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

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)

[i] ARG, autophagy-related genes; ABN, chromosomal abnormality; GOrilla, Gene Ontology enRIchmentanaLysis and visuaLizAtion; MM: multiple myeloma.

Table 2.

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)

[i] TT2 involves thalidomide treatment; TT3 involves bortezomib, thalidomide, and dexamethasone treatment. ABN, chromosomal abnormality; SD, standard deviation; MM: multiple myeloma; TT2, Total Therapy 2; TT3, Total Therapy 3.

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.

Table 3.

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

[i] ABN, chromosomal abnormality; EFS, event-free survival; OS, overall survival; SD, standard deviation.

Table 4.

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

* P < 0.05;

** P < 0.01;

*** P < 0.001.

ABN, chromosomal abnormality; CI, confidence interval; EFS, event-free survival; HR, Hazard ratio; OS, overall survival.

Table 5.

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

* P < 0.05;

** P < 0.01;

*** P < 0.001.

ABN, chromosomal abnormality.

Table 6.

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

* P < 0.05;

** P < 0.01;

*** P < 0.001.

ABN, chromosomal abnormality; ARG, autophagy-related genes; CI, confidence interval; HR, Hazard ratio; MM, Multiple myeloma

Table 7.

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

Gene	Univariate Cox regression				Multivariate Cox regression
Gene	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

* P < 0.05;

** P < 0.01;

*** P < 0.001.

ABN, chromosomal abnormality; ARG, autophagy-related genes; CI, confidence interval; HR, Hazard ratio; MM, Multiple myeloma.

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 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.

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

Table 8.

Validation of prognosis-related ARGs in MM patients with ABN

Gene	Univariate Cox regression
Gene	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

* P < 0.05;

** P < 0.01;

*** P < 0.001.

ABN, chromosomal abnormality; ARGs, autophagy-related genes; CI, confidence interval; HR, Hazard ratio; MM, Multiple myeloma

References

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Articles in this issue

DOI: https://doi.org/10.2478/abm-2022-0028 | Journal eISSN: 1875-855X | Journal ISSN: 1905-7415

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Language: English

Page range: 249 - 264

Published on: Jun 16, 2023

Published by: Chulalongkorn University

In partnership with: Paradigm Publishing Services

Keywords:

autophagy,

chromosomal abnormality,

gene,

multiple myeloma,

survival

Related subjects:

Medicine,

Assistive professions, nursing,

Basic medical science,

Basic medical science, other,

Clinical medicine,

Clinical medicine, other

© 2023 Gizem Ayna Duran, Yasemin Benderli Cihan, published by Chulalongkorn University
This work is licensed under the Creative Commons Attribution 4.0 License.

Volume 16 (2022): Issue 5 (October 2022)

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

Figures & Tables

Table 1.

Table 2.

Figure 1.

Table 3.

Table 4.

Table 5.

Table 6.

Table 7.

Figure 2.

Figure 3.

Figure 4.

Table 8.

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