Search for New Participants in the Pathogenesis of High-Grade Serous Ovarian Cancer with the Potential to Be Used as Diagnostic Molecules
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients
2.2. RNA Isolation from Peripheral Blood Plasma
2.3. RNA Isolation from Fimbriae and Ovary Tumor Tissues
2.4. miRNA Deep Sequencing
2.5. Reverse Transcription and Quantitative Real-Time PCR
2.6. Immunohistochemistry
2.7. Statistical Analysis of the Obtained Data
3. Results
3.1. miRNA Signatures of the BSC, SBT and HGSOC According to NGS Data
3.2. Validation of NGS Data by Quantitative RT-PCR
3.3. Evaluation of the Diagnostic Potential of miR-16-5p, miR-17-5p, miR-20a-5p, miR-93-5p and miR-30d-5p, Circulating in the Peripheral Blood Plasma of Patients with HGSOC
3.4. Evaluation of the Prognostic Potential of miR-16-5p, miR-17-5p, miR-20a-5p and miR-93-5p, Circulating in the Peripheral Blood Plasma of Patients with HGSOC
3.5. Functional Significance of miR-16-5p, miR-17-5p, miR-20a-5p and miR-93-5p in Determination of Different HGSOC Subtypes
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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miRNA | miRNA Accession Number (miRBase), available online: http://www.mirbase.org/ (accessed on 15 August 2022) | Nucleotide Sequence of Sense Primer for PCR, 5’-3’ | PCR Primer Annealing Temperature, °C |
---|---|---|---|
hsa-miR-16-5p | MIMAT0000069 | TAGCAGCACGTAAATATTGGCG | 62 |
hsa-miR-17-5p | MIMAT0000070 | CAAAGTGCTTACAGTGCAGGTAG | 55 |
hsa-miR-20a-5p | MIMAT0000075 | TAAAGTGCTTATAGTGCAGGTAG | 52 |
hsa-miR-93-5p | MIMAT0000093 | CAAAGTGCTGTTCGTGCAGGTAG | 55 |
hsa-miR-425-5p | MIMAT0003393 | AATGACACGATCACTCCCGTTGA | 60 |
hsa-miR-101-3p | MIMAT0000099 | TACAGTACTGTGATAACTGAA | 55 |
hsa-miR-140-3p | MIMAT0004597 | TACCACAGGGTAGAACCACGG | 55 |
hsa-miR-30d-5p | MIMAT0000245 | TGTAAACATCCCCGACTGGAAG | 55 |
Sample ID | Sample Description | Location in Lower Pelvis | Patient ID | Age | Menstrual Cycle Day | Duration of Menopause, Years | Diagnosis | FIGO [38] | pTNM [39] | NGS | PCR |
---|---|---|---|---|---|---|---|---|---|---|---|
s26 | Normal fimbriae | left side | P1 | 27 | 20 | 0 | Endometriosis of the sacro-uterine ligament. Mature cystic teratoma of the left ovary | - | - | Yes | Yes |
s27 | Normal fimbriae | right side | - | - | No | Yes | |||||
s25 | Normal fimbriae | right side | P2 | 30 | 13 | 0 | Serous cystadenoma of the left ovary, bicornuate uterus with non-functioning closed horn | - | - | Yes | Yes |
