scholarly journals The association between tumor mutational burden and prognosis is dependent on treatment context

2021 ◽  
Vol 53 (1) ◽  
pp. 11-15
Author(s):  
Cristina Valero ◽  
Mark Lee ◽  
Douglas Hoen ◽  
Jingming Wang ◽  
Zaineb Nadeem ◽  
...  
Keyword(s):  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Treatment Context

scholarly journals NCMP-17. MISMATCH REPAIR MUTATIONS AND THE CENTRAL NERVOUS SYSTEM: A CASE SERIES OF GERMLINE MUTATIONS AND CNS MALIGNANCY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii126-ii126
Author(s):  
Amber Ruiz ◽  
Jerome Graber
Keyword(s):  
Treatment Response ◽  
Mismatch Repair ◽  
Case Series ◽  
Germline Mutations ◽  
Molecular Characteristics ◽  
Loss Of Function ◽  
Dna Mismatch ◽  
Mutational Burden ◽  
Increased Risk ◽  
Tumor Mutational Burden

Abstract Our understanding of genetic predispositions for malignancy is continually evolving. One family of germline mutations well described in the literature is that of the DNA mismatch repair mechanism (MMR). Lynch syndrome (LS) is due to a loss of function mutation of several MMR genes- MSH2, MLH1, MSH6, and PMS2. Germline MMR mutations lead to microsatellite instability and loss of genomic integrity resulting in an increased risk for various cancers (colorectal, genitourinary, etc). LS may be as common as 1 in 400 people and some MMR mutations have been associated with gliomas. There is a paucity of information regarding frequency of glioma subtypes as well as tumor genetic and molecular characteristics which have important clinical implications. We describe a case series of 6 individuals with germline MMR mutations and brain tumors. Those with MSH2 and PMS2 mutations (n=3) developed glioblastomas at a mean age at diagnosis of 48 years. These tumors expressed MGMT hyper-methylation and high tumor mutational burden. Only one had IDH-1 mutation. Those with MLH1 mutations (n=3), did not develop gliomas. This raises the question of differential glioma subtype development based on MMR gene. It also highlights the possibility of Lynch-associated gliomas having more favorable treatment response due to MGMT methylation and potential response to immunotherapy based on high tumor mutational burden. Though the sample size is small, there appears to be a preponderance of women compared to men (5:1 respectively). Larger studies are needed to verify CNS involvement in germline MMR mutations. In doing so, we hope to identify factors that may influence clinical management and lead to a better understanding of treatment response and disease prognosis.

Comprehensive exploration of tumor mutational burden and immune infiltration in diffuse glioma

2021 ◽  
Vol 96 ◽  
pp. 107610
Author(s):  
Kai Kang ◽  
Fucun Xie ◽  
Yijun Wu ◽  
Zhile Wang ◽  
Li Wang ◽  
...  
Keyword(s):  
Diffuse Glioma ◽  
Immune Infiltration ◽  
Mutational Burden ◽  
Tumor Mutational Burden

scholarly journals Tumor mutational burden assessment in non-small-cell lung cancer samples: results from the TMB2 harmonization project comparing three NGS panels

2021 ◽  
Vol 9 (5) ◽  
pp. e001904
Author(s):  
Javier Ramos-Paradas ◽  
Susana Hernández-Prieto ◽  
David Lora ◽  
Elena Sanchez ◽  
Aranzazu Rosado ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Predictive Value ◽  
Predictive Biomarker ◽  
Small Cell ◽  
Small Cell Lung ◽  
Mutational Burden ◽  
Reproducibility Study ◽  
Tumor Mutational Burden

