Insights into FGFR4 (rs351855 and rs7708357) Gene Variants, Ki-67 and p53 in Pituitary Adenoma Pathophysiology
Abstract
1. Introduction
2. Results
2.1. By Gender: Females and Males
2.2. Associations of FGFR4 rs351855 and rs7708357 with Pituitary Adenoma’s Tumor Size
2.3. Associations of FGFR4 rs351855 and rs7708357 with Pituitary Adenoma’s Invasiveness
2.4. Associations of FGFR4 rs351855 and rs7708357 with Pituitary Adenomas’ Activity
2.5. Associations of FGFR4 rs351855 and rs7708357 with Pituitary Adenomas’ Recurrence
2.6. Serum FGFR4 Levels in Patients with PA and Controls
2.7. Ki-67 Labeling Index
2.8. p53 Analysis in PA Tissues
2.9. Correlation Between Ki-67 and p53
3. Discussion
4. Materials and Methods
4.1. Study Design
4.2. Study Population
4.3. DNA Extraction and Genotyping
4.4. Serum Level’s Measurement
4.5. Evaluation of Ki-67 and p53
4.6. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ACTH | Adrenocorticotropic Hormone |
APT/PC | Atypical Pituitary Tumor/Pituitary Carcinom |
CT | Computed Tomography |
DNA | Deoxyribonucleic Acid |
ELISA | Enzyme-Linked Immunosorbent Assay |
FGF | fibroblast growth factor |
FPA | functional pituitary adenoma |
FS H/LH | Follicle-Stimulating Hormone/Luteinizing Hormone |
GH | Growth Hormone |
GFG | Human Endogenous FGF Antisense Gene |
MRI | magnetic resonance imaging |
NFPA | non-functional pituitary adenomas |
PA | pituitary adenoma |
RT-PCR | real-time polymerase chain reaction |
SNV | single-nucleotide variant |
STAT3 | Signal Transducer and Activator of Transcription 3 |
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Characteristics | Group | p-Value | |
---|---|---|---|
PA, n (%) (n = 100) | Control, n (%) (n = 200) | ||
Age median (IQR) | 51 (21) | 53.5 (40) | 0.655 * |
Gender, n (%) | 0.294 ** | ||
Females | 64 (64) | 140 (70) | |
Males | 36 (36) | 60 (30) | |
Tumor size, n (%) | - | - | |
Micro PA | 38 (38) | ||
Macro PA | 62 (62) | ||
Hormonal activity, n (%) | - | - | |
Active | 59 (59) | ||
Non-active | 41 (41) | ||
Invasiveness, n (%) | - | - | |
Invasive | 53 (53) | ||
Non-invasive | 47 (47) | ||
Recurrence, n (%) | - | - | |
PA without recurrence | 77 (77) | ||
PA with recurrence | 23 (23) |
Gene | Genotype/Allele | PA Group n (%) (n = 100) | Control Group n (%) (n = 200) | p-Value | p-Value HWE |
---|---|---|---|---|---|
FGFR4 (rs351855) | GG | 45 (45) | 95 (47.5) | 0.885 | 0.134 |
GA | 49 (49) | 92 (46) | |||
AA | 6 (6) | 13 (6.5) | |||
In total: | 100 (100) | 200 (100) | |||
Allele: | 0.800 | ||||
G | 139 (69.5) | 282 (70.5) | |||
