ASIAN
NICALTI
FOUNDED 1976
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Asian Journal of Surgery
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Asian Journal of Surgery
Letter to Editor
Prognostic value of spindle and kinetochore-related complex family and its correlation with immune cell infiltration in adrenocortical carcinoma
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To the Editor,
Adrenocortical carcinoma (ACC) originates from the adrenal cor- tex, with 0.5-2 new case per million people per year.1 Despite the low incidence of the ACC, many patients progress to metastasis at the initial diagnosis, which made them lose the precious chance of surgery.2 Thus, patients with ACC usually have a dismally poor prognosis. In order to solve this dilemma, scientists are striving to find powerful biomarkers and drugs to predict prognosis, and pro- vide new therapeutic options for patients with ACC. Spindle and kinetochore-related (SKA) complex family can establish and/or maintain the stability of kinetochore-microtubule interactions and spindle checkpoint silencing. However, the association of SKA family and adrenocortical carcinoma (ACC) has not been reported. To clarify the association of SKA family and ACC, we analyzed the expression, and diagnostic and prognostic value of the SKA family genes in patients with ACC using online database. In addition, GSCALite was used to screen drugs sensitive to SKA family.
We first reported that the expression level of SKA family genes was higher in ACC tumor tissues than normal adrenal tissue (Fig. 1A, P < 0.001). The expression of SKA family genes was signif- icantly different in metastasis, tumor status, pathological stage, T stage in patients with ACC (Table 1, P < 0.005). In particular, the SKA family genes not only had a high ROC value for the diagnosis of ACC (Fig. 1C), but also could distinguish the T stage (Fig. 1D) and the pathological stage (Fig. 1E). In terms of prognostic value,
the high expression of SKA family genes groups had significantly worse overall survival (OS) than the low expression groups (Fig. 1F-H).
Recently, tumor-associated immune cells have received wide- spread interest. In the present study, the expression of SKA family genes was negatively associated with the tumor infiltration of mast cells, cytotoxic cells, CD8+ T cells, and was positively corre- lated with Th2 cell level. In a study of childhood ACC, high CD8+ T cells counts was associated with younger patients and stage I dis- ease.3 Similarly, Landwehr et al4 reported that a high number of CD8+ T cells was also associated with better OS by analyzing 146 ACC samples. Our results indicated that the high expression of SKA family genes was strongly associated with a reduced infiltra- tion of CD8+ T cells. We might infer that overexpression of SKA family genes may inhibit the immune infiltration of CD8+ T cells.
Using the Gene Set Cancer Analysis (GSCA) database, we analyzed the associations between the expression of SKA family genes and their sensitivity to drug activity by calculating Pearson’s correlation coefficient (r > 0.2 and P < 0.001). Overall, trametinib was the only drug active against all genes in the SKA family (Fig. 1B).
Our findings suggested that the SKA family genes might serve as a new biomarker predicting diagnosis and overall survival for pa- tients with ACC. Trametinib might be the sensitive drug to SKA fam- ily. Moreover, SKA family were closely related to the infiltration of mast cells, CD8+ T cells, cytotoxic cells, and Th2 cells.
A
B
Correlation between GDSC drug sensitivity and mRNA expression
6
J:
The expression levels Log2 (TPM+1)
SKA2
0
o
0
O
0
Correlation
4
₿
Normal
-0.3
Tumor
0.0
Symbol
SKA1
0.4
FDR
2
== 0.05
>0.05
SKA3
0
17-AAG
PD-0325001
RDEA119
CI-1040
~BET-762
Mothobra
QL-2-24
AW/519
BMS345541
8X-912 CP466722
GSK1070816
GSK890693
Genentech Cod 10
W-7-24-
KIND01-102 NPK78-B-7KM
Nastoclax
OS1-02
PHA-793687
04-103 PIK.93
Qt-X-138
TG101348
TPCA-
Vorinostat
WZ3105
SKA1
SKA2
SKA3
THZ-2-102-
C
D
E
1.0
1.0
1.0
0.8
0.8
0.8
Sensitivity (TPR)
Sensitivity (TPR)
Sensitivity (TPR)
0.6
0.6
0.6
0.4
0.4
0.4
0.2
0.2
SKA1 (AUC = 0.709)
0.2
SKA1 (AUC = 0.818)
SKA1 (AUC = 0.702)
SKA2 (AUC = 0.755)
SKA2 (AUC = 0.684)
SKA2 (AUC = 0.713)
SKA3 (AUC = 0.780)
d
SKA3 (AUC = 0.772)
