Dysregulated expression of piRNAs serve as diagnostic markers in cancers: a systematic review and meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

MA Xingyuan ^1,2,3 , WANG Zhe ² , WANG Shuaiyang ^1,2,3 , TIAN Ye ^1,2,3 , LI Jing ¹ , XIE Bei ³ ,  MA Bin ² ,  LI Linjing ¹

1. Lanzhou University Second Hospital, Lanzhou 730000, P. R. China;
2. Evidence-Based Medicine Centre, Lanzhou University, Lanzhou 730000, P. R. China;
3. School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, P. R. China;

Corresponding author：

MA Bin, Email: kittymb2017@163.com; LI Linjing, Email: lilinj@lzu.edu.cn

Keywords：

PIWI-interacting RNA; Diagnosis; Meta-analysis; Cancer

DOI：

10.7507/1672-2531.202309004

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective PIWI-interacting RNA (piRNA) has emerged as a promising tool for cancer diagnosis. The aim of this meta-analysis was to summarize the existing literature and systematically assess the diagnostic performance of piRNAs in cancer, as well as identify potential sources of inter-study heterogeneity to provide information for clinical practice. Methods The PubMed, Web of Science, Embase, Cochrane library, CNKI, WanFang, VIP and CBM databases were electronically searched to collect diagnostic trials of piRNAs in cancer from inception to April 2023. The methodological quality of the included studies was assessed using the QUADAS-2 tool, and statistical analysis was conducted using Stata 17.0 software. Results A total of 17 papers (46 studies) involving 4 956 cancer patients and 3 759 controls were included. The range of sensitivity was 21%-100% and the range of specificity was 50%-100%. Meta-analysis showed that the combined sensitivity of piRNA for the diagnosis of cancer was 0.74 (95%CI 0.68 to 0.79), the specificity was 0.79 (95%CI 0.75 to 0.82), the PLR was 3.49 (95%CI 3.01 to 4.05), the NLR was 0.33 (95%CI 0.27 to 0.40), DOR of 11 (95%CI 8 to 14), and AUC of 0.83 (95%CI 0.80 to 0.86), indicating that piRNA had high accuracy for cancer diagnosis. Conclusion piRNA shows promise as a reliable biomarker for cancer diagnosis, with good sensitivity and specificity. However, the lack of standardization and result reproducibility remain significant challenges in the clinical application of piRNA-based diagnostics.

Citation： MA Xingyuan, WANG Zhe, WANG Shuaiyang, TIAN Ye, LI Jing, XIE Bei, MA Bin, LI Linjing. Dysregulated expression of piRNAs serve as diagnostic markers in cancers: a systematic review and meta-analysis. Chinese Journal of Evidence-Based Medicine, 2024, 24(2): 164-174. doi: 10.7507/1672-2531.202309004 Copy