A | 61 (30.5) | 118 (29.5) | |||
FGFR4 (rs7708357) | GG | 40 (40) | 86 (43) | 0.755 | 0.791 |
GA | 49 (49) | 89 (44.5) | |||
AA | 11 (11) | 25 (12.5) | |||
In total: | 100 (100) | 200 (100) | |||
Allele: | 0.855 | ||||
G | 129 (64.5) | 261 (65.3) | |||
A | 71 (35.5) | 139 (34.7) |
Gene | Genotype/Allele | PA Group Females (n = 64) n (%) | Control Group Females (n = 140) n (%) | p-Value |
---|---|---|---|---|
FGFR4 (rs351855) | GG | 27 (42.2) | 69 (49.3) | 0.490 |
GA | 34 (53.1) | 62 (44.3) | ||
AA | 3 (4.7) | 9 (6.4) | ||
In total: | 64 (100) | 140 (100) | ||
Allele: | 0.581 | |||
G | 88 (68.75) | 200 (71.4) | ||
A | 40 (31.25) | 80 (28.6) | ||
FGFR4 (rs7708357) | GG | 25 (39.1) | 56 (40) | 0.726 |
GA | 33 (51.6) | 66 (47.1) | ||
AA | 6 (9.4) | 18 (12.9) | ||
In total: | 64 (100) | 140 (100) | ||
Allele: | 0.803 | |||
G | 83 (64.8) | 178 (63.6) | ||
A | 45 (35.2) | 102 (36.4) |
Gene | Genotype/Allele | PA Group Males (n = 36) n (%) | Control Group Males (n = 60) n (%) | p-Value |
---|---|---|---|---|
FGFR4 (rs351855) | GG | 18 (50) | 26 (43.3) | 0.727 |
GA | 15 (41.7) | 30 (50) | ||
AA | 3 (8.3) | 4 (6.7) | ||
In total: | 36 (100) | 60 (100) | ||
Allele: | 0.716 | |||
G | 51 (70.8) | 82 (68.3) | ||
A | 21 (29.2) | 38 (31.7) | ||
FGFR4 (rs7708357) | GG | 15 (41.7) | 30 (50) | 0.730 |
GA | 16 (44.4) | 23 (38.3) | ||
AA | 5 (13.9) | 7 (11.7) | ||
In total: | 36 (100) | 60 (100) | ||
Allele: | 0.450 | |||
G | 46 (63.9) | 83 (69.2) | ||
A | 26 (36.1) | 37 (30.8) |
Gene | Genotype/ Allele | Control Group (n = 200) n (%) | Micro PA (n = 38) n (%) | p-Value | Macro PA (n = 62) n (%) | p-Value |
---|---|---|---|---|---|---|
FGFR4 (rs351855) | GG | 95 (47.5) | 15 (39.5) | 0.577 | 30 (48.4) | 0.992 |
GA | 92 (46) | 21 (55.3) | 28 (45.2) | |||
AA | 13 (6.5) | 2 (5.3) | 4 (6.5) | |||
In total: | 200 (100) | 38 (100) | 62 (100) | |||
Allele: | 0.554 | 0.920 | ||||
G | 282 (70.5) | 51 (67.1) | 88 (71) | |||
A | 118 (29.5) | 25 (32.9) | 36 (29) | |||
FGFR4 (rs7708357) | GG | 86 (43) | 15 (39.5) | 0.836 | 25 (40.3) | 0.494 |
GA | 89 (44.5) | 17 (44.7) | 32 (51.6) | |||
AA | 25 (12.5) | 6 (15.8) | 5 (8.1) | |||
In total: | 200 (100) | 38 (100) | 62 (100) | |||
Allele: | 0.568 | 0.857 | ||||
G | 261 (65.3) | 47 (61.8) | 82 (66.1) | |||
A | 139 (34.7) | 29 (38.2) | 42 (33.9) |
Gene | Genotype/ Allele | Control Group (n = 200) n (%) | Non-Invasive PA (n = 47) n (%) | p-Value | Invasive PA (n = 53) n (%) | p-Value |
---|---|---|---|---|---|---|
FGFR4 (rs351855) | GG | 95 (47.5) | 17 (36.2) | 0.348 | 28 (52.8) | 0.787 |
