scholarly journals Comprehensive analyses of m6A regulators and interactive coding and non-coding RNAs across 32 cancer types

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Sipeng Shen ◽  
Ruyang Zhang ◽  
Yue Jiang ◽  
Yi Li ◽  
Lijuan Lin ◽  
...  
Keyword(s):  
Wnt Signaling Pathway ◽  
Rna Modification ◽  
Cancer Type ◽  
Individual Level ◽  
Mutation Burden ◽  
Cancer Types ◽  
Unsupervised Approach ◽  
Single Cancer ◽  
Non Coding Rnas ◽  
Interactive Coding

AbstractN6-Methyladenosine (m6A) is an RNA modification that interacts with numerous coding and non-coding RNAs and plays important roles in the development of cancers. Nonetheless, the clinical impacts of m6A interactive genes on these cancers largely remain unclear since most studies focus only on a single cancer type. We comprehensively evaluated m6A modification patterns, including 23 m6A regulators and 83 interactive coding and non-coding RNAs among 9,804 pan-cancer samples. We used clustering analysis to identify m6A subtypes and constructed the m6A signature based on an unsupervised approach. We used the signatures to identify potential m6A modification targets across the genome. The prognostic value of one target was further validated in 3,444 samples from six external datasets. We developed three distinct m6A modification subtypes with different tumor microenvironment cell infiltration degrees: immunological, intermediate, and tumor proliferative. They were significantly associated with overall survival in 24 of 27 cancer types. Our constructed individual-level m6A signature was associated with survival, tumor mutation burden, and classical pathways. With the signature, we identified 114 novel genes as potential m6A targets. The gene shared most commonly between cancer types, BCL9L, is an oncogene and interacts with m6A patterns in the Wnt signaling pathway. In conclusion, m6A regulators and their interactive genes impact the outcome of various cancers. Evaluating the m6A subtype and the signature of individual tumors may inform the design of adjuvant treatments.

scholarly journals Integrative analyses of the RNA modification machinery reveal tissue- and cancer-specific signatures

2019 ◽  
Author(s):  
Oguzhan Begik ◽  
Morghan C. Lucas ◽  
Huanle Liu ◽  
Jose Miguel Ramirez ◽  
John S. Mattick ◽  
...  
Keyword(s):  
Cancer Research ◽  
Expression Patterns ◽  
Rna Modification ◽  
Cancer Type ◽  
Evolutionary Analysis ◽  
Rna Modifications ◽  
Human Samples ◽  
Mammalian Tissues ◽  
Normal Human ◽  
Cancer Types

ABSTRACTBackgroundRNA modifications play central roles in cellular fate and differentiation. These features have placed the epitranscriptome in the forefront of developmental biology and cancer research. However, the machinery responsible for placing, removing and recognizing more than 170 RNA modifications remains largely uncharacterized and poorly annotated, and we currently lack integrative studies that identify which RNA modification–related proteins (RMPs) may be dysregulated in each cancer type.ResultsHere we have performed a comprehensive annotation and evolutionary analysis of human RMPs as well as an integrative analysis of their expression patterns across 32 tissues, 10 species and 13,358 paired tumor-normal human samples. Our analysis reveals an unanticipated heterogeneity of RMP expression patterns across mammalian tissues, with a vast proportion of duplicated enzymes displaying testis-specific expression, suggesting a key role for RNA modifications in sperm formation and possibly intergenerational inheritance. Moreover, through the analysis of paired tumor-normal human samples we uncover many RMPs that are dysregulated in various types of cancer, and whose expression levels are predictive of cancer progression. Surprisingly, we find that several commonly studied RNA modification enzymes such as METTL3 or FTO, are not significantly up-regulated in most cancer types, once the sample is properly scaled and normalized to the full dataset, whereas several less-characterized RMPs, such as LAGE3 and HENMT1, are dysregulated in many cancers.ConclusionsOur analyses reveal an unanticipated heterogeneity in the expression patterns of RMPs across mammalian tissues, and uncover a large proportion of dysregulated RMPs in multiple cancer types. We provide novel targets for future cancer research studies targeting the human epitranscriptome, as well as foundations to understand cell type-specific behaviours that are orchestrated by RNA modifications.

scholarly journals Cancer Type-Dependent Correlations betweenTP53Mutations and Antitumor Immunity