0.0
SKA3 (AUC = 0.834)
0.0
0.0
0.0
0.2
0.4
0.6
0.8
1.0
0.0
0.2
0.4
0.6
0.8
1.0
0.0
0.2
0.4
0.6
0.8
1.0
F
1-Specificity (FPR)
G
1-Specificity (FPR)
H
1-Specificity (FPR)
1.0
SKA1
1.0
SKA2
1.0
SKA3
Low
Low
Low
High
High
High
Survival probability
0.8
Survival probability
0.8
Survival probability
0.8
0.6
0.6
0.6
0.4
0.4
0.4
0.2
Overall Survival HR = 6.20 (2.48-15.47)
0.2
Overall Survival HR = 3.85 (1.67-8.84)
0.2
Overall Survival HR = 6.14 (2.46-15.30)
0.0
P < 0.001
0.0
P = 0.002
0.0
P < 0.001
0
50
100
150
0
50
100
150
0
50
100
150
Time (months)
J
Time (months)
K
Time (months)
Th2 cells
Th2 cells
The cells
T helper cells
T helper cells
T helper cells
aDC
Tgd
aDC
TReg
TReg
DC
aDC
TReg
Tgd
NK cells
NK cells
Tgd
P value
Tem
Tom
P value
DC
Tom
P value
PDC
0.75
0.75
Tem
Tem
0.75
NK CDG5dim cells
0.50
NK cells
0.50
PDC
0.25
NK CD56bright cells
0.50
Neutrophils
0 25
IDC
0.00
Th17 cells
Correlation
PDC
0.00
Eosinophils
0.25
0.00
IDC
02
Th17 cells
Neutrophils
Comolation
NK CD56dim cells
Comelation
Tom
0.4
0.2
DC
0.2
NK CD56dim cells
0.4
Neutrophils
0.4
Eosinophils
bud
T cells
Macrophages
DUB
DC
0.6
Thi cells
Eosinophils
TFH
NK CD56bright cells
B cells
Th17 cells
B cells
TFH
Thi cells
Macrophages
Thi cells
T cells
TFH
NK CD56bright cells
Macrophages
Mast cells
T cells
CDB T colls
CDS T cells
CD8 T cells
B cells
Cytotoxic cells
Cytotoxic cells
Mast cells
02
Mast cells
Cytotoxic cells
-0.4
-0.2
0.0
0.4
0.6
0.8
Correlation
-0.6
-0.4
-0.2
0.0
02
0.4
0.6
-0.4
-0.2
0.0
0.2
0.4
0.6
0.8
Correlation
Correlation
| Clinicopathologic features | SKA1 (P value) | SKA2 (P value) | SKA3 (P value) |
|---|---|---|---|
| Age(years) ≤50 vs. >50 | 0.142 | 1 | 0.907 |
| Gender Female vs. Male | 1 | 0.141 | 1 |
| Laterality Left vs. Right | 0.745 | 0.897 | 0.745 |
| T stage | |||
| T1-2 vs. T3-4 | 0.008 | 0.045 | 0.008 |
| Lymph node involvement no vs. yes | 0.087 | 0.154 | 0.087 |
| Metastasis no vs. yes | 0.018 | 0.025 | 0.018 |
| Pathologic stage Stage I-II vs. Stage III-IV | 0.013 | 0.045 | 0.013 |
| Tumor status Free vs. with tumor | <0.001 | <0.001 | <0.001 |
ACC: adrenocortical carcinoma; SKA: spindle and kinetochore-associated; vs: versus.
Author contributions
QXY and DCF collected, reviewed the literature and wrote the manuscript. DXL and HHZ pointed out writing design and revised the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Consent for publication
No consent is required because all data comes from online database.
Data availability statement
Not applicable.
Funding
None.
Declaration of competing interest
The authors declare that they have no known competing finan- cial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
None.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.org/10.1016/j.asjsur.2022.10.098.
References
1. Fassnacht M, et al. Adrenocortical carcinomas and malignant phaeochromocyto- mas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(11):1476-1490.
2. Tian X, et al. Identification of tumor-infiltrating immune cells and prognostic validation of tumor-infiltrating mast cells in adrenocortical carcinoma: results from bioinformatics and real-world data. OncoImmunology. 2020;9(1), 1784529.
3. Parise IZS, et al. The prognostic role of CD8(+) T lymphocytes in childhood adre- nocortical carcinomas compared to ki-67, PD-1, PD-L1, and the weiss score. Can- cers. 2019;11(11).
4. Landwehr LS, et al. Interplay between glucocorticoids and tumor-infiltrating lymphocytes on the prognosis of adrenocortical carcinoma. J Immunother Cancer. 2020;8(1).
Qing-Xin Yu1
Department of Pathology, Taizhou Hospital, Wenzhou Medical University, Linhai, Zhejiang Province, 317000, China
De-Chao Feng1
Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, China
Deng-Xiong Li2,
Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, China
Hai-Hong Zheng”,2
Department of Pathology, Taizhou Hospital, Wenzhou Medical University, Linhai, Zhejiang Province, 317000, China
* Corresponding author.
Corresponding author.
E-mail address: lidengxiongwch@stu.scu.edu.cn (D .- X. Li).
E-mail address: zhenghh@enzemed.com (H .- H. Zheng).
14 October 2022 Available online 20 November 2022
1 These authors have contributed equally to this work and share first authorship.
2 These authors contributed equally to this work and should be consider as cor- responding authors.