GA | 92 (46) | 27 (57.4) | 22 (41.5) | |||
AA | 13 (6.5) | 3 (6.4) | 3 (5.7) | |||
In total: | 200 (100) | 47 (100) | 53 (100) | |||
Allele: | 0.288 | 0.533 | ||||
G | 282 (70.5) | 61 (64.9) | 78 (73.6) | |||
A | 118 (29.5) | 33 (35.1) | 28 (26.4) | |||
FGFR4 (rs7708357) | GG | 86 (43) | 15 (31.9) | 0.353 | 25 (47.2) | 0.367 |
GA | 89 (44.5) | 24 (51.1) | 25 (47.2) | |||
AA | 25 (12.5) | 8 (17) | 3 (5.7) | |||
In total: | 200 (100) | 47 (100) | 53 (100) | |||
Allele: | 0.156 | 0.286 | ||||
G | 261 (65.3) | 54 (57.4) | 75 (70.8) | |||
A | 139 (34.7) | 40 (42.6) | 31 (29.2) |
Gene | Genotype/ Allele | Control Group (n = 200) n (%) | Non-Active PA (n = 41) n (%) | p-Value | Active PA (n = 59) n (%) | p-Value |
---|---|---|---|---|---|---|
FGFR4 (rs351855) | GG | 95 (47.5) | 20 (48.8) | 0.713 | 25 (42.4) | 0.435 |
GA | 92 (46) | 17 (41.5) | 32 (54.2) | |||
AA | 13 (6.5) | 4 (9.8) | 2 (3.4) | |||
In total: | 200 (100) | 41 (100) | 59 (100) | |||
Allele: | 0.858 | 0.833 | ||||
G | 282 (70.5) | 57 (69.5) | 82 (69.5) | |||
A | 118 (29.5) | 25 (30.5) | 36 (30.5) | |||
FGFR4 (rs7708357) | GG | 86 (43) | 13 (31.7) | 0.360 | 27 (45.8) | 0.866 |
GA | 89 (44.5) | 23 (56.1) | 26 (44.1) | |||
AA | 25 (12.5) | 5 (12.2) | 6 (10.2) | |||
In total: | 200 (100) | 41 (100) | 59 (100) | |||
Allele: | 0.344 | 0.608 | ||||
G | 261 (65.3) | 49 (59.8) | 80 (67.8) | |||
A | 139 (34.7) | 33 (40.2) | 38 (32.2) |
Gene | Genotype/ Allele |
Control Group (n = 200) n (%) | PA Without Recurrence (n = 77) n (%) | p-Value | PA with Recurrence (n = 23) n (%) | p-Value |
---|---|---|---|---|---|---|
FGFR4 (rs351855) | GG | 95 (47.5) | 34 (44.2) | 0.316 | 11 (47.8) | 0.150 |
GA | 92 (46) | 41 (53.2) | 8 (34.8) | |||
AA | 13 (6.5) | 2 (2.6) | 4 (17.4) | |||
In total: | 200 (100) | 77 (100) | 23 (100) | |||
Allele: | 0.948 | 0.459 | ||||
G | 282 (70.5) | 109 (70.8) | 30 (65.2) | |||
A | 118 (29.5) | 45 (29.2) | 16 (34.8) | |||
FGFR4 (rs7708357) | GG | 86 (43) | 27 (35.1) | 0.465 | 13 (56.5) | 0.339 |
GA | 89 (44.5) | 40 (51.9) | 9 (39.1) | |||
AA | 25 (12.5) | 10 (13) | 1 (4.3) | |||
In total: | 200 (100) | 77 (100) | 23 (100) | |||
Allele: | 0.354 | 0.140 | ||||
G | 261 (65.3) | 94 (61) | 35 (76.1) | |||
A | 139 (34.7) | 60 (39) | 11 (23.9) |
FGFR4 (rs351855) | |||||
Model | Genotype/Allele | OR (95% CI) | p-value | AIC | |
PA without recurrence | |||||
Codominant | GA vs. GG | 1.245 (0.727–2.131) | 0.424 | 328.894 | |
AA vs. GG | 0.430 (0.092–2.004) | 0.282 | |||
Dominant | GA + AA vs. GG | 1.144 (0.675–1.941) | 0.617 | 329.182 | |