s11 | Normal fimbriae | right side | P3 | 71 | 0 | 21 | Right ovarian benign serous cystadenoma | - | - | No | Yes |
s12 | BSC | right side | - | - | No | Yes | |||||
s28 | Normal fimbriae | left side | P4 | 64 | 0 | 12 | Right ovarian benign serous cystadenoma | - | - | No | Yes |
s29 | Normal fimbriae | right side | - | - | No | Yes | |||||
s30 | BSC | right side | - | - | Yes | Yes | |||||
s5 | Normal fimbriae | left side | P5 | 77 | 0 | 22 | Benign serous cystadenomas of both ovaries | - | - | No | Yes |
s7 | Normal fimbriae | right side | - | - | No | Yes | |||||
s6 | BSC | left side | - | - | Yes | Yes | |||||
s8 | BSC | right side | - | - | Yes | Yes | |||||
s15 | Normal fimbriae | right side | P6 | 45 | 28 | 0 | Right ovarian benign serous cystadenoma | - | - | Yes | Yes |
s16 | BSC | right side | - | - | No | Yes | |||||
s4 | BSC | right side | P7 | 69 | 0 | 19 | Benign serous cystadenomas of both ovaries | - | - | No | Yes |
s2 | SBT | right side | P8 | 51 | 0 | 2 | Borderline serous papillary cystadenoma of the right ovary. Multiple myoma of the uterine corpus. Adenomyosis. | Ic1 | pT1c1N0M0 | Yes | Yes |
s10 | SBT | left side | P9 | 29 | 12 | 0 | Borderline serous papillary cystadenoma of the left ovary. | Ia | pT1aCN0M0 | Yes | Yes |
s24 | SBT | right side | P10 | 27 | 7 | 0 | Borderline serous papillary cystadenoma of the right ovary. | IIa | pT2aCN0M0 | Yes | Yes |
s18 | HGSOC | right side | P11 | 45 | 0 | 1 | High-grade serous carcinoma of the right ovary. | IIa | pT2aCN0M0 | Yes | Yes |
s21 | HGSOC | right side | P12 | 58 | 0 | 10 | High-grade serous carcinoma of the right ovary. Ascites. Adhesive process in the abdominal cavity. | IIIa2 | pT3aCN0M0 | Yes | Yes |
s14 | HGSOC | left side | P13 | 44 | 22 | 0 | High-grade serous carcinomas of both ovaries. Small-size uterine myomas. | IIIa2 | pT3aCN0M0 | No | Yes |
s22 | HGSOC | right side | P14 | 53 | 0 | 3 | High-grade serous carcinoma of the right ovary. Ascites. | IIIa2 | pT3aCN0M0 | No | Yes |
s33 | HGSOC | left side | P15 | 24 | 0 | 28 | High-grade serous carcinomas of both ovaries. Metastases in the inguinal lymph nodes. Adhesive process in the abdominal cavity. Endometrial polyp. | IVB | pT3aN0M1 | No | Yes |
s34 | HGSOC | right side | Yes | Yes |
miRNA | log2 (Fold Change in Expression Level) | lfcSE | p-Value * | s6 | s8 | s30 | s2 | s24 | s10 | s18 | s21 | s34 |
