Significance of tumor mutation burden combined with immune infiltrates in the progression and prognosis of ovarian cancer

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Abstract

Background

Ovarian cancer (OC) is the most malignant tumor in the female reproductive system. About 75% of OC in complete remission of clinical symptoms still develop a recurrence. Therefore, searching for new treatment methods plays an important role in improving the prognosis of OC.

Methods

We downloaded the MAF files, RNA-seq data and clinical information from the TCGA database. The “maftools” package in R software was used to visualize the OC mutation data. We calculated the tumor mutation burden (TMB) of OC and analyzed its correlation with clinicopathological parameters and prognostic value. Tumor mutation burden related signature model was constructed to predict the overall survival (OS) of OC.

Results

The results revealed that there was a statistical correlation between TMB and FIGO stage, grade and tumor residual size of ovarian cancer patients. The Kaplan–Meier curve indicated that a high TMB is associated with better clinical outcomes of OC. The difference analysis indicated 24 upregulated genes and 619 downregulated genes in the high-TMB group compared with the low-TMB group. Besides, the TMBRS model based on five hub genes (RBMS3, PLA2G5, CDH2, AMHR2 and ADAMTS8) was constructed to predict the OS of OC. The ROC curve and validation data sets all revealed that the TMBRS model was reliable in predicting recurrence risk. Immune microenvironment analysis indicated the correlations between TMB and infiltrating immune cells.

Conclusions

Our results suggest that TMB plays an important role in the prognosis and guiding immunotherapy of OC. By detecting the TMB of OC, clinicians can more accurately treat patients with immunotherapy, thereby improving their survival rate.

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Most cited references 12

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Recent progress in the diagnosis and treatment of ovarian cancer.

Danijela Jelovac, Deborah Armstrong (2011)

Epithelial ovarian cancer is the most lethal of the gynecologic malignancies, largely due to the advanced stage at diagnosis in most patients. Screening strategies using ultrasound and the cancer antigen (CA) 125 tumor marker are currently under study and may lower stage at diagnosis but have not yet been shown to improve survival. Women who have inherited a deleterious mutation in the BRCA1 or BRCA2 gene and those with the Lynch syndrome (hereditary nonpolyposis colorectal cancer) have the highest risk of developing ovarian cancer but account for only approximately 10% of those with the disease. Other less common and less well-defined genetic syndromes may increase the risk of ovarian cancer, but their contribution to genetic risk is small. A clear etiology for sporadic ovarian cancer has not been identified, but risk is affected by reproductive and hormonal factors. Surgery has a unique role in ovarian cancer, as it is used not only for diagnosis and staging but also therapeutically, even in patients with widely disseminated, advanced disease. Ovarian cancer is highly sensitive to chemotherapy drugs, particularly the platinum agents, and most patients will attain a remission with initial treatment. Recent advances in the delivery of chemotherapy using the intraperitoneal route have further improved survival after initial therapy. Although the majority of ovarian cancer patients will respond to initial chemotherapy, most will ultimately develop disease recurrence. Chemotherapy for recurrent disease includes platinum-based, multiagent regimens for women whose disease recurs more than 6 to 12 months after the completion of initial therapy and sequential single agents for those whose disease recurs earlier. New targeted biologic agents, particularly those involved with the vascular endothelial growth factor pathway and those targeting the poly (ADP-ribose) polymerase (PARP) enzyme, hold great promise for improving the outcome of ovarian cancer.

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Human breast cancer cells educate macrophages toward the M2 activation status

Sofia Sousa, Régis Brion, Minnamaija Lintunen … (2015)

Introduction The immune system plays a major role in cancer progression. In solid tumors, 5-40 % of the tumor mass consists of tumor-associated macrophages (TAMs) and there is usually a correlation between the number of TAMs and poor prognosis, depending on the tumor type. TAMs usually resemble M2 macrophages. Unlike M1-macrophages which have pro-inflammatory and anti-cancer functions, M2-macrophages are immunosuppressive, contribute to the matrix-remodeling, and hence favor tumor growth. The role of TAMs is not fully understood in breast cancer progression. Methods Macrophage infiltration (CD68) and activation status (HLA-DRIIα, CD163) were evaluated in a large cohort of human primary breast tumors (562 tissue microarray samples), by immunohistochemistry and scored by automated image analysis algorithms. Survival between groups was compared using the Kaplan-Meier life-table method and a Cox multivariate proportional hazards model. Macrophage education by breast cancer cells was assessed by ex vivo differentiation of peripheral blood mononuclear cells (PBMCs) in the presence or absence of breast cancer cell conditioned media (MDA-MB231, MCF-7 or T47D cell lines) and M1 or M2 inducing cytokines (respectively IFN-γ, IL-4 and IL-10). Obtained macrophages were analyzed by flow cytometry (CD14, CD16, CD64, CD86, CD200R and CD163), ELISA (IL-6, IL-8, IL-10, monocyte colony stimulating factor M-CSF) and zymography (matrix metalloproteinase 9, MMP-9). Results Clinically, we found that high numbers of CD163+ M2-macrophages were strongly associated with fast proliferation, poor differentiation, estrogen receptor negativity and histological ductal type (p<0.001) in the studied cohort of human primary breast tumors. We demonstrated ex vivo that breast cancer cell-secreted factors modulate macrophage differentiation toward the M2 phenotype. Furthermore, the more aggressive mesenchymal-like cell line MDA-MB231, which secretes high levels of M-CSF, skews macrophages toward the more immunosuppressive M2c subtype. Conclusions This study demonstrates that human breast cancer cells influence macrophage differentiation and that TAM differentiation status correlates with recurrence free survival, thus further emphasizing that TAMs can similarly affect therapy efficacy and patient outcome. Electronic supplementary material The online version of this article (doi:10.1186/s13058-015-0621-0) contains supplementary material, which is available to authorized users.