2019 ◽  
Author(s):  
Lin Li ◽  
Mengyuan Li ◽  
Xiaosheng Wang
Keyword(s):  
Antitumor Immunity ◽  
Colon Adenocarcinoma ◽  
Joint Effect ◽  
The Cancer Genome Atlas ◽  
Cancer Type ◽  
Mutation Burden ◽  
Cancer Genome Atlas ◽  
Negative Role ◽  
Stomach Adenocarcinoma ◽  
Cancer Types

AbstractMany studies have shown thatTP53mutations play a negative role in antitumor immunity. However, a few studies reported thatTP53mutations could promote antitumor immunity. To explain these contradictory findings, we analyzed five cancer cohorts from The Cancer Genome Atlas (TCGA) project. We found thatTP53-mutated cancers had significantly higher levels of antitumor immune signatures thanTP53-wildtype cancers in breast invasive carcinoma (BRCA) and lung adenocarcinoma (LUAD). In contrast,TP53-mutated cancers had significantly lower antitumor immune signature levels thanTP53-wildtype cancers in stomach adenocarcinoma (STAD), colon adenocarcinoma (COAD), and head and neck squamous cell carcinoma (HNSC). Moreover,TP53-mutated cancers likely had higher tumor mutation burden (TMB) and tumor aneuploidy level (TAL) thanTP53-wildtype cancers. However, the TMB differences were more marked betweenTP53-mutated andTP53-wildtype cancers than the TAL differences in BRCA and LUAD, and the TAL differences were more significant in STAD and COAD. Furthermore, we showed that TMB and TAL had a positive and a negative correlation with antitumor immunity and that TMB affected antitumor immunity more greatly than TAL did in BRCA and LUAD while TAL affected antitumor immunity more strongly than TMB in STAD and HNSC. These findings indicate that the distinct correlations betweenTP53mutations and antitumor immunity in different cancer types are a consequence of the joint effect of the altered TMB and TAL caused byTP53mutations on tumor immunity. Our data suggest that theTP53mutation status could be a useful biomarker for cancer immunotherapy response depending on cancer types.

Tumor mutation burden analysis in a 5,660 cancer patient cohort reveals cancer type-specific mechanisms for high mutation burden.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2589-2589
Author(s):  
Xiaodong Jiao ◽  
Xiaochun Zhang ◽  
Baodong Qin ◽  
Dong Liu ◽  
Liang Liu ◽  
...  
Keyword(s):  
Effective Means ◽  
Lung Squamous Cell Carcinoma ◽  
Biological Pathways ◽  
Formalin Fixed Paraffin Embed ◽  
Cancer Type ◽  
Biological Mechanisms ◽  
Tumor Mutation Burden ◽  
Molecular Features ◽  
Mutation Burden ◽  
Cancer Types

2589 Background: Tumor mutation burden (TMB), calculated by whole-exome sequencing (WES) or large NGS panels, has an important association with immunotherapy responses. Elucidating the underlying biological mechanisms of high TMB might help develop more precise and effective means for TMB and immunotherapy response prediction. Meanwhile, the landscape of TMB across different cancer types and its association with other molecular features have not been well investigated in large cohorts in China. Methods: Cancer patients whose fresh tissue (n = 1556), formalin-fixed, paraffin-embed (FFPE) specimen (n = 1794), and pleural fluid (n = 84) were profiled using 295- or 520-gene NGS panel. The association of the TMB status with a series of molecular features and biological pathways was interrogated using bootstrapping. Results: TMB, measured by 295- or 520-cancer-related gene panels, were correlated with WES TMB based on in silico simulation in the TCGA cohort. We compared the TMB landscape across 11 cancer type groups and found the highest average TMB in lung squamous cell carcinoma, whereas the lowest TMB was established in sarcoma. High microsatellite instability, DNA damage response deficiency, and homologous recombination repair deficiency indicated significantly higher TMB. The independent predictive power for TMB of twenty-six biological pathways was tested in 10 cancer groups. FoxO signaling pathway most commonly correlated with low-TMB; significant association was identified in four cancer groups. In contrast, no pathway was significantly correlated with high-TMB in more than two cancer groups. Overall, we discovered that the underlying pathways which may be the main drivers of TMB status varied greatly and sometimes had an opposite association with TMB across different cancer types. Moreover, we developed a 14- and 22-gene signature for TMB prediction for LUAD and LUSC, respectively, with only 10 genes shared by both signatures, indicating a histology-specific mechanism for driving high-TMB in lung cancer. Conclusions: The findings extended the knowledge of the underlying biological mechanisms for high TMB and might be helpful for developing more precise and accessible TMB assessment panels and algorithms in more cancer types.

