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Autophagy-related genes affect the survival of multiple myeloma patients depending on chromosomal abnormality

Gizem Ayna Duran
Gizem Ayna Duran
 et 
Yasemin Benderli Cihan
Yasemin Benderli Cihan
   | 16 juin 2023
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Article Category: Original article
Publié en ligne: 16 juin 2023
Pages: 249 - 264
DOI: https://doi.org/10.2478/abm-2022-0028
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© 2022 Gizem Ayna Duran et al., published by Sciendo
This work is licensed under the Creative Commons Attribution 4.0 International License.

Figure 1.

The significant effect of ABN on the EFS of MM patients. The effect of independent variables on both EFS of MM patients is shown using Kaplan–Meier survival plots as indicated in (A) ABN; EFS (B) sex and EFS; (C) age and EFS; (D) race and EFS; and (E) treatment protocol. ABN, chromosomal abnormality; EFS, event-free survival; MM: multiple myeloma.
The significant effect of ABN on the EFS of MM patients. The effect of independent variables on both EFS of MM patients is shown using Kaplan–Meier survival plots as indicated in (A) ABN; EFS (B) sex and EFS; (C) age and EFS; (D) race and EFS; and (E) treatment protocol. ABN, chromosomal abnormality; EFS, event-free survival; MM: multiple myeloma.

Figure 2.

Survival analysis of selected ARGs in MM patients without ABN; Kaplan–Meier plots of 6 prognosis-related ARGs in MM patients without ABN. (A) ARSA, (B) ATG9A, (C) FKBP1B, (D) FOXO3, (E) NCKAP1, and (F) RAB24.ARSA, arylsulfatase A; ATG9A, ATG9 autophagy-related 9 homolog A (Saccharomyces cerevisiae); FKBP1B, FK506 binding protein 1B, 12.6 kDa; FOXO3, forkhead box O3; NCKAP1, NCK-associated protein 1; RAB24, RAB24, member RAS oncogene family. ABN, chromosomal abnormality; ARGs, autophagy-related genes.
Survival analysis of selected ARGs in MM patients without ABN; Kaplan–Meier plots of 6 prognosis-related ARGs in MM patients without ABN. (A) ARSA, (B) ATG9A, (C) FKBP1B, (D) FOXO3, (E) NCKAP1, and (F) RAB24.ARSA, arylsulfatase A; ATG9A, ATG9 autophagy-related 9 homolog A (Saccharomyces cerevisiae); FKBP1B, FK506 binding protein 1B, 12.6 kDa; FOXO3, forkhead box O3; NCKAP1, NCK-associated protein 1; RAB24, RAB24, member RAS oncogene family. ABN, chromosomal abnormality; ARGs, autophagy-related genes.

Figure 3.

Survival analysis of selected ARGs in MM patients with ABN; Kaplan–Meier plots of 6 prognosis-related ARGs in MM patients with ABN. (A) ATG4D (S. cerevisiae); (B) ATIC; (C) BIRC5; (D) CDKN1A (p21, Cip1); (E) CXCR4; (F) EIF2S1, 35 kDa; (G) EIF4EBP1; (H) EIF4G1; (I) FKBP1A, 12 kDa; (J) FOXO1; (K) GABARAP; (L) ITGA6; (M) ATG13, KIAA0652; (N) PARP1; (O) TP53; (P) VAMP3 (cellubrevin).ABN, chromosomal abnormality; ARGs, autophagy-related genes; ATG4D, TG4 autophagy-related 4 homolog D; ATG13, Autophagy-Related Protein 13; ATIC, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase–IMP cyclohydrolase; BIRC5, baculoviral IAP repeat-containing 5; CDKN1A, cyclin-dependent kinase inhibitor 1A; CXCR4, chemokine (C-X-C motif) receptor 4; EIF2S1, eukaryotic translation initiation factor 2, subunit 1 alpha; EIF4EBP1, eukaryotic translation initiation factor 4E binding protein 1; EIF4G1, eukaryotic translation initiation factor 4 gamma, 1; FKBP1A, FK506 binding protein 1A; FOXO1, forkhead box O1; GABARAP, GABA(A) receptor-associated protein; ITGA6, integrin, alpha 6; MM: multiple myeloma; PARP1, poly (ADP-ribose) polymerase 1; TP53, tumor protein p53; VAMP3, vesicle-associated membrane protein 3.
Survival analysis of selected ARGs in MM patients with ABN; Kaplan–Meier plots of 6 prognosis-related ARGs in MM patients with ABN. (A) ATG4D (S. cerevisiae); (B) ATIC; (C) BIRC5; (D) CDKN1A (p21, Cip1); (E) CXCR4; (F) EIF2S1, 35 kDa; (G) EIF4EBP1; (H) EIF4G1; (I) FKBP1A, 12 kDa; (J) FOXO1; (K) GABARAP; (L) ITGA6; (M) ATG13, KIAA0652; (N) PARP1; (O) TP53; (P) VAMP3 (cellubrevin).ABN, chromosomal abnormality; ARGs, autophagy-related genes; ATG4D, TG4 autophagy-related 4 homolog D; ATG13, Autophagy-Related Protein 13; ATIC, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase–IMP cyclohydrolase; BIRC5, baculoviral IAP repeat-containing 5; CDKN1A, cyclin-dependent kinase inhibitor 1A; CXCR4, chemokine (C-X-C motif) receptor 4; EIF2S1, eukaryotic translation initiation factor 2, subunit 1 alpha; EIF4EBP1, eukaryotic translation initiation factor 4E binding protein 1; EIF4G1, eukaryotic translation initiation factor 4 gamma, 1; FKBP1A, FK506 binding protein 1A; FOXO1, forkhead box O1; GABARAP, GABA(A) receptor-associated protein; ITGA6, integrin, alpha 6; MM: multiple myeloma; PARP1, poly (ADP-ribose) polymerase 1; TP53, tumor protein p53; VAMP3, vesicle-associated membrane protein 3.