BackgroundTumor mutational burden (TMB) is a recently proposed predictive biomarker for immunotherapy in solid tumors, including non-small cell lung cancer (NSCLC). Available assays for TMB determination differ in horizontal coverage, gene content and algorithms, leading to discrepancies in results, impacting patient selection. A harmonization study of TMB assessment with available assays in a cohort of patients with NSCLC is urgently needed.MethodsWe evaluated the TMB assessment obtained with two marketed next generation sequencing panels: TruSight Oncology 500 (TSO500) and Oncomine Tumor Mutation Load (OTML) versus a reference assay (Foundation One, FO) in 96 NSCLC samples. Additionally, we studied the level of agreement among the three methods with respect to PD-L1 expression in tumors, checked the level of different immune infiltrates versus TMB, and performed an inter-laboratory reproducibility study. Finally, adjusted cut-off values were determined.ResultsBoth panels showed strong agreement with FO, with concordance correlation coefficients (CCC) of 0.933 (95% CI 0.908 to 0.959) for TSO500 and 0.881 (95% CI 0.840 to 0.922) for OTML. The corresponding CCCs were 0.951 (TSO500-FO) and 0.919 (OTML-FO) in tumors with <1% of cells expressing PD-L1 (PD-L1<1%; N=55), and 0.861 (TSO500-FO) and 0.722 (OTML-FO) in tumors with PD-L1≥1% (N=41). Inter-laboratory reproducibility analyses showed higher reproducibility with TSO500. No significant differences were found in terms of immune infiltration versus TMB. Adjusted cut-off values corresponding to 10 muts/Mb with FO needed to be lowered to 7.847 muts/Mb (TSO500) and 8.380 muts/Mb (OTML) to ensure a sensitivity >88%. With these cut-offs, the positive predictive value was 78.57% (95% CI 67.82 to 89.32) and the negative predictive value was 87.50% (95% CI 77.25 to 97.75) for TSO500, while for OTML they were 73.33% (95% CI 62.14 to 84.52) and 86.11% (95% CI 74.81 to 97.41), respectively.ConclusionsBoth panels exhibited robust analytical performances for TMB assessment, with stronger concordances in patients with negative PD-L1 expression. TSO500 showed a higher inter-laboratory reproducibility. The cut-offs for each assay were lowered to optimal overlap with FO.

scholarly journals Identification and validation of a miRNA-related expression signature for tumor mutational burden in colorectal cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Lijun Xu ◽  
Qing Zheng
Keyword(s):  
Colorectal Cancer ◽  
Immune Response ◽  
Validation Cohort ◽  
Expression Profiles ◽  
Functional Enrichment ◽  
Immune Checkpoints ◽  
Positive Correlation ◽  
Expression Signature ◽  
Mutational Burden ◽  
Tumor Mutational Burden

Abstract Background Tumor mutational burden (TMB) is a promising predictor, which could stratify colorectal cancer (CRC) patients based on the response to immune checkpoint inhibitors (ICIs). MicroRNAs (miRNAs) act as the key regulators of anti-cancer immune response. However, the relationship between TMB and miRNA expression profiles is not elucidated in CRC. Methods Differentially expressed miRNAs (DE miRNAs) between the TMBhigh group and the TMBlow group were identified for the CRC cohort of the TCGA database. In the training cohort, a miRNA-related expression signature for predicting TMB level was developed by the least absolute shrinkage and selection operator (LASSO) method and tested with reference to its discrimination, calibration, and decision curve analysis (DCA) in the validation cohort. Functional enrichment analysis of these TMB-related miRNAs was performed. The correlation between this miRNA-related expression signature and three immune checkpoints was analyzed. Results Twenty-one out of 43 DE miRNAs were identified as TMB-related miRNAs, which were used to develop a miRNA-related expression signature. This TMB-related miRNA signature demonstrated great discrimination (AUCtest set = 0.970), satisfactory calibration (P > 0.05), and clinical utility in the validation cohort. Functional enrichment results revealed that these TMB-related miRNAs were mainly involved in biological processes associated with immune response and signaling pathways related with cancer. This miRNA-related expression signature showed a median positive correlation with PD-L1 (R = 0.47, P < 0.05) and CTLA4 (R = 0.39, P < 0.05) and a low positive correlation with PD-1 (R = 0.16, P < 0.05). Conclusion This study presents a miRNA-related expression signature which could stratify CRC patients with different TMB levels.

scholarly journals Cytotoxic T-lymphocyte infiltration and chemokine predict long-term patient survival independently of tumor mutational burden in triple-negative breast cancer