scholarly journals m6A target microRNAs in serum for cancer detection

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Bo Zhang ◽  
Zhenmei Chen ◽  
Baorui Tao ◽  
Chenhe Yi ◽  
Zhifei Lin ◽  
...  
Keyword(s):  
Cancer Detection ◽  
External Validation ◽  
High Accuracy ◽  
Rna Modification ◽  
Support Vector ◽  
Cancer Type ◽  
Mass Detection ◽  
Serum Samples ◽  
Multiple Cancer ◽  
Cancer Types

AbstractRecent studies have revealed the significant dysregulation of m6A level in peripheral blood in several cancer types and its value in diagnosis. Nonetheless, a biomarker for accurate screening of multiple cancer types has not been established based on the perspective of m6A modification. In this study, we aimed to develop a serum diagnostic signature based on the m6A target miRNAs for the mass detection of cancer. A total of 14965 serum samples with 12 cancer types were included. Based on training cohort (n=7299), we developed the m6A-miRNAs signature using a support vector machine algorithm for cancer detection. The m6A-miRNAs signature showed high accuracy, and its area under the curve (AUC) in the training, internal validation and external validation cohort reached 0.979 (95%CI 0.976 - 0.982), 0.976 (95%CI 0.973 - 0.979) and 0.936 (95%CI 0.922 - 0.951), respectively. In the performance of distinguishing cancer types, the m6A-miRNAs signature showed superior sensitivity in each cancer type and presented a satisfactory AUC in identifying lung cancer, gastric cancer and hepatocellular carcinoma. Additionally, the diagnostic performance of m6A-miRNAs was not interfered by the gender, age and benign disease. In short, this study revealed the value of serum circulating m6A miRNAs in cancer detection and provided a new direction and strategy for the development of novel biomarkers with high accuracy, low cost and less invasiveness for mass cancer screening, such as RNA modification.

Mutation burden as a biomarker of response to immune checkpoint therapy in nine solid cancers.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 35-35 ◽  
Author(s):  
Shridar Ganesan ◽  
Gyan Bhanot ◽  
Janice M. Mehnert ◽  
Ann W. Silk ◽  
Jeffrey S. Ross ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
T Cells ◽  
Immune Checkpoint ◽  
Solid Cancer ◽  
Cancer Type ◽  
Her2 Breast Cancer ◽  
Mutation Burden ◽  
Gene Expression Signatures ◽  
Cancer Types

35 Background: A high mutation burden a biomarker of response to immune checkpoint therapy in melanoma, non-small cell lung cancer, and colorectal cancer. It is unknown whether mutation burden is predictive of response in other cancer types, and whether it is identifiable using available clinical assays. Methods: Using data for 10,745 tumors from 33 solid cancer types in TCGA, we looked for a mutation burden threshold (iCAM) in each cancer type associated with gene expression signatures of a blocked immune response of robust CD8+T cell response and up-regulation of immune checkpoint genes. Results: A unique iCAM threshold was identified in nine cancers: melanoma and lung, colon, endometrial, and gastric adenocarcinoma; serous ovarian, bladder urothelial, cervical, and ER+ HER2− breast cancer. iCAM thresholds applied to published clinical data for patients treated with immune checkpoint therapy showed that iCAM+ patients had significantly better response. iCAM+ tumors can be identified from clinical-grade NGS assays with high accuracy . In a prospective melanoma cohort of patients treated with anti- PD-1 patients with iCAM+ tumors had significantly better objective response rates, progression free survival, and overall survival compared patients to iCAM− tumors. Pattern of somatic mutations were different in iCAM+ and iCAM− tumors, suggesting different mechanism of carcinogenesis in iCAM+ versus iCAM− tumors. Higher fractions of leukocytes were NK (Natural Killer) cells and macrophages were M1 polarized, and a lower fraction of T cells were regulatory T cells in iCAM+ tumors compared to iCAM− tumors. Over 75% of the genes significantly up-regulated in iCAM+ tumors in every cancer types were in the immune response pathway, confirming immune response to be the main differentiator in iCAM+ veruss iCAM− tumors. Conclusions: In nine cancer types, a clinically useful mutation burden threshold (iCAM) associated with gene expression signatures of blocked immune response can identify likely responders to immune checkpoint therapy, and iCAM status is identifiable using currently available clinical NGS assays.

