Volume 25, Issue 5 (9-2021)                   IBJ 2021, 25(5): 323-333 | Back to browse issues page

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Alikhani M, Saberi S, Esmaily M, Michel V, Tashakoripour M, Abdirad A, et al . Mitochondrial DNA Copy Number Variations and Serum Pepsinogen Levels for Risk Assessment in Gastric Cancer. IBJ 2021; 25 (5) :323-333
URL: http://ibj.pasteur.ac.ir/article-1-3395-en.html
Mitochondrial DNA Copy Number Variations and Serum Pepsinogen Levels for Risk Assessment in Gastric Cancer
Mehdi Alikhani , Samaneh Saberi , Maryam Esmaily , Valérie Michel , Mohammad Tashakoripour , Afshin Abdirad , Arezoo Aghakhani , Sana Eybpoosh , Massoud Vosough , Mohammad Ali Mohagheghi , Mahmoud Eshagh Hosseini , Eliette Touati , Marjan Mohammadi
Abstract:  
Background: Variations in mitochondrial DNA copy number (mtDNA-CN) of peripheral blood leukocytes (PBLs), as a potential biomarker for gastric cancer (GC) screening has currently been subject to controversy. Herein, we have assessed its efficiency in GC screening, in parallel and in combination with serum pepsinogen (sPG) I/II ratio, as an established indicator of gastric atrophy. Methods: The study population included GC (n = 53) and non-GC (n = 207) dyspeptic patients. The non-GC group was histologically categorized into CG (n = 104) and NM (n = 103) subgroups. The MtDNA-CN of PBLs was measured by quantitative real-time PCR. The sPG I and II levels and anti-H. pylori serum IgG were measured by ELISA. Results: The mtDNA-CN was found significantly higher in GC vs. non-GC (OR = 3.0; 95% CI = 1.4, 6.4) subjects. Conversely, GC patients had significantly lower sPG I/II ratio than the non-GC (OR = 3.2; CI = 1.4, 7.2) subjects. The combination of these two biomarkers yielded a dramatic amplification of the odds of GC risk in double-positive (high mtDNA-CN-low sPGI/II) subjects, in reference to double-negatives (low mtDNA-CN-high sPGI/II), when assessed against non-GC (OR = 27.1; CI = 5.0, 147.3), CG (OR = 13.1; CI = 2.4, 72.6), or NM (OR = 49.5; CI = 7.9, 311.6) groups. Conclusion: The combination of these two biomarkers, namely mtDNA-CN in PBLs and serum PG I/II ratio, drastically enhanced the efficiency of GC risk assessment, which calls for further validations.
Keywords: Biomarkers, DNA copy number variation, Mitochondrial DNA, Stomach neoplasmsr
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Type of Study: Full Length/Original Article | Subject: Medical Biotechnology
References
1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. A cancer journal clinicians 2018; 68: 394-424. [DOI:10.3322/caac.21492]
2. Matsuoka T, Yashiro M. Biomarkers of gastric cancer: Current topics and future perspective. World journal of gastroenterology 2018; 24(26): 2818-2832. [DOI:10.3748/wjg.v24.i26.2818]
3. Hurtado-Roca Y, Ledesma M, Gonzalez-Lazaro M, Moreno-Loshuertos R, Fernandez-Silva P, Enriquez JA, Laclaustra M. Adjusting MtDNA quantification in whole blood for peripheral blood platelet and leukocyte counts. PLoS one 2016; 11(10): e0163770. [DOI:10.1371/journal.pone.0163770]
4. Javadov S, Kozlov AV, Camara AK. Mitochondria in health and disease. Cells 2020; 9(5): 1177. [DOI:10.3390/cells9051177]
5. Malik AN, Czajka A. Is mitochondrial DNA content a potential biomarker of mitochondrial dysfunction? Mitochondrion 2013; 13(5): 481-492. [DOI:10.1016/j.mito.2012.10.011]
6. Alikhani M, Touati E, Karimipoor M, Vosough M, Eybpoosh S, Mohammadi M. Dynamic changes of mitochondrial DNA copy number in gastrointestinal tract cancers: A systematic review and meta-analysis. Cancer investigation 2021; 39(2): 163-179. [DOI:10.1007/s12029-021-00707-w]