2021 ◽  
Vol 13 ◽  
pp. 175883592110066
Author(s):  
Eriko Katsuta ◽  
Li Yan ◽  
Mateusz Opyrchal ◽  
Pawel Kalinski ◽  
Kazuaki Takabe
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Patient Survival ◽  
Cytotoxic T Lymphocyte ◽  
Breast Cancer Patients ◽  
Mutational Burden ◽  
Cancer Immunity ◽  
Anti Cancer ◽  
Tumor Mutational Burden ◽  
Patient Prognosis

Background: Cytotoxic T-lymphocyte (CTL) infiltration into tumor is a positive prognostic factor in breast cancer. High tumor mutational burden (TMB) is also considered as a predictor of tumor immunogenicity and response to immunotherapy. However, it is unclear whether the infiltration of functional CTL simply reflects the TMB or represents an independent prognostic value. Methods: Utilizing The Cancer Genome Atlas (TCGA) breast cancer cohort, we established the Functional Hotness Score (FHS). The associations of FHS and breast cancer patient prognosis as well as distinct immunity markers were analyzed in a total of 3011 breast cancer patients using TCGA, METABRIC and metastatic breast cancer (MBC) cohort GSE110590. Results: We established FHS, based on CD8A, GZMB and CXCL10 gene expression levels of bulk tumors, which delivered the best prognostic value among some gene combinations. Breast cancer patients with the high-FHS tumors showed significantly better survival. FHS was lower in the MBCs. Triple-negative breast cancer (TNBC) showed the highest FHS among subtypes. FHS predicted patient survival in hormone receptor (HR)-negative, especially in TNBC, but not in HR-positive breast cancer. FHS predicted patient prognosis independently in TNBC. The high-FHS TNBCs showed not only higher CD8+ T cell infiltration, but also enhanced broader type-1 anti-cancer immunity. The patients with the high-FHS tumors showed better prognosis not only in high-TMB tumors but also in low-TMB TNBCs. The combination of high-TMB with high-FHS identified a unique subset of patients who do not recur over time in TNBC. Conclusion: TNBCs with high FHS based on the expression levels of CD8A, GZMB and CXCL10 showed improved prognosis with enhanced anti-cancer immunity regardless of TMB. FHS constitutes an independent prognostic marker of survival, particularly robustly when combined with TMB in TNBC.

scholarly journals Relationship between tumor mutational burden and maximum standardized uptake value in 2-[18F]FDG PET (positron emission tomography) scan in cancer patients

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Amin Haghighat Jahromi ◽  
Donald A. Barkauskas ◽  
Matthew Zabel ◽  
Aaron M. Goodman ◽  
Garret Frampton ◽  
...  
Keyword(s):  
Fdg Pet ◽  
Standardized Uptake Value ◽  
Emission Tomography ◽  
Maximum Standardized Uptake Value ◽  
Tissue Biopsy ◽  
Mutational Burden ◽  
Positron Emission ◽  
Pet Ct ◽  
Tumor Mutational Burden ◽  
Fdg Pet Ct

Abstract Purpose Deriving links between imaging and genomic markers is an evolving field. 2-[18F]FDG PET/CT (18F-fluorodeoxyglucose positron emission tomography–computed tomography) is commonly used for cancer imaging, with maximum standardized uptake value (SUVmax) as the main quantitative parameter. Tumor mutational burden (TMB), the quantitative variable obtained using next-generation sequencing on a tissue biopsy sample, is a putative immunotherapy response predictor. We report the relationship between TMB and SUVmax, linking these two important parameters. Methods In this pilot study, we analyzed 1923 patients with diverse cancers and available TMB values. Overall, 273 patients met our eligibility criteria in that they had no systemic treatment prior to imaging/biopsy, and also had 2-[18F]FDG PET/CT within 6 months prior to the tissue biopsy, to ensure acceptable temporal correlation between imaging and genomic evaluation. Results We found a linear correlation between TMB and SUVmax (p < 0.001). In the multivariate analysis, only TMB independently correlated with SUVmax, whereas age, gender, and tumor organ did not. Conclusion Our observations link SUVmax in readily available, routinely used, and noninvasive 2-[18F]FDG PET/CT imaging to the TMB, which requires a tissue biopsy and time to process. Since higher TMB has been implicated as a prognostic biomarker for better outcomes after immunotherapy, further investigation will be needed to determine if SUVmax can stratify patient response to immunotherapy.

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