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2.	Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
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4.	Mascalchi M, Belli G, Zappa M, et al. Risk-benefit analysis of X-ray exposure associated with lung cancer screening in the Italung-CT trial. Am J Roentgenol, 2006, 187(2): 421-429.
5.	Chen C, Chen Q, Zhao Q, et al. Value of combined detection of serum CEA, CA72-4, CA19-9, CA15-3 and CA12-5 in the diagnosis of gastric cancer. Ann Clin Lab Sci, 2017, 47(3): 260-263.
6.	Iwasaki YW, Siomi MC, Siomi H. PIWI-interacting RNA: its biogenesis and functions. Annu Rev Biochem, 2015, 84: 405-433.
7.	Cheng J, Guo JM, Xiao BX, et al. piRNA, the new non-coding RNA, is aberrantly expressed in human cancer cells. Clin Chim Acta, 2011, 412(17-18): 1621-1625.
8.	Martinez VD, Vucic EA, Thu KL, et al. Unique somatic and malignant expression patterns implicate PIWI-interacting RNAs in cancer-type specific biology. Sci Rep, 2015, 5: 10423.
9.	Guo B, Li D, Du L, et al. piRNAs: biogenesis and their potential roles in cancer. Cancer Metastasis Rev, 2020, 39(2): 567-575.
10.	Weng W, Liu N, Toiyama Y, et al. Novel evidence for a PIWI-interacting RNA (piRNA) as an oncogenic mediator of disease progression, and a potential prognostic biomarker in colorectal cancer. Mol Cancer, 2018, 17(1): 16.
11.	Huang G, Hu H, Xue X, et al. Altered expression of piRNAs and their relation with clinicopathologic features of breast cancer. Clin Transl Oncol, 2013, 15(7): 563-568.
12.	Yang X, Cheng Y, Lu Q, et al. Detection of stably expressed piRNAs in human blood. Int J Clin Exp Med, 2015, 8(8): 13353-13358.
13.	Ng KW, Anderson C, Marshall EA, et al. Piwi-interacting RNAs in cancer: emerging functions and clinical utility. Mol Cancer, 2016, 15: 5.
14.	Iliev R, Stanik M, Fedorko M, et al. Decreased expression levels of PIWIL1, PIWIL2, and PIWIL4 are associated with worse survival in renal cell carcinoma patients. Onco Targets Ther, 2016, 9: 217-222.
15.	Su JF, Zhao F, Gao ZW, et al. piR-823 demonstrates tumor oncogenic activity in esophageal squamous cell carcinoma through DNA methylation induction via DNA methyltransferase 3B. Pathol Res Pract, 2020, 216(4): 152848.
16.	McGrath TA, Alabousi M, Skidmore B, et al. Recommendations for reporting of systematic reviews and meta-analyses of diagnostic test accuracy: a systematic review. Syst Rev, 2017, 6(1): 194.
17.	Cochrane library. Cochrane handbook for systematic reviews of diagnostic test accuracy version 1.0.
18.	Whiting PF, Rutjes AW, Westwood ME, et al. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med, 2011, 155(8): 529-536.
19.	Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ, 2003, 327(7414): 557-560.
20.	Thompson SG, Higgins JP. How should meta-regression analyses be undertaken and interpreted. Stat Med, 2002, 21(11): 1559-1573.
21.	Deeks JJ, Macaskill P, Irwig L. The performance of tests of publication bias and other sample size effects in systematic reviews of diagnostic test accuracy was assessed. J Clin Epidemiol, 2005, 58(9): 882-893.
22.	Bartos M, Siegl F, Kopkova A, et al. Small RNA sequencing identifies PIWI-interacting RNAs deregulated in glioblastoma-piR-9491 and piR-12488 reduce tumor cell colonies in vitro. Front Oncol, 2021, 11: 707017.
23.	Busch J, Ralla B, Jung M, et al. Piwi-interacting RNAs as novel prognostic markers in clear cell renal cell carcinomas. J Exp Clin Cancer Res, 2015, 34(1): 61.
24.	Chang Z, Ji G, Huang R, et al. PIWI-interacting RNAs piR-13643 and piR-21238 are promising diagnostic biomarkers of papillary thyroid carcinoma. Aging (Albany NY), 2020, 12(10): 9292-9310.