Figure 4.

GOrilla biological process in MM patients with ABN.ABN, chromosomal abnormality; GOrilla, Gene Ontology enRIchmentanaLysis and visuaLizAtion; MM: multiple myeloma.
GOrilla biological process in MM patients with ABN.ABN, chromosomal abnormality; GOrilla, Gene Ontology enRIchmentanaLysis and visuaLizAtion; MM: multiple myeloma.

Univariate and Multivariate Cox regression results of prognosis-associated ARG in MM patients with ABN

Gene Univariate Cox regression Multivariate Cox regression
HR Lower 95% CI Upper 95% CI P HR Lower 95% CI Upper 95% CI P
ARNT 1.5304* 1.064 2.202 0.0219 1.498746* 1.0238 2.194 0.0374
ATG4B 0.5552* 0.3172 0.972 0.0395 0.554451* 0.3167 0.9708 0.0391
ATG4D 0.5521*** 0.3891 0.7833 0.0008 0.568641** 0.3919 0.825 0.00295
ATIC 1.8684** 1.236 2.824 0.00302 1.857592** 1.2147 2.841 0.00427
BIRC5 1.30634*** 1.163 1.467 6.22e–06 1.343899*** 1.1901 1.518 1.87e–06
CAPN10 1.21016* 1.008 1.453 0.041 1.26361* 1.0470 1.525 0.0147
CASP3 1.4334* 1.013 2.029 0.0422 1.505861* 1.0472 2.165 0.0272
CDKN1A 0.7103** 0.5645 0.8938 0.00353 0.726627** 0.5787 0.9124 0.00598
CDKN2A 1.4842* 1.056 2.085 0.0228 1.54526* 1.0525 2.269 0.0263
CXCR4 0.73568*** 0.6289 0.8606 0.000125 0.765047** 0.6486 0.9025 0.00148
DNAJB9 0.6088* 0.389 0.9529 0.0299 0.593613* 0.3766 0.9356 0.0246
EIF2S1 1.6981** 1.156 2.494 0.00692 1.79448** 1.1872 2.712 0.00553
EIF4EBP1 1.34577*** 1.128 1.605 0.000955 1.312952** 1.1006 1.566 0.00249
EIF4G1 2.3264*** 1.493 3.626 0.000193 2.206738*** 1.3948 3.491 0.000721
FADD 1.5694* 1.063 2.317 0.0234 1.61684* 1.0894 2.400 0.01708
FKBP1A 1.8452** 1.187 2.868 0.00647 1.88003** 1.1997 2.946 0.00588
FKBP1B 0.82577** 0.7243 0.9414 0.0042 0.851602* 0.7454 0.973 0.0181
FOXO1 0.6549* 0.4739 0.9051 0.0103 0.645133** 0.4668 0.8917 0.00794
FOXO3 0.7363* 0.5657 0.9583 0.0228 0.72246* 0.5501 0.9489 0.01942
GABARAP 0.4739** 0.2896 0.7753 0.00295 0.464234** 0.2809 0.7672 0.00276
GNAI3 1.5955* 1.082 2.353 0.0184 1.542438* 1.0415 2.284 0.0305
HDAC6 1.7322* 1.059 2.834 0.0288 1.645421* 1.0051 2.694 0.0477
HGS 1.8098* 1.14 2.873 0.0119 1.696411* 1.0619 2.710 0.027
HSP90AB1 1.6281* 1.088 2.436 0.0178 1.594093* 1.0567 2.405 0.0262
IL24 0.82369* 0.6869 0.9877 0.0363 0.795624* 0.6579 0.9622 0.0184
IRGM 0.81103* 0.6737 0.9763 0.0269 0.823283* 0.6834 0.9919 0.0408
ITGA6 0.67844*** 0.5709 0.8063 1.06e–05 0.686741** 0.5770 0.8174 2.35e–05
ATG13 0.4507*** 0.2866 0.7087 0.000558 0.425973** 0.2721 0.6669 0.00019
LAMP2 0.7123* 0.5495 0.9234 0.0104 0.73084* 0.5619 0.9505 0.0193
MAPK1 1.496* 1.027 2.18 0.0359 1.481801* 1.0079 2.179 0.0455
MBTPS2 1.445* 1.039 2.009 0.0287 1.435077* 1.0182 2.023 0.0391
NCKAP1 0.8715* 0.7823 0.9709 0.0126 0.8927* 0.7987 0.9978 0.0456
PARP1 1.8204*** 1.286 2.577 0.000729 1.938906*** 0.8540 2.094 0.000271
PRKCD 0.7481* 0.5748 0.9735 0.0308 0.751456* 0.5741 0.9837 0.03755
SIRT2 0.5835** 0.4089 0.8327 0.00298 0.662074* 0.4521 0.9696 0.0341
TNFSF10 0.88013* 0.7841 0.988 0.0304 0.87052* 0.7759 0.9767 0.01824
TP53 0.7408** 0.6079 0.9029 0.00296 0.726943** 0.5947 0.8887 0.00186
TSC2 1.5559* 1.099 2.202 0.0126 1.4891644* 1.0499 2.112 0.0255
VAMP3 0.571*** 0.4168 0.7823 0.000485 0.596231** 0.4317 0.8235 0.0017
WDFY3 1.1406* 1.017 1.28 0.025 1.132911* 1.0127 1.267 0.0293
WDR45L 0.5495* 0.3283 0.9198 0.0227 0.57379* 0.3396 0.9696 0.0379