Pan-cancer opportunities for off-label immunotherapy based on nonsynonymous mutation burden.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 14-14
Author(s):  
Todd Cory Knepper ◽  
Jamie K. Teer ◽  
Christine Marie Walko ◽  
Howard L. McLeod
Keyword(s):  
Clinical Benefit ◽  
Solid Cancer ◽  
Cancer Type ◽  
Synonymous Mutation ◽  
Nonsynonymous Mutation ◽  
Off Label ◽  
Action Committee ◽  
Mutation Burden ◽  
Cancer Types

14 Background: In an effort to better predict which cancer patients (pts) are more likely to derive clinical benefit from immunotherapy, an association between increased non-synonymous mutation burden and likelihood of clinical response has been described. This study reports the mutation burden of pts with a variety of advanced cancers within a real-world clinical genomics database in order to highlight opportunities where off-label immunotherapy can be considered. Methods: For each solid cancer assayed by FoundationOne within Moffitt’s Clinical Genomic Action Committee (CGAC) database, a non-synonymous mutation burden was determined. Pts were then grouped by cancer type and descriptive statistics used to describe the mutation burden. For cancers with at least 5 cases, the percentage of pts with a non-synonymous mutation burden exceeding a threshold shown to be suggestive of clinical benefit from immunotherapy ( ≥ 13) is reported. The threshold was derived via linear regression from the “intermediate-high” mutation burden classification of the FoundationOne assay. Results: 520 pts received a FoundationOne test. The median non-synonymous mutation burden was 7 and the mean was 11.4. More pts with cancers that have demonstrated response to immunotherapy had a mutation burden exceeding the threshold (19.7% for lung – 45.0% for melanoma). Pt tumors from cancer types without immunotherapy indications sometimes (5.0% for salivary gland – 10.5% for breast and colorectal cancer) exceeded mutation threshold suggestive of benefit. Conclusions: A meaningful proportion of pts with cancer types without FDA-approved immunotherapies have a mutation burden for which immunotherapy may represent a clinical consideration. [Table: see text]

scholarly journals Genomic and Immunologic Correlates of Indoleamine 2,3-Dioxygenase Pathway Expression in Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Anshuman Panda ◽  
Shridar Ganesan
Keyword(s):  
Clinical Trials ◽  
Phase Iii ◽  
Cancer Type ◽  
Over Expression ◽  
Indoleamine 2,3 Dioxygenase ◽  
Her2 Breast Cancer ◽  
Specific Subset ◽  
Pathway Expression ◽  
Mutation Burden ◽  
Cancer Types

Immune checkpoint blockade leads to unprecedented responses in many cancer types. An alternative method of unleashing anti-tumor immune response is to target immunosuppressive metabolic pathways like the indoleamine 2,3-dioxygenase (IDO) pathway. Despite promising results in Phase I/II clinical trials, an IDO-1 inhibitor did not show clinical benefit in a Phase III clinical trial. Since, a treatment can be quite effective in a specific subset without being effective in the whole cancer type, it is important to identify the subsets of cancers that may benefit from IDO-1 inhibitors. In this study, we looked for the genomic and immunologic correlates of IDO pathway expression in cancer using the Cancer Genome Atlas (TCGA) dataset. Strong CD8+ T-cell infiltration, high mutation burden, and expression of exogenous viruses [Epstein-Barr virus (EBV), Human papilloma virus (HPV), and Hepatitis C virus (HCV)] or endogenous retrovirus (ERV3-2) were associated with over-expression of IDO-1 in most cancer types, IDO-2 in many cancer types, and TDO-2 in a few cancer types. High mutation burden in ER+ HER2− breast cancer, and ERV3-2 expression in ER− HER2− and HER2+ breast, colon, and endometrial cancers were associated with over-expression of all three genes. These results may have important implications for guiding development clinical trials of IDO-1 inhibitors.

scholarly journals Proportion of children with cancer that have an indication for genetic counseling and testing based on the cancer type irrespective of other features