25.	Ge L, Zhang N, Li D, et al. Circulating exosomal small RNAs are promising non-invasive diagnostic biomarkers for gastric cancer. J Cell Mol Med, 2020, 24(24): 14502-14513.
26.	Lyer DN, Wan TM, Man JH, et al. Small RNA profiling of piRNAs in colorectal cancer identifies consistent overexpression of piR-24000 that correlates clinically with an aggressive disease phenotype. Cancers (Basel), 2020, 12(1): 188.
27.	Li J, Wang N, Zhang F, et al. PIWI-interacting RNAs are aberrantly expressed and may serve as novel biomarkers for diagnosis of lung adenocarcinoma. Thorac Cancer, 2021, 12(18): 2468-2477.
28.	Li Y, Dong Y, Zhao S, et al. Serum-derived piR-hsa-164586 of extracellular vesicles as a novel biomarker for early diagnosis of non-small cell lung cancer. Front Oncol, 2022, 12: 850363.
29.	Mai D, Zheng Y, Guo H, et al. Serum piRNA-54265 is a new biomarker for early detection and clinical surveillance of human colorectal cancer. Theranostics, 2020, 10(19): 8468-8478.
30.	Peng Q, Chiu PK, Wong CY, et al. Identification of piRNA Targets in urinary extracellular vesicles for the diagnosis of prostate cancer. Diagnostics (Basel), 2021, 11(10): 1828.
31.	Qu A, Wang W, Yang Y, et al. A serum piRNA signature as promising non-invasive diagnostic and prognostic biomarkers for colorectal cancer. Cancer Manag Res, 2019, 11: 3703-3720.
32.	Sabbah NA, Abdalla WM, Mawla WA, et al. piRNA-823 is a unique potential diagnostic non-invasive biomarker in colorectal cancer patients. Genes (Basel), 2021, 12(4): 598.
33.	Vychytilova-Faltejskova P, Stitkovcova K, Radova L, et al. Circulating PIWI-interacting RNAs piR-5937 and piR-28876 are promising diagnostic biomarkers of colon cancer. Cancer Epidemiol Biomarkers Prev, 2018, 27(9): 1019-1028.
34.	Wang Z, Yang H, Ma D, et al. Serum PIWI-interacting RNAs piR-020619 and piR-020450 are promising novel biomarkers for early detection of colorectal cancer. Cancer Epidemiol Biomarkers Prev, 2020, 29(5): 990-998.
35.	Zhao C, Tolkach Y, Schmidt D, et al. Mitochondrial PIWI-interacting RNAs are novel biomarkers for clear cell renal cell carcinoma. World J Urol, 2019, 37(8): 1639-1647.
36.	Zhou X, Liu J, Meng A, et al. Gastric juice piR-1245: a promising prognostic biomarker for gastric cancer. J Clin Lab Anal, 2020, 34(4): e23131.
37.	Sterne JA, Gavaghan D, Egger M. Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol, 2000, 53(11): 1119-1129.
38.	Deeks JJ, Altman DG. Diagnostic tests 4: likelihood ratios. BMJ, 2004, 329(7458): 168-169.
39.	Liu Y, Dou M, Song X, et al. The emerging role of the piRNA/piwi complex in cancer. Mol Cancer, 2019, 18(1): 123.
40.	Glas AS, Lijmer JG, Prins MH, et al. The diagnostic odds ratio: a single indicator of test performance. J Clin Epidemiol, 2003, 56(11): 1129-1135.
41.	Cochrane library. Systematic reviews of evaluations of diagnostic and screening tests.
42.	Yao J, Wang YW, Fang BB, et al. piR-651 and its function in 95-D lung cancer cells. Biomed Rep, 2016, 4(5): 546-550.
43.	Law PT, Qin H, Ching AK, et al. Deep sequencing of small RNA transcriptome reveals novel non-coding RNAs in hepatocellular carcinoma. J Hepatol, 2013, 58(6): 1165-1173.
44.	Zamora J, Abraira V, Muriel A, et al. Meta-DiSc: a software for meta-analysis of test accuracy data. BMC Med Res Methodol, 2006, 6: 31.
45.	Guest PC, Rahmoune H. Blood bio-sampling procedures for multiplex biomarkers studies. Methods Mol Biol, 2017, 1546: 161-168.
46.	Chen S, Ben S, Xin J, et al. The biogenesis and biological function of PIWI-interacting RNA in cancer. J Hematol Oncol, 2021, 14(1): 93.

1. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2021. CA Cancer J Clin, 2021, 71(1): 7-33.
2. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
3. Ott JJ, Ullrich A, Miller AB. The importance of early symptom recognition in the context of early detection and cancer survival. Eur J Cancer, 2009, 45(16): 2743-2748.
4. Mascalchi M, Belli G, Zappa M, et al. Risk-benefit analysis of X-ray exposure associated with lung cancer screening in the Italung-CT trial. Am J Roentgenol, 2006, 187(2): 421-429.
5. Chen C, Chen Q, Zhao Q, et al. Value of combined detection of serum CEA, CA72-4, CA19-9, CA15-3 and CA12-5 in the diagnosis of gastric cancer. Ann Clin Lab Sci, 2017, 47(3): 260-263.
6. Iwasaki YW, Siomi MC, Siomi H. PIWI-interacting RNA: its biogenesis and functions. Annu Rev Biochem, 2015, 84: 405-433.
7. Cheng J, Guo JM, Xiao BX, et al. piRNA, the new non-coding RNA, is aberrantly expressed in human cancer cells. Clin Chim Acta, 2011, 412(17-18): 1621-1625.
8. Martinez VD, Vucic EA, Thu KL, et al. Unique somatic and malignant expression patterns implicate PIWI-interacting RNAs in cancer-type specific biology. Sci Rep, 2015, 5: 10423.
9. Guo B, Li D, Du L, et al. piRNAs: biogenesis and their potential roles in cancer. Cancer Metastasis Rev, 2020, 39(2): 567-575.
10. Weng W, Liu N, Toiyama Y, et al. Novel evidence for a PIWI-interacting RNA (piRNA) as an oncogenic mediator of disease progression, and a potential prognostic biomarker in colorectal cancer. Mol Cancer, 2018, 17(1): 16.
11. Huang G, Hu H, Xue X, et al. Altered expression of piRNAs and their relation with clinicopathologic features of breast cancer. Clin Transl Oncol, 2013, 15(7): 563-568.
12. Yang X, Cheng Y, Lu Q, et al. Detection of stably expressed piRNAs in human blood. Int J Clin Exp Med, 2015, 8(8): 13353-13358.
13. Ng KW, Anderson C, Marshall EA, et al. Piwi-interacting RNAs in cancer: emerging functions and clinical utility. Mol Cancer, 2016, 15: 5.
14. Iliev R, Stanik M, Fedorko M, et al. Decreased expression levels of PIWIL1, PIWIL2, and PIWIL4 are associated with worse survival in renal cell carcinoma patients. Onco Targets Ther, 2016, 9: 217-222.
15. Su JF, Zhao F, Gao ZW, et al. piR-823 demonstrates tumor oncogenic activity in esophageal squamous cell carcinoma through DNA methylation induction via DNA methyltransferase 3B. Pathol Res Pract, 2020, 216(4): 152848.
16. McGrath TA, Alabousi M, Skidmore B, et al. Recommendations for reporting of systematic reviews and meta-analyses of diagnostic test accuracy: a systematic review. Syst Rev, 2017, 6(1): 194.
17. Cochrane library. Cochrane handbook for systematic reviews of diagnostic test accuracy version 1.0.
18. Whiting PF, Rutjes AW, Westwood ME, et al. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med, 2011, 155(8): 529-536.
19. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ, 2003, 327(7414): 557-560.
20. Thompson SG, Higgins JP. How should meta-regression analyses be undertaken and interpreted. Stat Med, 2002, 21(11): 1559-1573.
21. Deeks JJ, Macaskill P, Irwig L. The performance of tests of publication bias and other sample size effects in systematic reviews of diagnostic test accuracy was assessed. J Clin Epidemiol, 2005, 58(9): 882-893.
22. Bartos M, Siegl F, Kopkova A, et al. Small RNA sequencing identifies PIWI-interacting RNAs deregulated in glioblastoma-piR-9491 and piR-12488 reduce tumor cell colonies in vitro. Front Oncol, 2021, 11: 707017.
23. Busch J, Ralla B, Jung M, et al. Piwi-interacting RNAs as novel prognostic markers in clear cell renal cell carcinomas. J Exp Clin Cancer Res, 2015, 34(1): 61.
24. Chang Z, Ji G, Huang R, et al. PIWI-interacting RNAs piR-13643 and piR-21238 are promising diagnostic biomarkers of papillary thyroid carcinoma. Aging (Albany NY), 2020, 12(10): 9292-9310.
