DNA Damage Repair-related Gene Signature Predicts Prognosis and Indicates Immune Cell Infiltration Landscape in Skin Cutaneous Melanoma

Overview

Journal Front Endocrinol (Lausanne)

Specialty Endocrinology

Date 2022 Aug 12

PMID 35957812

Authors

Liping Liang

Shijie Mai

Genghui Mai

Ye Chen

Le Liu

Affiliations

Soon will be listed here.

Abstract

Background: DNA damage repair plays an important role in the onset and progression of cancers and its resistance to treatment therapy. This study aims to assess the prognostic potential of DNA damage repair markers in skin cutaneous melanoma (SKCM).

Method: In this study, we have analyzed the gene expression profiles being downloaded from TCGA, GTEx, and GEO databases. We sequentially used univariate and LASSO Cox regression analyses to screen DNA repair genes associated with prognosis. Then, we have conducted a multivariate regression analysis to construct the prognostic profile of DNA repair-related genes (DRRGs). The risk coefficient is used to calculate the risk scores and divide the patients into two cohorts. Additionally, we validated our prognosis model on an external cohort as well as evaluated the link between immune response and the DRRGs prognostic profiles. The risk signature is compared to immune cell infiltration, chemotherapy, and immune checkpoint inhibitors (ICIs) treatment.

Results: An analysis using LASSO-Cox stepwise regression established a prognostic signature consisting of twelve DRRGs with strong predictive ability. Disease-specific survival (DSS) is found to be lower among high-risk patients group as compared to low-risk patients. The signature may be employed as an independent prognostic predictor after controlling for clinicopathological factors, as demonstrated by validation on one external GSE65904 cohort. A strong correlation is also found between the risk score and the immune microenvironment, along with the infiltrating immune cells, and ICIs key molecules. The gene enrichment analysis results indicate a wide range of biological activities and pathways to be exhibited by high-risk groups. Furthermore, Cisplatin exhibited a considerable response sensitivity in low-risk groups as opposed to the high-risk incidents, while docetaxel exhibited a considerable response sensitivity in high-risk groups.

Conclusions: Our findings provide a thorough investigation of DRRGs to develop an DSS-related prognostic indicator which may be useful in forecasting SKCM progression and enabling more enhanced clinical benefits from immunotherapy.

Citing Articles

Comprehensive investigation of matrix metalloproteinases in skin cutaneous melanoma: diagnostic, prognostic, and therapeutic insights.

Wu L, Liu C, Hu W Sci Rep. 2025; 15(1):2152.

PMID: 39820824 PMC: 11739484. DOI: 10.1038/s41598-025-85887-2.

The DNA damage repair-related lncRNAs signature predicts the prognosis and immunotherapy response in gastric cancer.

Zhao Z, Mak T, Shi Y, Huang H, Huo M, Zhang C Front Immunol. 2023; 14:1117255.

PMID: 37457685 PMC: 10339815. DOI: 10.3389/fimmu.2023.1117255.

A novel DNA damage repair-related gene signature predicting survival, immune infiltration and drug sensitivity in cervical cancer based on single cell sequencing.

Xiang X, Kang J, Jiang J, Zhang Y, Zhang Y, Li L Front Immunol. 2023; 14:1198391.

PMID: 37449209 PMC: 10337997. DOI: 10.3389/fimmu.2023.1198391.

References

Desai N, Bagrodia A . The challenge of matching assays to biology in DNA damage response biomarkers for response to radiotherapy in bladder cancer. Transl Androl Urol. 2020; 8(Suppl 5):S514-S516. PMC: 6989838. DOI: 10.21037/tau.2019.07.05. View

Yin C, Zhu B, Zhang T, Liu T, Chen S, Liu Y . Pharmacological Targeting of STK19 Inhibits Oncogenic NRAS-Driven Melanomagenesis. Cell. 2019; 176(5):1113-1127.e16. DOI: 10.1016/j.cell.2019.01.002. View

Ssi S, Chraa D, El Azhary K, Sahraoui S, Olive D, Badou A . Prognostic Gene Expression Signature in Patients With Distinct Glioma Grades. Front Immunol. 2021; 12:685213. PMC: 8448281. DOI: 10.3389/fimmu.2021.685213. View

Petitprez F, Meylan M, De Reynies A, Sautes-Fridman C, Fridman W . The Tumor Microenvironment in the Response to Immune Checkpoint Blockade Therapies. Front Immunol. 2020; 11:784. PMC: 7221158. DOI: 10.3389/fimmu.2020.00784. View

Zhao L, Cheng Q, Wang Z, Xi Z, Xu D, Liu Y . Cisplatin binds to human copper chaperone Cox17: the mechanistic implication of drug delivery to mitochondria. Chem Commun (Camb). 2014; 50(20):2667-9. DOI: 10.1039/c3cc48847k. View