Outline of the study

Study dataset (548 MM patients, GSE24080) Validation dataset 1576 MM patients, GSE4204, GSE4452, GSE4581, and GSE2658)
Demographic properties of patients (Table 2)Survival Time According to Patients with/without Chromosomal Abnormality(Table 3)Univariate and multivariate Cox regression analyses and focus on the significant effect of ABN on survival of MM patients (Figure 1, Tables 4 and 5)Prognosis-related (survival-triggering or hazardous) ARG identification in patients with or without ABN (Figures 2 and 3)Table 6 (for patients without ABN), Table 7 (for patients with ABN)GOrilla Analysis (Figure 4) Validation of prognosis-related ARGs in MM patients with ABN (only for 1q21 amplification) (Table 8)

Demographic properties in MM patients

Parameters (n = 548) n (%)
Age (years); mean ± SD; 57.04 ± 9.37
Gender
  Male 217 (39.59)
  Female 331 (60.40)
ABN
  Yes 349 (63.68)
  No 199 (36.31)
Treatment protocol
  TT2 334 (60.94)
  TT3 214 (39.05)
Race
  Caucasian 486 (88.68)
  Other 62 (11.31)

Validation of prognosis-related ARGs in MM patients with ABN

Gene Univariate Cox regression
HR Lower 95% CI Upper 95% CI P
ARNT 0.78874** 0.6672 0.9324 0.00543
ATG4B 2.1821*** 1.51 3.154 3.29e–05
ATG4D 0.2839*** 0.1907 0.4226 5.56e–10
ATIC 3.5622*** 2.485 5.107 4.72e–12
CAPN10 0.4837*** 0.3665 0.6383 2.87e–07
CASP3 0.84905* 0.7409 0.973 0.0186
CDKN1A 0.76380*** 0.6658 0.8762 0.00012
CDKN2A 1.51399*** 1.356 1.69 1.55e–13
CXCR4 0.5576*** 0.4568 0.6807 9.5e–09
DNAJB9 1.7560** 1.193 2.584 0.00427
EIF4EBP1 0.81096*** 0.726 0.9059 0.000207
EIF4G1 0.6512** 0.4911 0.8633 0.00287
FADD 1.6059** 1.179 2.188 0.00268
FKBP1A 0.3130*** 0.2093 0.4679 1.5e–08
FKBP1B 0.6616*** 0.5228 0.8374 0.000589
FOXO1 0.3332*** 0.24 0.4626 5.25e–11
FOXO3 0.7879* 0.6265 0.9908 0.0415
GNAI3 0.79854** 0.6732 0.9472 0.00981
HGS 0.70614*** 0.6254 0.7973 1.98e–08
HSP90AB1 0.76746*** 0.6908 0.8526 8.12e–07
IL24 2.5083*** 1.675 3.756 7.98e–06
IRGM 2.3205*** 1.664 3.236 7.07e–07
ITGA6 4.0435*** 2.847 5.744 6.11e–15
ATG13 0.3571*** 0.2254 0.5658 1.16e–05
LAMP2 2.4952*** 1.774 3.509 1.48e–07
MAPK1 2.0933*** 1.395 3.142 0.000363
TNFSF10 1.2571* 1.021 1.548 0.0314
TP53 1.25520* 1.038 1.518 0.019
TSC2 1.4152* 1.04 1.925 0.027