7. Căinap C, Nagy V, Gherman A, Cetean S, Laszlo I, Constantin AM, Căinap S. Classic tumor markers in gastric cancer. Current standards and limitations. Clujul medical 2015; 88(2): 111-115 [DOI:10.15386/cjmed-409]
8. Kim K, Shin DG, Park MK, Baik SH, Kim TH, Kim S, Lee SY. Circulating cell-free DNA as a promising biomarker in patients with gastric cancer: Diagnostic validity and significant reduction of cfDNA after surgical resection. Annals of surgical treatment and research 2014; 86(3): 136-142. [DOI:10.4174/astr.2014.86.3.136]
9. Ye DM, Xu G, Ma W, Li Y, Luo W, Xiao Y, Liu Y, Zhang Z. Significant function and research progress of biomarkers in gastric cancer. Oncology letters 2020; 19(1):17-29. [DOI:10.3892/ol.2019.11078]
10. Mansour-Ghanaei F, Joukar F, Baghaee M, Sepehrimanesh M, Hojati A. Only serum pepsinogen I and pepsinogen I/II ratio are specific and sensitive biomarkers for screening of gastric cancer. Biomolecular concepts 2019; 10(1): 82-90. [DOI:10.1515/bmc-2019-0010]
11. Cho EJ, Kim HK, Jeong TD, Ko DH, Bae SE, Lee JS, Lee W, Choe JW, Chun S, Jung HY, Min WK. Method evaluation of pepsinogen I/II assay based on chemiluminescent immunoassays and comparison with other test methods. Clinica chimica acta 2016; 452: 149-154. [DOI:10.1016/j.cca.2015.11.015]
12. Eybpoosh S, Talebkhan Y, Saberi S, Esmaeili M, Oghalaie A, Ebrahimzadeh F, Karimi T, Abdirad A, Nahvijou A, Mohagheghi MA, Hosseini ME, Mohammadi M. Age-specific gastric cancer risk indicated by the combination of helicobacter pylori sero-status and serum pepsinogen levels. Iranian biomedical journal 2015;19: 133-142.
13. Dixon MF, Genta RM, Yardley JH, Correa P. Classification and grading of Gastritis: The updated Sydney system. The american journal of surgical pathology 1996; 20(10): 1161-1181. [DOI:10.1097/00000478-199610000-00001]
14. Rugge M, De Boni M, Pennelli G, De Bona M, Giacomelli L, Fassan M, Basso D, Plebani M, Graham DY. Gastritis OLGA-staging and gastric cancer risk: A twelve-year clinico-pathological follow-up study. Alimentary pharmacology and therapeutic 2010; 31(10): 1104-1111. [DOI:10.1111/j.1365-2036.2010.04277.x]
15. Rugge M, Genta RM, Fassan M, Valentini E, Coati I, Guzzinati S, Savarino E, Zorzi M, Farinati F, Malfertheiner P. OLGA gastritis staging for the prediction of gastric cancer risk: A long-term follow-up study of 7436 patients. American journal of gastroenterology 2018; 113(11): 1621-1628. [DOI:10.1038/s41395-018-0353-8]
16. Sobin L H, Fleming I D. TNM classification of malignant tumors, fifth edition (1997). :union: Internationale Contre le Cancer and the American Joint Committee on Cancer. Cancer 1997; 80(9): 1803-1804. https://doi.org/10.1002/(SICI)1097-0142(19971101)80:9<1803::AID-CNCR16>3.0.CO;2-9 [DOI:10.1002/(SICI)1097-0142(19971101)80:93.0.CO;2-9]
17. Lauren P. The two histological main types of gastric carcinoma: Diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta pathologica et microbiologica scandinavica 1965; 64: 31-49. [DOI:10.1111/apm.1965.64.1.31]
18. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic acids research 1988; 16(3): 1215. [DOI:10.1093/nar/16.3.1215]
19. Fernandes J, Michel V, Camorlinga-Ponce M, Gomez A, Maldonado C, De Reuse H, Torres J, Touati E. Circulating mitochondrial DNA level, a noninvasive biomarker for the early detection of gastric cancer. Cancer epidemiology biomarkers and prevention 2014; 23(11): 2430-2438. [DOI:10.1158/1055-9965.EPI-14-0471]
20. Puza B, O'neill T. Generalised clopper-pearson confidence intervals for the binomial proportion. Journal of statictial computation and simulation 2006; 76(6): 489-508. [DOI:10.1080/10629360500107527]
