Keers S, Durham S, McCarthy M, Hitman G, Hattersley A, Walker M: Role of the mitochondrial DNA 16184–16193 poly-C tract in type 2 diabetes. Lancet. 2005, 366 (9497): 1650-1651. 10.1016/S0140-6736(05)67492-2.View ArticlePubMedGoogle Scholar
  25. Ashtiani ZO, Heidari M, Hasheminasab S-M, Ayati M, Rakhshani N: Mitochondrial D-Loop polymorphism and microsatellite instability in prostate cancer and benign hyperplasia patients. Asian Pac J Cancer Prev. 2012, 13: 3863-3868. 10.7314/APJCP.2012.13.8.3863.View ArticlePubMedGoogle Scholar
  26. Lesina M, Kurkowski MU, Ludes K, Rose-John S, Treiber M, Klöppel G, Yoshimura A, Reindl W, Sipos B, Akira S: Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell. 2011, 19 (4): 456-469. 10.1016/j.ccr.2011.03.009.View ArticlePubMedGoogle Scholar
  27. Czarnecka AM, Klemba A, Semczuk A, Plak K, Marzec B, Krawczyk T, Kofler B, Golik P, Bartnik E: Common mitochondrial polymorphisms as risk factor for endometrial cancer. Int Arch Med. 2009, 2 (1): 33-10.1186/1755-7682-2-33.PubMed CentralView ArticlePubMedGoogle Scholar
  28. Rahmani B, Azimi C, Omranipour R, Raoofian R, Zendehdel K, Saee-Rad S, Heidari M: Mutation screening in the mitochondrial D-loop region of tumoral and non-tumoral breast cancer in Iranian patients. Acta Med Iran. 2012, 50 (7): 447-453.PubMedGoogle Scholar
  29. Rosson D, Keshgegian AA: Frequent mutations in the mitochondrial control region DNA in breast tissue. Cancer Lett. 2004, 215 (1): 89-94. 10.1016/j.canlet.2004.04.030.View ArticlePubMedGoogle Scholar
  30. Seyedhassani SM, Houshmand M, Kalantar SM, Modabber G, Aflatoonian A: No mitochondrial DNA deletions but more D-loop point mutations in repeated pregnancy loss. J Assist Reprod Genet. 2010, 27 (11): 641-648. 10.1007/s10815-010-9435-2.PubMed CentralView ArticlePubMedGoogle Scholar
  31. Mueller EE, Schaier E, Brunner SM, Eder W, Mayr JA, Egger SF, Nischler C, Oberkofler H, Reitsamer HA, Patsch W: Mitochondrial haplogroups and control region polymorphisms in age-related macular degeneration: a case–control study. PLoS One. 2012, 7 (2): e30874-10.1371/journal.pone.0030874.PubMed CentralView ArticlePubMedGoogle Scholar
  32. Zhang J, Asin-Cayuela J, Fish J, Michikawa Y, Bonafé M, Olivieri F, Passarino G, De Benedictis G, Franceschi C, Attardi G: Strikingly higher frequency in centenarians and twins of mtDNA mutation causing remodeling of replication origin in leukocytes. Proc Natl Acad Sci. 2003, 100 (3): 1116-10.1073/pnas.242719399.PubMed CentralView ArticlePubMedGoogle Scholar
  33. Kamalidehghan B, Houshmand M, Panahi MSS, Abbaszadegan MR, Ismail P, Shiroudi MB: Tumoral Cell mtDNA 8.9 kb deletion is more common than other deletions in gastric cancer. Arch Med Res. 2006, 37 (7): 848-853. 10.1016/j.arcmed.2006.03.007.View ArticlePubMedGoogle Scholar
  34. Kamalidehghan B, Houshmand M, Ismail P, Panahi MSS, Akbari MHH: ΔmtDNA < sup > 4977</sup > is more common in non-tumoral cells from gastric cancer sample. Arch Med Res. 2006, 37 (6): 730-735. 10.1016/j.arcmed.2006.02.005.View ArticlePubMedGoogle Scholar
  35. Marchington D, Hartshorne G, Barlow D, Poulton J: Homopolymeric tract heteroplasmy in mtDNA from tissues and single oocytes: support for a genetic bottleneck. Am J Hum Genet. 1997, 60 (2): 408-PubMed CentralPubMedGoogle Scholar
  36. Sanchez-Cespedes M, Parrella P, Nomoto S, Cohen D, Xiao Y, Esteller M, Jeronimo C, Jordan RCK, Nicol T, Koch WM: Identification of a mononucleotide repeat as a major target for mitochondrial DNA alterations in human tumors. Cancer Res. 2001, 61 (19): 7015-PubMedGoogle Scholar
  37. Schwartz S, Alazzouzi H, Perucho M: Mutational dynamics in human tumors confirm the neutral intrinsic instability of the mitochondrial D‒loop poly‒cytidine repeat. Genes Chromosomes Cancer. 2006, 45 (8): 770-780. 10.1002/gcc.20340.View ArticlePubMedGoogle Scholar
  38. Dakubo GD: Mitochondrial Genetics and Cancer. 2010, Heidelberg Dordrecht London New York: Springer, 14-123.View ArticleGoogle Scholar
  39. Lievre A, Blons H, Houllier A, Laccourreye O, Brasnu D, Beaune P, Laurent-Puig P: Clinicopathological significance of mitochondrial D-Loop mutations in head and neck carcinoma. Br J Cancer. 2006, 94 (5): 692-697.PubMed CentralPubMedGoogle Scholar

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