Recessive | AA vs. GG + GA | 0.384 (0.085–1.741) | 0.214 | 327.535 | |
Overdominant | GA vs. GG + AA | 1.337 (0.789–2.265) | 0.280 | 328.263 | |
Additive | A | 0.984 (0.631–1.535) | 0.944 | 329.428 | |
PA with recurrence | |||||
Model | Genotype/Allele | OR (95% CI) | p-value | AIC | |
Codominant | GA vs. GG | 0.751 (0.289–1.951) | 0.557 | 148.963 | |
AA vs. GG | 2.657 (0.737–9.584) | 0.135 | |||
Dominant | GA + AA vs. GG | 0.987 (0.416–2.342) | 0.976 | 150.038 | |
Recessive | AA vs. GG + GA | 3.028 (0.898–10.216) | 0.074 | 147.312 | |
Overdominant | GA vs. GG + AA | 0.626 (0.254–1.543) | 0.309 | 148.969 | |
Additive | A | 1.298 (0.665–2.537) | 0.445 | 149.464 | |
FGFR4 (rs7708357) | |||||
Model | Genotype/Allele | OR (95% CI) | p-value | AIC | |
PA without recurrence | |||||
Codominant | GA vs. GG | 1.432 (0.809–2.534) | 0.218 | 329.890 | |
AA vs. GG | 1.274 (0.544–2.985) | 0.577 | |||
Dominant | GA + AA vs. GG | 1.397 (0.810–2.410) | 0.230 | 327.967 | |
Recessive | AA vs. GG + GA | 1.045 (0.476–2.292) | 0.913 | 329.421 | |
Overdominant | GA vs. GG + AA | 1.348 (0.796–2.284) | 0.266 | 328.195 | |
Additive | A | 1.201 (0.816–1.769) | 0.353 | 328.571 | |
PA with recurrence | |||||
Model | Genotype/Allele | OR (95% CI) | p-value | AIC | |
Codominant | GA vs. GG | 0.669 (0.272–1.646) | 0.381 | 149.601 | |
AA vs. GG | 0.265 (0.033–2.123) | 0.211 | |||
Dominant | GA + AA vs. GG | 0.580 (0.243–1.386) | 0.221 | 148.522 | |
Recessive | AA vs. GG + GA | 0.318 (0.041–2.465) | 0.273 | 148.379 | |
Overdominant | GA vs. GG + AA | 0.802 (0.332–1.938) | 0.624 | 149.795 | |
Additive | A | 0.593 (0.292–1.204) | 0.148 | 147.781 |
Ki-67 LI | Tumor Size | p-Value | |
---|---|---|---|
Micro PA (n = 20) (%) | Macro PA (n = 35) (%) | ||
<1% | 7 (35) | 7 (20) | 0.333 |
1% | 1 (5) | 5 (14.3) | |
>1% | 12 (60) | 23 (65.7) |
Ki-67 LI | Invasiveness | p-Value | |
---|---|---|---|
Non-Invasive PA (n = 22) (%) | Invasive PA) (n = 33) (%) | ||
<1% | 7 (31.8) | 7 (21.2) | 0.666 |
1% | 2 (9.1) | 4 (12.1) | |
>1% | 13 (59.1) | 22 (66.7) |
Ki-67 LI | Activeness | p-Value | |
---|---|---|---|
Non-Active PA (n = 24) (%) | Active PA (n = 31) (%) | ||
<1% | 5 (20.8) | 9 (29) | 0.224 |
1% | 1 (4.2) | 5 (16.1) | |
>1% | 18 (75) | 17 (54.8) |
Ki-67 LI | Recurrence | p-Value | |
---|---|---|---|
PA Without Recurrence (n = 37) (%) | PA with Recurrence (n = 18) (%) | ||
<1% | 9 (24.3) | 5 (27.8) | 0.671 |
1% | 5 (13.5) | 1 (5.6) | |
>1% | 23 (62.2) | 12 (66.7) |
Gene, SNV | Genotype/Allele | Ki-67 LI | p-Value | ||
---|---|---|---|---|---|
<1% | 1% | >1% | |||