2021 ◽  
Author(s):  
Thi Minh Kha Nguyen ◽  
Astrid Behnert ◽  
Torsten Pietsch ◽  
Christian Vokuhl ◽  
Christian Peter Kratz
Keyword(s):  
Childhood Cancer ◽  
Rhabdoid Tumor ◽  
Juvenile Myelomonocytic Leukemia ◽  
Cancer Type ◽  
Nerve Sheath Tumor ◽  
Children With Cancer ◽  
Pediatric Pathology ◽  
Cancer Trial ◽  
Cancer Predisposition Syndrome ◽  
Cancer Types

Abstract In children with cancer, specific clinical features such as physical anomalies, occurrence of cancer in young relatives, specific cancer histologies, and unique mutation/methylation signatures may indicate the presence of an underlying cancer predisposition syndrome (CPS). The proportion of children with a cancer type suggesting a CPS among all children with cancer is unknown. To determine the proportion of children with cancer types suggesting an underlying CPS among children with cancer. We evaluated the number of children with cancer types strongly associated with CPS diagnosed in Germany between 2007 and 2016. Data were obtained from various sources including two national pediatric pathology reference laboratories for brain and solid tumors, respectively, various childhood cancer trial offices as well as the German Childhood Cancer Registry. Among 21,127 children diagnosed with cancer between 2007 and 2016, 2554 (12.1%) had a cancer type strongly associated with a CPS. The most common diagnoses were myelodysplastic syndrome and juvenile myelomonocytic leukemia, retinoblastoma, malignant peripheral nerve sheath tumor, infantile myofibromatosis, medulloblastomaSHH, rhabdoid tumor as well as atypical teratoid/rhabdoid tumor. Based on cancer type only, 12.1% of all children with cancer have an indication for a genetic evaluation. Pediatric oncology patients require access to genetic counselling and testing.

scholarly journals Non-Coding RNAs as Prognostic Markers for Endometrial Cancer

2021 ◽  
Vol 22 (6) ◽  
pp. 3151 ◽  
Author(s):  
Roberto Piergentili ◽  
Simona Zaami ◽  
Anna Franca Cavaliere ◽  
Fabrizio Signore ◽  
Giovanni Scambia ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Prognostic Markers ◽  
Classification Systems ◽  
Prognostic Role ◽  
Protein Coding ◽  
Pathological Characteristics ◽  
Epigenetic Events ◽  
Cancer Types ◽  
Non Coding Rnas

Endometrial cancer (EC) has been classified over the years, for prognostic and therapeutic purposes. In recent years, classification systems have been emerging not only based on EC clinical and pathological characteristics but also on its genetic and epigenetic features. Noncoding RNAs (ncRNAs) are emerging as promising markers in several cancer types, including EC, for which their prognostic value is currently under investigation and will likely integrate the present prognostic tools based on protein coding genes. This review aims to underline the importance of the genetic and epigenetic events in the EC tumorigenesis, by expounding upon the prognostic role of ncRNAs.

scholarly journals Estimating the predictive power of silent mutations on cancer classification and prognosis

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Tal Gutman ◽  
Guy Goren ◽  
Omri Efroni ◽  
Tamir Tuller
Keyword(s):  
Gene Expression ◽  
Predictive Power ◽  
Predictive Ability ◽  
Cancer Classification ◽  
Silent Mutation ◽  
Cancer Type ◽  
Coding Region ◽  
Probability Of Survival ◽  
Diagnosis And Prognosis ◽  
Cancer Types

AbstractIn recent years it has been shown that silent mutations, in and out of the coding region, can affect gene expression and may be related to tumorigenesis and cancer cell fitness. However, the predictive ability of these mutations for cancer type diagnosis and prognosis has not been evaluated yet. In the current study, based on the analysis of 9,915 cancer genomes and approximately three million mutations, we provide a comprehensive quantitative evaluation of the predictive power of various types of silent and non-silent mutations over cancer classification and prognosis. The results indicate that silent-mutation models outperform the equivalent null models in classifying all examined cancer types and in estimating the probability of survival 10 years after the initial diagnosis. Additionally, combining both non-silent and silent mutations achieved the best classification results for 68% of the cancer types and the best survival estimation results for up to nine years after the diagnosis. Thus, silent mutations hold considerable predictive power over both cancer classification and prognosis, most likely due to their effect on gene expression. It is highly advised that silent mutations are integrated in cancer research in order to unravel the full genomic landscape of cancer and its ramifications on cancer fitness.

Sign in / Sign up

Export Citation Format

Share Document