Univariate Cox regression results of OS and EFS analyses (n = 548)

Dependent variables EFS OS
Independent variables HR Lower 95% CI Upper 95% CI P HR Lower 95% CI Upper 95% CI P
Age 1.0126 0.9989 1.027 0.0725 1.0222* 1.005 1.04 0.0107
Sex 0.9900 0.7652 1.281 0.9390 1.0018 0.7334 1.369 0.9910
Race 1.4538 0.9372 2.255 0.0948 1.0279 0.6367 1.657 0.9120
Treatment protocol 1.6409** 1.203 2.238 0.0017 1.1982 0.8316 1.727 0.3320
ABN 1.8009*** 1.398 2.319 0.0000519 2.2054*** 1.624 2.995 0.0000408

Survival time according to patients with or without ABN

Patients (months) OS (mean ± SD) EFS (mean ± SD)
All patients (n = 548) 48.23 ± 22.36 42.61 ± 22.15
Patients with ABN (n = 349) 42.70 ± 24.79 37.63 ± 23.96
Patients without ABN (n = 199) 50.56 ± 20.50 44.93 ± 20.50

Univariate and multivariate Cox regression results of prognosis-associated ARG in MM patients without ABN

Univariate and multivariate Cox regression results of prognosis-associated ARG in MM patients without ABNGene Univariate Cox regression Multivariate Cox regression
HR Lower 95% CI Upper 95% CI P HR Lower 95% CI Upper 95% CI P
APOL1 0.80962* 0.6862 0.9553 0.0124 0.828576* 0.6996 0.9813 0.02935
ARSA 0.83103** 0.7354 0.9391 0.003 0.845735** 0.7462 0.9586 0.00873
ATG16L2 1.2505* 1.013 1.543 0.0374 1.30139* 1.0507 1.612 0.01583
ATG9A 0.6562*** 0.5114 0.8419 0.000923 0.705951** 0.5506 0.9051 0.00603
ATG101 0.6862** 0.5156 0.9132 0.0098 0.703135* 0.5146 0.9608 0.02703
CDKN1A 0.7468* 0.5849 0.9536 0.0192 0.74999* 0.5830 0.9648 0.02519
DNAJB1 0.7074* 0.5316 0.9414 0.0176 0.72321* 0.5419 0.9653 0.02781
DRAM1 0.7561* 0.5756 0.9932 0.0446 0.74669* 0.5729 0.9733 0.030754
FKBP1B 0.82008** 0.7218 0.9318 0.00233 0.830138** 0.7293 0.9449 0.00483
FOXO3 0.7109** 0.5585 0.905 0.00559 0.70415** 0.5516 0.899 0.00488
MAPK9 0.6577* 0.4565 0.9474 0.0244 0.649662* 0.4491 0.9398 0.022037
NCKAP1 0.8088*** 0.7198 0.9089 0.000362 0.82788** 0.7360 0.9312 0.00164
RAB24 0.7536* 0.5958 0.953 0.0182 0.727826** 0.5723 0.9256 0.009599

Multivariate Cox regression results of overall and event free survival analysis

Dependent variables EFS OS
Independent variables Hazard ratio Lower 95% C.I Upper 95% C.I P Hazard ratio Lower 95% C.I Upper 95% C.I P
Age 1.0113 0.9971 1.026 0.1202 1.0234 1.0057 1.041 0.0093
Sex 0.9962 0.7689 1.291 0.9773 1.0308 0.7537 1.41 0.8489
Race 1.4049 0.8969 2.201 0.1375 0.9012 0.5515 1.473 0.6781
Treatment protocol 1.6626** 1.2168 2.272 0.0014 1.2065 0.8357 1.742 0.3163
Chromosomal abnormality 1.7627*** 1.3676 2.272 0.00012 2.1790*** 1.6038 2.961 0.0000633
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