---|---|---|---|---|---|---|---|---|---|---|---|---|
BSC | SBT | HGSOC | ||||||||||
hsa-miR-17-5p | 3.2 | 0.5 | 3.4 × 10−11 | 70.0 | 56.9 | 48.6 | 62.1 | 61.1 | 90.4 | 703.3 | 294.1 | 675.4 |
hsa-miR-425-5p | 2.8 | 0.5 | 8.9 × 10−9 | 56.6 | 48.4 | 75.5 | 97.6 | 53.7 | 119.5 | 548.0 | 357.7 | 316.9 |
hsa-miR-20a-5p | 2.8 | 0.5 | 3.4 × 10−8 | 75.8 | 75.1 | 73.8 | 52.8 | 44.4 | 65.5 | 693.2 | 237.4 | 607.9 |
hsa-miR-93-5p | 2.7 | 0.5 | 1.8 × 10−7 | 386.9 | 207.7 | 131.6 | 366.0 | 218.3 | 342.7 | 1487.4 | 1260.6 | 2003.0 |
hsa-miR-101-3p | −2.5 | 0.5 | 2.2 × 10−7 | 989.6 | 2245.5 | 2097.1 | 724.5 | 1243.3 | 983.9 | 353.5 | 238.5 | 353.3 |
hsa-miR-30d-5p | 1.4 | 0.4 | 1.5 × 10−4 | 14401.1 | 15283.7 | 11120.3 | 14318.1 | 15006.9 | 12790.1 | 38252.0 | 26761.8 | 46379.9 |
hsa-miR-140-3p | −1.9 | 0.5 | 4.1 × 10−4 | 1836.6 | 2932.8 | 5613.0 | 2193.9 | 2908.5 | 3463.5 | 717.2 | 1319.7 | 709.2 |
hsa-miR-16-5p | 1.9 | 0.7 | 6.9 × 10−3 | 36.0 | 50.3 | 127.5 | 60.9 | 35.2 | 111.6 | 116.2 | 249.9 | 423.5 |
miRNA | Group | Normal Fimbriae | BSC | SBT |
---|---|---|---|---|
miR-16-5p | BSC | 0.2238 | 1 | 0.7143 |
miR-16-5p | SBT | 0.7273 | 0.7143 | 1 |
miR-16-5p | HGSOC | 0.0048 | 0.0087 | 0.0476 |
miR-425-5p | BSC | 0.3277 | 1 | 0.5476 |
miR-425-5p | SBT | 1 | 0.5476 | 1 |
miR-425-5p | HGSOC | 0.0663 | 0.0152 | 0.1667 |
miR-17-5p | BSC | 0.2721 | 1 | 1 |
miR-17-5p | SBT | 0.1455 | 1 | 1 |
miR-17-5p | HGSOC | 0.0004 | 0.0022 | 0.0238 |
miR-20a-5p | BSC | 0.3884 | 1 | 0.5476 |
miR-20a-5p | SBT | 0.7273 | 0.5476 | 1 |
miR-20a-5p | HGSOC | 0.0008 | 0.0022 | 0.0238 |
miR-93-5p | BSC | 0.7756 | 1 | 0.0476 |
miR-93-5p | SBT | 0.0182 | 0.0476 | 1 |
miR-93-5p | HGSOC | 0.0004 | 0.0022 | 0.0238 |
miR-30d-5p | BSC | 0.4559 | 1 | 0.9048 |
miR-30d-5p | SBT | 0.8636 | 0.9048 | 1 |
miR-30d-5p | HGSOC | 0.0016 | 0.0087 | 0.0238 |
miR-140-3p | BSC | 0.4559 | 1 | 0.3810 |
miR-140-3p | SBT | 0.4818 | 0.3810 | 1 |
miR-140-3p | HGSOC | 0.0663 | 0.0931 | 0.5476 |
miR-101-3p | BSC | 0.8639 | 1 | 0.2619 |
miR-101-3p | SBT | 0.2091 | 0.2619 | 1 |
miR-101-3p | HGSOC | 0.1447 | 0.2403 | 0.7143 |