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PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers

Géraldine Gentric, Yann Kieffer, Virginie Mieulet … (2019)

Summary High-grade serous ovarian cancer (HGSOC) remains an unmet medical challenge. Here, we unravel an unanticipated metabolic heterogeneity in HGSOC. By combining proteomic, metabolomic, and bioergenetic analyses, we identify two molecular subgroups, low- and high-OXPHOS. While low-OXPHOS exhibit a glycolytic metabolism, high-OXPHOS HGSOCs rely on oxidative phosphorylation, supported by glutamine and fatty acid oxidation, and show chronic oxidative stress. We identify an important role for the PML-PGC-1α axis in the metabolic features of high-OXPHOS HGSOC. In high-OXPHOS tumors, chronic oxidative stress promotes aggregation of PML-nuclear bodies, resulting in activation of the transcriptional co-activator PGC-1α. Active PGC-1α increases synthesis of electron transport chain complexes, thereby promoting mitochondrial respiration. Importantly, high-OXPHOS HGSOCs exhibit increased response to conventional chemotherapies, in which increased oxidative stress, PML, and potentially ferroptosis play key functions. Collectively, our data establish a stress-mediated PML-PGC-1α-dependent mechanism that promotes OXPHOS metabolism and chemosensitivity in ovarian cancer.

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Author and article information

Contributors

Qing Yang:

ORCID: http://orcid.org/0000-0002-7324-6103

yangqing_sj@126.com

Journal

Journal ID (nlm-ta): Cancer Cell Int

Journal ID (iso-abbrev): Cancer Cell Int

Title: Cancer Cell International

Publisher: BioMed Central (London )

ISSN (Electronic): 1475-2867

Publication date (Electronic): 5 August 2020

Publication date PMC-release: 5 August 2020

Publication date Collection: 2020

Volume: 20

Electronic Location Identifier: 373

Affiliations

[1 ]GRID grid.412467.2, ISNI 0000 0004 1806 3501, Department of Obstetrics and Gynecology, , Shengjing Hospital of China Medical University, ; NO. 36 Sanhao Road, Shenyang, 110000 China

[2 ]GRID grid.268505.c, ISNI 0000 0000 8744 8924, Department of Ultrasound, , Jiangnan Hospital Affiliated to Zhejiang University of Traditional Chinese Medicine, ; Hangzhou, China

Author information

Qing Yang http://orcid.org/0000-0002-7324-6103

Article

Publisher ID: 1472

DOI: 10.1186/s12935-020-01472-9

PMC ID: 7405355

PubMed ID: 32774167

SO-VID: 4d25a056-017c-4249-8e37-c9c0c7de99e1

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 18 January 2020

Date accepted : 31 July 2020

Funding

Funded by: the National Natural Science Foundation of China

Award ID: (No. 81872125)

Award Recipient : Qing Yang

Funded by: the Promotion Project of Standardized Diagnosis and Treatment Technology

Award ID: No. LNCCC‐ a01‐2015

Award Recipient : Qing Yang

Funded by: Basic and Clinical Research on the Accurate Treatment of OC Based on Dig Data from China Medical University Subject Ascension Project in 2017

Award ID: No. 2017CXTD05

Award Recipient : Qing Yang

Funded by: Shengjing Free Researcher Project

Award ID: No. 201704

Award Recipient : Qing Yang

Funded by: The mechanism of miRNA-130 regulating PARP-1 resistance in OC

Award ID: No.201601128

Award Recipient : Fangfang Bi

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: oc,tiics,prognosis,tmb,maftools,cibersort,cmap

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: oc, tiics, prognosis, tmb, maftools, cibersort, cmap

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Significance of tumor mutation burden combined with immune infiltrates in the progression and prognosis of ovarian cancer

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Abstract

Background

Methods

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Conclusions

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Karger: Oncology

Most cited references 12

Recent progress in the diagnosis and treatment of ovarian cancer.

Human breast cancer cells educate macrophages toward the M2 activation status

PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers

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Cited by 36

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