21. Afrifa J, Zhao T, Yu J. Circulating mitochondria DNA, a noninvasive cancer diagnostic biomarker candidate. Mitochondrion 2019; 47: 238-243. [DOI:10.1016/j.mito.2018.12.003]
22. Lee HC, Wei YH. Mitochondrial biogenesis and mitochondrial DNA maintenance of mammalian cells under oxidative stress. International journal of biochemistry and cell biology 2005; 37(4): 822-834. [DOI:10.1016/j.biocel.2004.09.010]
23. Chatterjee A, Dasgupta S, Sidransky D. Mitochondrial subversion in cancer. Cancer prevention research 2011; 4(5): 638-6354. [DOI:10.1158/1940-6207.CAPR-10-0326]
24. Robinson JM. Reactive oxygen species in phagocytic leukocytes. Histochemistry and cell biology 2008; 130(2): 281-297. [DOI:10.1007/s00418-008-0461-4]
25. Bouchez C, Devin A. Mitochondrial biogenesis and mitochondrial reactive oxygen species (ROS): A complex relationship regulated by the cAMP/PKA signaling pathway. Cells 2019; 8(4): 287. [DOI:10.3390/cells8040287]
26. Weinberg SE, Sena LA, Chandel NS. Mitochondria in the regulation of innate and adaptive immunity. Immunity 2015; 42(3): 406-417. [DOI:10.1016/j.immuni.2015.02.002]
27. Banoth B, Cassel SL. Mitochondria in innate immune signaling. Translation research 2018; 202: 52-68. [DOI:10.1016/j.trsl.2018.07.014]
28. Nissanka N, Minczuk M, Moraes CT. Mechanisms of mitochondrial DNA deletion formation. Trends in genetics 2019; 35(3): 235-244. [DOI:10.1016/j.tig.2019.01.001]
29. Lee HC, Lu CY, Fahn HJ, Wei YH. Aging- and smoking-associated alteration in the relative content of mitochondrial DNA in human lung. Febs letters 1998; 441(2): 292-296. [DOI:10.1016/S0014-5793(98)01564-6]
30. Li Z, Zhu M, Du J, Ma H, Jin G, Dai J. Genetic variants in nuclear DNA along with environmental factors modify mitochondrial DNA copy number: A population-based exome-wide association study. BMC genomics 2018; 19(1): 752. [DOI:10.1186/s12864-018-5142-7]
31. Kumar B, Bhat ZI, Bansal S, Saini S, Naseem A, Wahabi K, Burman A, Kumar GT, Saluja SS, Rizvi MMA. Association of mitochondrial copy number variation and T16189C polymorphism with colorectal cancer in North Indian population. Tumor biology 2017; 39 (11): 1010428317740296. [DOI:10.1177/1010428317740296]
32. Qu F, Liu X, Zhou F, Yang H, Bao G, He X, Xing J. Association between mitochondrial DNA content in leukocytes and colorectal cancer risk. Cancer 2011; 117(14): 3148-3155. [DOI:10.1002/cncr.25906]
33. He Y, Gong Y, Gu J, Lee JJ, Lippman SM, Wu X. Increased leukocyte mitochondrial DNA copy number is associated with oral premalignant lesions: An epidemiology study. Carcinogenesis integrative cancer research 2014; 35(8): 1760-1764. [DOI:10.1093/carcin/bgu093]
34. Sun Y, Gu J, Ajani JA, Chang DW, Wu X, Stroehlein JR. Genetic and intermediate phenotypic susceptibility markers of gastric cancer in hispanic americans: A case-control study. Cancer 2014; 120(19): 3040-3048. [DOI:10.1002/cncr.28792]
35. Xu E, Sun W, Gu J, Chow WH, Ajani JA, Wu X. Association of mitochondrial DNA copy number in peripheral blood leukocytes with risk of esophageal adenocarcinoma. Carcinogenesis integrative cancer research 2013; 34(11): 2521-2524. [DOI:10.1093/carcin/bgt230]
36. Thyagarajan B, Guan W, Fedirko V, Barcelo H, Tu H, Gross M, Goodman M, Bostick RM. No association between mitochondrial DNA copy number and colorectal adenomas. Molecular carcinogenesis 2016; 55(8): 1290-1296. [DOI:10.1002/mc.22370]
37. Liao LM, Baccarelli A, Shu XO, Gao YT, Ji BT, Yang G, Li HL, Hoxha M, Dioni L, Rothman N, Zheng W, Chow WH. Mitochondrial DNA copy number and risk of gastric cancer: A report from the Shanghai women's health study. Cancer epidemiology biomarkers and prevention 2011; 20(9): 1944-1949. [DOI:10.1158/1055-9965.EPI-11-0379]