Sample ID | Age, Years | FIGO | CA 125 Level before Treatment, U/mL | Risk of Malignancy Index (RMI) | Neoadjuvant Chemotherapy | Tumor Length, cm * | Tumor Width, cm * | Tumor Height, cm * | Ascites, mL | Extent of Blood Loss, mL | Surgery Time, min | 0—Complete Cytoreduction (Size of Residual Tumor Foci Less than 2.5 mm), 1—Suboptimal Cytoreduction (Size of Residual Tumor Foci 2.5 mm–2.5 cm) | Progesterone Receptor Expression in Tumor, Allred Score ** | Cluster Number in Figure 4 | RECIST 1.1 MRI/CT Criteria: 1—Complete Response, 2—Partial Response, 3—Stable Disease, 4—Progressive Disease |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1008 | 38 | IVB | 1244 | 10,359 | No | 7 | 10.5 | 11 | 2000 | 700 | 480 | 1 | 0 | 1 | 3 |
766 | 54 | IIB | 29 | 261 | No | 4 | 3 | 3 | 20 | 150 | 140 | 0 | 0 | 1 | 1 |
690 | 48 | IVB | 1340 | 12,060 | No | 5.5 | 3.5 | 4 | 50 | 700 | 206 | 0 | 0 | 1 | 3 |
679 | 51 | IIIC | 2000 | 18,000 | No | 9.5 | 6 | 8 | 1000 | 750 | 235 | 0 | 0 | 1 | 3 |
649 | 54 | IIIC | 200 | 1800 | Yes | 5 | 6 | 7 | 3000 | 650 | 285 | 1 | 0 | 1 | 4 |
15 | 57 | IIC | 198 | 1782 | No | 18 | 14 | 10 | 1000 | 400 | 190 | 1 | 0 | 1 | 4 |
19 | 63 | IIIC | 41 | 1206 | No | 6 | 2.4 | 4.6 | 200 | 400 | 265 | 1 | 0 | 1 | 1 |
782 | 45 | IIB | 517 | 1551 | No | 16 | 16 | 11.7 | 50 | 500 | 215 | 0 | 2 | 1 | 3 |
10 | 44 | IIIB | 129 | 387 | No | 6 | 7 | 6 | 700 | 500 | 175 | 1 | 5 | 1 | 1 |
13 | 71 | IIIB | 517 | 1551 | yes | 13 | 10 | 8 | 10 | 250 | 165 | 1 | 0 | 1 | 4 |
12 | 45 | IIA | 60 | 180 | No | 4 | 3 | 2 | 10 | 100 | 80 | 0 | 0 | 1 | 3 |
16 | 44 | IIIC | 92 | 277 | No | 5 | 4 | 4 | 10 | 300 | 185 | 1 | 0 | 1 | 3 |
17 | 47 | IA | 60 | 60 | No | 8.3 | 7.1 | 6.6 | 10 | 150 | 151 | 1 | 0 | 1 | 3 |
1060 | 77 | IIIC | 1203 | 10,827 | No | 10 | 9 | 8 | 1200 | 650 | 365 | 0 | 4 | 2 | 1 |
939 | 33 | IIIC | 59 | 270 | No | 13 | 12 | 10 | 2000 | 800 | 205 | 1 | 6 | 2 | 1 |
672 | 41 | IIIC | 1088 | 3264 | No | 9 | 7.5 | 10 | 1500 | 800 | 275 | 0 | 3 | 2 | 1 |
684 | 42 | IIIC | 1293 | 3879 | No | 14 | 8 | 6 | 1500 | 500 | 280 | 0 | 3 | 2 | 1 |
448 | 51 | IVB | 3808 | 11,424 | No | 15 | 17 | 18 | 10 | 3000 | 360 | 0 | 0 | 2 | 1 |
1061 | 49 | IIIC | 1756 | 5540 | No | 29.9 | 15 | 18.8 | 9000 | 3000 | 590 | 1 | 0 | 2 | 1 |
11 | 48 | IC | 189 | 567 | No | 18 | 10 | 8 | 10 | 300 | 375 | 0 | 6 | 2 | 4 |
miR-16-5p * | miR-17-5p * | miR-20a-5p * | miR-93-5p * | |
---|---|---|---|---|
Control 1 | 3.96 (−4.06; −3.64) | −3.07 (1.31; 4.08) | −2.76 (0.79; 3.83) | −2.57 (1.88; 3.07) |
Control 2 | 0.59 (−1.5; −0.2) | −3.81 (2.96; 4.94) | −3.34 (2.35; 4.94) | −4.41 (2.87; 5.45) |
HGSOC, cluster 1 | 5.06 (−5.51; −3.91) | −0.21 (−0.37; 1.35) | −0.22 (−0.47; 1.05) | −1.01 (0.19; 2.46) |
