Dataset Information

MicroRNAs Expression Patterns Predict Tumor Mutational Burden in Colorectal Cancer.

ABSTRACT:

Background

Tumor mutational burden (TMB) could be a measure of response to immune checkpoint inhibitors therapy for patients with colorectal cancer (CRC). MicroRNAs (miRNAs) participate in anticancer immune responses. In the present study, we determined miRNA expression patterns in patients with CRC and built a signature that predicts TMB.

Methods

Next generation sequencing (NGS) on formalin-fixed paraffin-embedded samples from CRC patients was performed to measure TMB levels. We used datasets from The Cancer Genome Atlas to compare miRNA expression patterns in samples with high and low TMB from patients with CRC. We created an miRNA-based signature index using the selection operator (LASSO) and least absolute shrinkage method from the training set. We used an independent test set as internal validation. We used real-time polymerase chain reaction (RT-PCR) to validate the miRNA-based signature classifier.

Results

Twenty-seven samples from CRC patients underwent NGS to determine the TMB level. We identified four miRNA candidates in the training set for predicting TMB (N = 311). We used the test set (N = 204) for internal validation. The four-miRNA-based signature classifier was an accurate predictor of TMB, with accuracy 0.963 in the training set. In the test set, it was 0.902; and it was 0.946 in the total set. The classifier was superior to microsatellite instability (MSI) for predicting TMB in TCGA dataset. In the validation cohort, MSI status more positively correlated with TMB levels than did the classifier. Validation from RT-qPCR showed good target discrimination of the classifier for TMB prediction.

Conclusion

To our knowledge, this is the first miRNA-based signature classifier validated using high quality clinical data to accurately predict TMB level in patients with CRC.

SUBMITTER: Huang J

PROVIDER: S-EPMC7900489 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

MicroRNAs Expression Patterns Predict Tumor Mutational Burden in Colorectal Cancer.

Huang Jiahao J Liu Haizhou H Zhao Yang Y Luo Tao T Liu Jungang J Liu Junjie J Pan Xiaoyan X Tang Weizhong W

Frontiers in oncology 20210209

<h4>Background</h4>Tumor mutational burden (TMB) could be a measure of response to immune checkpoint inhibitors therapy for patients with colorectal cancer (CRC). MicroRNAs (miRNAs) participate in anticancer immune responses. In the present study, we determined miRNA expression patterns in patients with CRC and built a signature that predicts TMB.<h4>Methods</h4>Next generation sequencing (NGS) on formalin-fixed paraffin-embedded samples from CRC patients was performed to measure TMB levels. We ...[more]

PMID: 33634010

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Project description:BackgroundMicrosatellite unstable colorectal cancers (MSI+ CRCs) expressing PD-L1, respond to anti-PD-1 or anti-PD-L1 checkpoint blockade, whereas microsatellite-stable tumors do not respond the same. Our aim was to examine how the immune landscape relates to different aspects of the CRC's biology, including neoepitope burden.MethodsWe used TCGA data to stratify patients based on a cytolytic T-cell activity expression index and correlated immune cytolytic activity (CYT) with mutational, structural, and neoepitope features of each tumor sample. The expression of several immune checkpoints was verified in an independent cohort of 72 CRC patients, relative to their MSI status, using immunohistochemistry and RT-qPCR.ResultsCRC exhibits a range of intertumoral cytolytic T-cell activity, with lower cytolytic levels in the tumor, compared to the normal tissue. We separated CRC patients into CYT-high and CYT-low subgroups. High cytolytic activity correlated with increased mutational load in colon tumors, the count of MHC-I/-II classically defined and alternatively defined neoepitopes, high microsatellite instability and deregulated expression of several inhibitory immune checkpoints (VISTA, TIGIT, PD-1, IDO1, CTLA-4, and PD-L1, among others). Many immune checkpoint molecules (IDO1, LAG3, TIGIT, VISTA, PD-1, PD-L1 and CTLA-4) expressed significantly higher in MSI+ CRCs compared to MSS tumors. The expression of Treg markers was also significantly higher in CYT-high tumors. Both individual and simultaneous high levels of CTLA-4 and PD-L1 had a positive effect on the patients' overall survival. On the reverse, simultaneous low expression of both genes led to a significant shift towards negative effect. Assessed globally, CYT-low CRCs contained more recurrent somatic copy number alterations. PD-L1 protein was absent in most samples in the independent cohort and stained lowly in 33% of MSI CRCs. PD-L1+ CRCs stained moderately for CD8 and weakly for FOXP3. CYT-high colon tumors had higher TIL load, whereas CYT-high rectum tumors had higher TAN load compared to their CYT-low counterparts.ConclusionsOverall, we highlight the link between different genetic events and the immune microenvironment in CRC, taking into consideration the status of microsatellite instability. Our data provide further evidence that MSI+ and CYT-high tumors are better candidates for combinatorial checkpoint inhibition.

Project description:BackgroundLung cancer is the leading cause of cancer death worldwide. With the growing number of targeted therapies and the introduction of immuno-oncology (IO), personalized medicine has become standard of care in patients with metastatic disease. The development of predictive and prognostic biomarkers is of great importance. Mutational signatures harbor potential clinical value as predictors of therapy response in cancer. Here we set out to investigate particular mutational processes by assessing mutational signatures and associations with clinical features, tumor mutational burden (TMB) and targetable mutations.MethodsIn this retrospective study, we studied tumor DNA from patients with non-small cell lung cancer (NSCLC) irrespective of stage. The samples were sequenced using a 2 megabase (Mb) gene panel. On each sample TMB was determined and defined as the total number of single nucleotide mutations per Mb (mut/Mb) including non-synonymous mutations. Mutational signature profiling was performed on tumor samples in which at least 30 somatic single base substitutions (SBS) were detected.ResultsIn total 195 samples were sequenced. Median total TMB was 10.3 mut/Mb (range 0-109.3). Mutational signatures were evaluated in 76 tumor samples (39%; median TMB 15.2 mut/Mb). SBS signature 4 (SBS4), associated with tobacco smoking, was prominently present in 25 of 76 samples (33%). SBS2 and/or SBS13, both associated with activity of the AID/APOBEC family of cytidine deaminases, were observed in 11 of 76 samples (14%). SBS4 was significantly more present in early stages (I and II) versus advanced stages (III and IV; P = .005).ConclusionIn a large proportion of NSCLC patients tissue panel sequencing with a 2 Mb panel can be used to determine the mutational signatures. In general, mutational signature SBS4 was more often found in early versus advanced stages of NSCLC. Further studies are needed to determine the clinical utility of mutational signature analyses.

Dataset Information

MicroRNAs Expression Patterns Predict Tumor Mutational Burden in Colorectal Cancer.

Background

Methods

Results

Conclusion

Publications

MicroRNAs Expression Patterns Predict Tumor Mutational Burden in Colorectal Cancer.

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