38. Jiang J, Zhao JH, Wang XL, Di J, Liu ZB, Li GY, Wang MZ, Li Y, Chen R, Ge RL. Analysis of mitochondrial DNA in Tibetan gastric cancer patients at high altitude. Molecular and clinical oncology 2015; 3(4): 875-879. [DOI:10.3892/mco.2015.539]
39. Huang B, Gao YT, Shu XO, Wen W, Yang G, Li G, Courtney R, Ji BT, Li HL, Purdue MP, Zheng W, Cai Q. Association of leukocyte mitochondrial DNA copy number with colorectal cancer risk: Results from the shanghai women's health study. Cancer epidemiology; biomarkers and prevention 2014; 23(11): 2357-2365. [DOI:10.1158/1055-9965.EPI-14-0297]
40. Yang K, Li X, Forman MR, Monahan PO, Graham BH, Joshi A, Song M, Hang D, Ogino S, Giovannucci EL, De Vivo I, Chan AT, Nan H. Pre-diagnostic leukocyte mitochondrial DNA copy number and colorectal cancer risk. Carcinogenesis integative cancer research 2019; 40(12): 1462-1468. [DOI:10.1093/carcin/bgz159]
41. Chatre L, Fernandes J, Michel V, Fiette L, Avé P, Arena G, Jain U, Haas R, Wang TC, Ricchetti M, Touati E. Helicobacter pylori targets mitochondrial import and components of mitochondrial DNA replication machinery through an alternative VacA-dependent and a VacA-independent mechanisms. Scientific reports 2017; 7(1): 15901. [DOI:10.1038/s41598-017-15567-3]
42. Guo W, Jiang L, Bhasin S, Khan SM, Swerdlow RH. DNA extraction procedures meaningfully influence qPCR-based mtDNA copy number determination. Mitochondrion 2009; 9(4): 261-265. [DOI:10.1016/j.mito.2009.03.003]
43. Tong Y, Wu Y, Song Z, Yu Y, Yu X. The potential value of serum pepsinogen for the diagnosis of atrophic gastritis among the health check-up populations in China: A diagnostic clinical research. BMC gastroenterology 2017; 17(1): 88. [DOI:10.1186/s12876-017-0641-6]
44. Huang YK, Yu JC, Kang WM, Ma ZQ, Ye X, Tian SB, Yan C. Significance of serum pepsinogens as a biomarker for gastric cancer and atrophic gastritis screening: A systematic review and meta-analysis. PLoS one 2015 ; 10(11): e0142080. [DOI:10.1371/journal.pone.0142080]
45. Kim N, Jung HC. The role of serum pepsinogen in the detection of gastric cancer. Gut and liver 2010; 4(3):307-319. [DOI:10.5009/gnl.2010.4.3.307]
46. Sasazuki S, Inoue M, Iwasaki M, Otani T, Yamamoto S, Ikeda S, Hanaoka T, Tsugane S. Effect of helicobacter pylori infection combined with CagAa and pepsinogen status on gastric cancer development among Japanese men and women: A nested case-control study. Cancer epidemiology, biomarkers and prevention 2006; 15(7): 1341-1347. [DOI:10.1158/1055-9965.EPI-05-0901]
47. Ohata H, Oka M, Yanaoka K, Shimizu Y, Mukoubayashi C, Mugitani K, Iwane M, Nakamura H, Tamai H, Arii K, Nakata H, Yoshimura N, Takeshita T, Miki K, Mohara O, Ichinose M. Gastric cancer screening of a high-risk population in Japan using serum pepsinogen and barium digital radiography. Cancer science 2005; 96(10): 713-720. [DOI:10.1111/j.1349-7006.2005.00098.x]
48. Zeng W, Zhang S, Yang L, Wei W, Gao J, Guo N, Wu F. Serum miR-101-3p combined with pepsinogen contributes to the early diagnosis of gastric cancer. BMC medical genetics 2020; 21(1): 28. [DOI:10.1186/s12881-020-0967-8]
49. Chung HW, Kim JW, Lee JH, Song SY, Chung JB, Kwon OH, Lim JB. Comparison of the validity of three biomarkers for gastric cancer screening: Carcinoembryonic antigen, pepsinogens, and high sensitive C-reactive protein. Journal of clinical gastroenterology 2009; 43(1): 19-26. [DOI:10.1097/MCG.0b013e318135427c]
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