HGSOC, cluster 2 | 3.03 (−3.9; −2.33) | −3.69 (3.44; 4.47) | −3.75 (3.59; 4.47) | −3.94 (3.63; 4.53) |
LGSOC | 2.45 (−3.21; −2.06) | −4.32 (3.54; 4.86) | −3.88 (2.25; 4.42) | −4.17 (3.54; 4.63) |
SBT | 2.4 (−3.23; −1.89) | −2.24 (1.33; 3.96) | −2.31 (0.97; 4.39) | −2.95 (1.95; 4.83) |
BSC | 2.22 (−3.45; −1.39) | −2.79 (1.06; 4.69) | −1.89 (0.91; 3.42) | −2.87 (1.2; 4.54) |
Ovarian endometrioma | 3.22 (−3.98; −2.51) | −3.39 (1.69; 4.46) | −1.76 (0.74; 3.87) | −4.39 (3.84; 5.19) |
Deep infiltrating endometriosis | 1.97 (−2.87; −1.25) | −2.54 (1.9; 3.58) | −2.11 (1.85; 2.85) | −3.4 (2.81; 5.85) |
miRNA | Group | Control 1 (33–54 Age) * | Control 2 (25–33 Age) * | HGSOC, Cluster 1 * | HGSOC, Cluster 2 * | LGSOC * | SBT * | BSC * | Ovarian Endometrioma * | Deep Infiltrating Endometriosis * |
---|---|---|---|---|---|---|---|---|---|---|
miR-17-5p | Control 2 (25–33 age) | 0.1077 | NA | NA | NA | NA | NA | NA | NA | NA |
miR-17-5p | HGSOC, cluster 1 | 0.017 | 0 | NA | NA | NA | NA | NA | NA | NA |
miR-17-5p | HGSOC, cluster 2 | 0.2441 | 0.9699 | 0.0024 | NA | NA | NA | NA | NA | NA |
miR-17-5p | LGSOC | 0.1306 | 0.935 | 0.0019 | 0.7925 | NA | NA | NA | NA | NA |
miR-17-5p | SBT | 0.6787 | 0.0202 | 0.0224 | 0.0895 | 0.0987 | NA | NA | NA | NA |
miR-17-5p | BSC | 0.7689 | 0.2174 | 0.0031 | 0.3355 | 0.5387 | 0.5732 | NA | NA | NA |
miR-17-5p | Ovarian endometrioma | 0.649 | 0.1639 | 0.0108 | 0.3502 | 0.3494 | 0.412 | 0.9279 | NA | NA |
miR-17-5p | Deep infiltrating endometriosis | 1 | 0.0594 | 0.0031 | 0.1246 | 0.2829 | 0.6615 | 0.8428 | 0.8328 | NA |
miR-93-5p | Control 2 (25–33 age) | 0.0096 | NA | NA | NA | NA | NA | NA | NA | NA |
miR-93-5p | HGSOC, cluster 1 | 0.0413 | 2.00 × 10−4 | NA | NA | NA | NA | NA | NA | NA |
miR-93-5p | HGSOC, cluster 2 | 0.0125 | 0.9699 | 0.0062 | NA | NA | NA | NA | NA | NA |
miR-93-5p | LGSOC | 0.0493 | 0.4952 | 0.0054 | 0.9578 | NA | NA | NA | NA | NA |
miR-93-5p | SBT | 0.3732 | 0.093 | 0.0106 | 0.3432 | 0.7595 | NA | NA | NA | NA |
miR-93-5p | BSC | 0.6495 | 0.1257 | 0.0667 | 0.2496 | 0.4176 | 0.8187 | NA | NA | NA |
miR-93-5p | Ovarian endometrioma | 0.0073 | 0.9188 | 0.0016 | 0.6605 | 0.5116 | 0.2204 | 0.1896 | NA | NA |
miR-93-5p | Deep infiltrating endometriosis | 0.0597 | 0.8667 | 0.0017 | 0.4371 | 0.8212 | 0.2665 | 0.2657 | 0.4865 | NA |
miR-16-5p | Control 2 (25–33 age) | 0 | NA | NA | NA | NA | NA | NA | NA | NA |
miR-16-5p | HGSOC, cluster 1 | 0.1184 | 0 | NA | NA | NA | NA | NA | NA | NA |