FGFR4 rs351855 | GG | 7 (50) | 4 (66.7) | 14 (40) | 0.754 |
GA | 6 (42.9) | 2 (33.3) | 19 (54.3) | ||
AA | 1 (7.1) | 0 (0) | 2 (5.7) | ||
In total: | 14 (100) | 6 (100) | 35 (100) | ||
Allele: | 0.518 | ||||
G | 20 (71.4) | 10 (83.3) | 47 (67.1) | ||
A | 8 (28.6) | 2 (16.7) | 23 (32.9) | ||
FGFR4 rs7708357 | GG | 8 (57.1) | 2 (33.3) | 16 (45.7) | 0.885 |
GA | 5 (35.7) | 3 (50) | 15 (42.9) | ||
AA | 1 (7.1) | 1 (16.7) | 4 (11.4) | ||
In total: | 14 (100) | 6 (100) | 35 (100) | ||
Allele: | 0.556 | ||||
G | 21 (75) | 7 (58.3) | 47 (67.1) | ||
A | 7 (25) | 5 (41.7) | 23 (32.9) |
PA Subgroups | p53 H Score Median (IQR) | p-Value * |
---|---|---|
Micro PA | 18.34 (17.65) | 0.005 |
Macro PA | 30.33 (28.68) | |
Non-invasive PA | 21.32 (17.65) | 0.324 |
Invasive PA | 27.5 (26.25) | |
Non-active PA | 21.02 (17.65) | 0.068 |
Active PA | 28.33 (49.5) | |
PA without recurrence | 28.66 (25.41) | 0.360 |
PA with recurrence | 21.02 (14.65) |
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Juskiene, M.; Duseikaite, M.; Vilkeviciute, A.; Kariniauske, E.; Baikstiene, I.; Makstiene, J.; Poskiene, L.; Tamasauskas, A.; Liutkeviciene, R.; Verkauskiene, R.; et al. Insights into FGFR4 (rs351855 and rs7708357) Gene Variants, Ki-67 and p53 in Pituitary Adenoma Pathophysiology. Int. J. Mol. Sci. 2025, 26, 7565. https://doi.org/10.3390/ijms26157565
Juskiene M, Duseikaite M, Vilkeviciute A, Kariniauske E, Baikstiene I, Makstiene J, Poskiene L, Tamasauskas A, Liutkeviciene R, Verkauskiene R, et al. Insights into FGFR4 (rs351855 and rs7708357) Gene Variants, Ki-67 and p53 in Pituitary Adenoma Pathophysiology. International Journal of Molecular Sciences. 2025; 26(15):7565. https://doi.org/10.3390/ijms26157565
Chicago/Turabian StyleJuskiene, Martyna, Monika Duseikaite, Alvita Vilkeviciute, Egle Kariniauske, Ieva Baikstiene, Jurgita Makstiene, Lina Poskiene, Arimantas Tamasauskas, Rasa Liutkeviciene, Rasa Verkauskiene, and et al. 2025. "Insights into FGFR4 (rs351855 and rs7708357) Gene Variants, Ki-67 and p53 in Pituitary Adenoma Pathophysiology" International Journal of Molecular Sciences 26, no. 15: 7565. https://doi.org/10.3390/ijms26157565
APA StyleJuskiene, M., Duseikaite, M., Vilkeviciute, A., Kariniauske, E., Baikstiene, I., Makstiene, J., Poskiene, L., Tamasauskas, A., Liutkeviciene, R., Verkauskiene, R., & Zilaitiene, B. (2025). Insights into FGFR4 (rs351855 and rs7708357) Gene Variants, Ki-67 and p53 in Pituitary Adenoma Pathophysiology. International Journal of Molecular Sciences, 26(15), 7565. https://doi.org/10.3390/ijms26157565