25. Ge L, Zhang N, Li D, et al. Circulating exosomal small RNAs are promising non-invasive diagnostic biomarkers for gastric cancer. J Cell Mol Med, 2020, 24(24): 14502-14513.
26. Lyer DN, Wan TM, Man JH, et al. Small RNA profiling of piRNAs in colorectal cancer identifies consistent overexpression of piR-24000 that correlates clinically with an aggressive disease phenotype. Cancers (Basel), 2020, 12(1): 188.
27. Li J, Wang N, Zhang F, et al. PIWI-interacting RNAs are aberrantly expressed and may serve as novel biomarkers for diagnosis of lung adenocarcinoma. Thorac Cancer, 2021, 12(18): 2468-2477.
28. Li Y, Dong Y, Zhao S, et al. Serum-derived piR-hsa-164586 of extracellular vesicles as a novel biomarker for early diagnosis of non-small cell lung cancer. Front Oncol, 2022, 12: 850363.
29. Mai D, Zheng Y, Guo H, et al. Serum piRNA-54265 is a new biomarker for early detection and clinical surveillance of human colorectal cancer. Theranostics, 2020, 10(19): 8468-8478.
30. Peng Q, Chiu PK, Wong CY, et al. Identification of piRNA Targets in urinary extracellular vesicles for the diagnosis of prostate cancer. Diagnostics (Basel), 2021, 11(10): 1828.
31. Qu A, Wang W, Yang Y, et al. A serum piRNA signature as promising non-invasive diagnostic and prognostic biomarkers for colorectal cancer. Cancer Manag Res, 2019, 11: 3703-3720.
32. Sabbah NA, Abdalla WM, Mawla WA, et al. piRNA-823 is a unique potential diagnostic non-invasive biomarker in colorectal cancer patients. Genes (Basel), 2021, 12(4): 598.
33. Vychytilova-Faltejskova P, Stitkovcova K, Radova L, et al. Circulating PIWI-interacting RNAs piR-5937 and piR-28876 are promising diagnostic biomarkers of colon cancer. Cancer Epidemiol Biomarkers Prev, 2018, 27(9): 1019-1028.
34. Wang Z, Yang H, Ma D, et al. Serum PIWI-interacting RNAs piR-020619 and piR-020450 are promising novel biomarkers for early detection of colorectal cancer. Cancer Epidemiol Biomarkers Prev, 2020, 29(5): 990-998.
35. Zhao C, Tolkach Y, Schmidt D, et al. Mitochondrial PIWI-interacting RNAs are novel biomarkers for clear cell renal cell carcinoma. World J Urol, 2019, 37(8): 1639-1647.
36. Zhou X, Liu J, Meng A, et al. Gastric juice piR-1245: a promising prognostic biomarker for gastric cancer. J Clin Lab Anal, 2020, 34(4): e23131.
37. Sterne JA, Gavaghan D, Egger M. Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol, 2000, 53(11): 1119-1129.
38. Deeks JJ, Altman DG. Diagnostic tests 4: likelihood ratios. BMJ, 2004, 329(7458): 168-169.
39. Liu Y, Dou M, Song X, et al. The emerging role of the piRNA/piwi complex in cancer. Mol Cancer, 2019, 18(1): 123.
40. Glas AS, Lijmer JG, Prins MH, et al. The diagnostic odds ratio: a single indicator of test performance. J Clin Epidemiol, 2003, 56(11): 1129-1135.
41. Cochrane library. Systematic reviews of evaluations of diagnostic and screening tests.
42. Yao J, Wang YW, Fang BB, et al. piR-651 and its function in 95-D lung cancer cells. Biomed Rep, 2016, 4(5): 546-550.
43. Law PT, Qin H, Ching AK, et al. Deep sequencing of small RNA transcriptome reveals novel non-coding RNAs in hepatocellular carcinoma. J Hepatol, 2013, 58(6): 1165-1173.
44. Zamora J, Abraira V, Muriel A, et al. Meta-DiSc: a software for meta-analysis of test accuracy data. BMC Med Res Methodol, 2006, 6: 31.
45. Guest PC, Rahmoune H. Blood bio-sampling procedures for multiplex biomarkers studies. Methods Mol Biol, 2017, 1546: 161-168.
46. Chen S, Ben S, Xin J, et al. The biogenesis and biological function of PIWI-interacting RNA in cancer. J Hematol Oncol, 2021, 14(1): 93.

Chinese Journal of Evidence-Based Medicine

Dysregulated expression of piRNAs serve as diagnostic markers in cancers: a systematic review and meta-analysis

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