miR-16-5p | HGSOC, cluster 2 | 0.2441 | 0.0016 | 0.0365 | NA | NA | NA | NA | NA | NA |
miR-16-5p | LGSOC | 0.008 | 0.0192 | 0.0029 | 0.4923 | NA | NA | NA | NA | NA |
miR-16-5p | SBT | 0.0073 | 0.001 | 0.0066 | 0.4537 | 0.9812 | NA | NA | NA | NA |
miR-16-5p | BSC | 0.0457 | 0.0087 | 0.0063 | 0.3845 | 0.9742 | 0.7231 | NA | NA | NA |
miR-16-5p | Ovarian endometrioma | 0.0821 | 6.00 × 10−4 | 0.0037 | 0.8836 | 0.1971 | 0.2962 | 0.4491 | NA | NA |
miR-16-5p | Deep infiltrating endometriosis | 6.00 × 10−4 | 0.0414 | 5.00 × 10−4 | 0.0668 | 0.381 | 0.3048 | 0.5512 | 0.0688 | NA |
miR-20a-5p | Control 2 (25–33 age) | 0.2005 | NA | NA | NA | NA | NA | NA | NA | NA |
miR-20a-5p | HGSOC, cluster 1 | 0.0044 | 1.00 × 10−4 | NA | NA | NA | NA | NA | NA | NA |
miR-20a-5p | HGSOC, cluster 2 | 0.21 | 0.791 | 0.0062 | NA | NA | NA | NA | NA | NA |
miR-20a-5p | LGSOC | 0.1306 | 0.8065 | 1.00 × 10−4 | 0.9578 | NA | NA | NA | NA | NA |
miR-20a-5p | SBT | 0.8902 | 0.1896 | 0.0027 | 0.2796 | 0.2449 | NA | NA | NA | NA |
miR-20a-5p | BSC | 0.7689 | 0.1523 | 0.0119 | 0.2496 | 0.0804 | 0.8187 | NA | NA | NA |
miR-20a-5p | Ovarian endometrioma | 0.8646 | 0.2171 | 0.0362 | 0.2561 | 0.1971 | 0.8079 | 0.8801 | NA | NA |
miR-20a-5p | Deep infiltrating endometriosis | 0.4696 | 0.0529 | 0.0021 | 0.1025 | 0.1072 | 0.8841 | 0.8428 | 0.9759 | NA |
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Timofeeva, A.V.; Asaturova, A.V.; Sannikova, M.V.; Khabas, G.N.; Chagovets, V.V.; Fedorov, I.S.; Frankevich, V.E.; Sukhikh, G.T. Search for New Participants in the Pathogenesis of High-Grade Serous Ovarian Cancer with the Potential to Be Used as Diagnostic Molecules. Life 2022, 12, 2017. https://doi.org/10.3390/life12122017
Timofeeva AV, Asaturova AV, Sannikova MV, Khabas GN, Chagovets VV, Fedorov IS, Frankevich VE, Sukhikh GT. Search for New Participants in the Pathogenesis of High-Grade Serous Ovarian Cancer with the Potential to Be Used as Diagnostic Molecules. Life. 2022; 12(12):2017. https://doi.org/10.3390/life12122017
Chicago/Turabian StyleTimofeeva, Angelika V., Aleksandra V. Asaturova, Maya V. Sannikova, Grigory N. Khabas, Vitaliy V. Chagovets, Ivan S. Fedorov, Vladimir E. Frankevich, and Gennady T. Sukhikh. 2022. "Search for New Participants in the Pathogenesis of High-Grade Serous Ovarian Cancer with the Potential to Be Used as Diagnostic Molecules" Life 12, no. 12: 2017. https://doi.org/10.3390/life12122017