Chandler B, Moubadder L, Ritter C, Liu M, Cameron M, Wilder-Romans K . TTK inhibition radiosensitizes basal-like breast cancer through impaired homologous recombination. J Clin Invest. 2020; 130(2):958-973. PMC: 6994133. DOI: 10.1172/JCI130435. View

Kashiwagi E, Shiota M, Yokomizo A, Itsumi M, Inokuchi J, Uchiumi T . Downregulation of phosphodiesterase 4B (PDE4B) activates protein kinase A and contributes to the progression of prostate cancer. Prostate. 2012; 72(7):741-51. DOI: 10.1002/pros.21478. View

Wakula M, Balcerak A, Rubel T, Chmielarczyk M, Konopinski R, Lyczek F . The interactome of multifunctional HAX1 protein suggests its role in the regulation of energy metabolism, de-aggregation, cytoskeleton organization and RNA-processing. Biosci Rep. 2020; 40(11). PMC: 7670567. DOI: 10.1042/BSR20203094. View

Zhang X, Wang Y, A G, Qu C, Chen J . Pan-Cancer Analysis of PARP1 Alterations as Biomarkers in the Prediction of Immunotherapeutic Effects and the Association of Its Expression Levels and Immunotherapy Signatures. Front Immunol. 2021; 12:721030. PMC: 8438309. DOI: 10.3389/fimmu.2021.721030. View

10.

Leonardi G, Falzone L, Salemi R, Zanghi A, Spandidos D, McCubrey J . Cutaneous melanoma: From pathogenesis to therapy (Review). Int J Oncol. 2018; 52(4):1071-1080. PMC: 5843392. DOI: 10.3892/ijo.2018.4287. View

11.

Jing X, Yang F, Shao C, Wei K, Xie M, Shen H . Role of hypoxia in cancer therapy by regulating the tumor microenvironment. Mol Cancer. 2019; 18(1):157. PMC: 6844052. DOI: 10.1186/s12943-019-1089-9. View

12.

Clayton E, Pujol T, McDonald J, Qiu P . Leveraging TCGA gene expression data to build predictive models for cancer drug response. BMC Bioinformatics. 2020; 21(Suppl 14):364. PMC: 7526215. DOI: 10.1186/s12859-020-03690-4. View

13.

Ali R, Alabdullah M, Algethami M, Alblihy A, Miligy I, Shoqafi A . Ligase 1 is a predictor of platinum resistance and its blockade is synthetically lethal in XRCC1 deficient epithelial ovarian cancers. Theranostics. 2021; 11(17):8350-8361. PMC: 8344016. DOI: 10.7150/thno.51456. View

14.

Yang F, Li S, Cheng Y, Li J, Han X . Karyopherin α 2 promotes proliferation, migration and invasion through activating NF-κB/p65 signaling pathways in melanoma cells. Life Sci. 2020; 252:117611. DOI: 10.1016/j.lfs.2020.117611. View

15.

Li X, Cai Y . Risk stratification of cutaneous melanoma reveals carcinogen metabolism enrichment and immune inhibition in high-risk patients. Aging (Albany NY). 2020; 12(16):16457-16475. PMC: 7485700. DOI: 10.18632/aging.103734. View

16.

Hansen A, Arora P, Khayat M, Smith L, Lewis A, Rossetti L . Germline mutation in : a heterogeneous, multi-systemic developmental disorder characterized by transcriptional dysregulation. HGG Adv. 2021; 2(1). PMC: 7928427. DOI: 10.1016/j.xhgg.2020.100014. View

17.

Jiao S, Xia W, Yamaguchi H, Wei Y, Chen M, Hsu J . PARP Inhibitor Upregulates PD-L1 Expression and Enhances Cancer-Associated Immunosuppression. Clin Cancer Res. 2017; 23(14):3711-3720. PMC: 5511572. DOI: 10.1158/1078-0432.CCR-16-3215. View

18.

Yang C, Chang M, Chang C, Shyur L . Phytogalactolipid dLGG Inhibits Mouse Melanoma Brain Metastasis through Regulating Oxylipin Activity and Re-Programming Macrophage Polarity in the Tumor Microenvironment. Cancers (Basel). 2021; 13(16). PMC: 8391228. DOI: 10.3390/cancers13164120. View

19.

Farquhar N, Thornton S, Coupland S, Coulson J, Sacco J, Krishna Y . Patterns of BAP1 protein expression provide insights into prognostic significance and the biology of uveal melanoma. J Pathol Clin Res. 2018; 4(1):26-38. PMC: 5783957. DOI: 10.1002/cjp2.86. View

20.

Lee K, Nathan P . Cutaneous Melanoma - A Review of Systemic Therapies. Acta Derm Venereol. 2020; 100(11):adv00141. PMC: 9189748. DOI: 10.2340/00015555-3496. View