scholarly journals 71 Tumors with higher heterogeneity were associated with superior survival outcome amongst stage I lung cancer patients with low tumor mutational burden (TMB)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A79-A79
Author(s):  
Stanislav Fridland ◽  
Young Kwang Chae
Keyword(s):  
Tumor Heterogeneity ◽  
Immune Cell ◽  
Cancer Genomics ◽  
Stage I ◽  
P Value ◽  
Driver Genes ◽  
Mutational Burden ◽  
Cell Enrichment ◽  
Tumor Mutational Burden ◽  
Adults And Children

BackgroundTumor mutational burden (TMB) has been shown to predict response to immune checkpoint inhibitors.1 Furthermore, the FDA has approved the use of TMB as a biomarker for response to pembrolizumab in solid tumors.2 Simultaneously, the relationship between tumor heterogeneity and outcome has been studied across a range of cancer indications and has shown predictive value.3 For Lung Squamous Cell Carcinoma (LUSC) the utility of heterogeneity metrics has not been established. To study this relationship we used both TMB and tumor heterogeneity to stratify patients, compare outcomes, explore differences in immune cell enrichment, and predict driver genes.MethodsWe obtained Tumor Cancer Genome Atlas (TCGA) LUSC SNP, CNV, and RNASeq data from the GDC Data Portal4 and clinical data from the PanCancer Atlas dataset through cBioPortal.5 TMB was calculated by dividing the number of mutations by 38 to yield a mut/Mb value. To estimate tumor heterogeneity we ran PyClone, an algorithm that estimates the number of tumor clones.6 PyClone uses a random seed and output for the same sample may differ. We ran each sample in triplicate on three separate days yielding 9 runs per sample, yielding an average PyClone clone number. Clones with >2 mutations were counted. Using p-value minimization we chose 5 for the TMB cutoff and 4.6 for the PyClone cutoff. This yielded 4 groups: HTHP, HTLP, LTHP, and LTLP, where H - high, L- low, T-TMB, and P-Pyclone. Immune cell enrichment analysis was accomplished with ssGSEA via the GenePattern platform.7 Driver gene prediction was performed with OncoDriveClust8 via the R package maftools.9ResultsA statistically significant difference was found in progression free survival (PFS) between stage I LTHP (LTHPI, N = 15) and stage I LTLP (LTLPI, N = 77) patients (51.27 months vs. 25.4 months, p-value = 0.0059). Intriguingly, highly heterogeneous tumors revealed superior survival outcomes compared to less heterogeneous tumors in this subgroup. LTLPI patients were enriched for immature B cells, regulatory T cells, and myeloid derived suppressor cells (figure 1). Three driver genes were predicted for the LTLPI cohort (NFE2L2, PIK3CA, and TP53), while none were predicted for the LTHPI cohort.Abstract 71 Figure 1Immune Cell Gene Set EnrichmentConclusionsContrary to previous literature, superior survival outcomes were observed in high tumor heterogeneity, low TMB Stage I LUSC patients. Early stage patients can be stratified using heterogeneity metrics like PyClone. Given the presence of specific driver genes and an immunosuppressive tumor microenvironment, this population warrants further investigation for therapeutic implications.AcknowledgementsThis research was supported in part through the computational resources and staff contributions provided by the Genomics Compute Cluster which is jointly supported by the Feinberg School of Medicine, the Center for Genetic Medicine, and Feinberg’s Department of Biochemistry and Molecular Genetics, the Office of the Provost, the Office for Research, and Northwestern Information Technology. The Genomics Compute Cluster is part of Quest, Northwestern University’s high performance computing facility, with the purpose to advance research in genomics.Trial RegistrationN/AReferencesSamstein RM, Lee C-H, Shoushtari AN, Hellmann MD, Shen R, Janjigian YY, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nature Genetics 2019;51(2):202–6.Center for Drug Evaluation and Research. FDA approves pembrolizumab for adults and children With TMB-H solid tu [Internet]. U.S. Food and Drug Administration. FDA; [cited 2021 Jul 28]. Available from: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-adults-and-children-tmb-h-solid-tumorsMorris LGT, Riaz N, Desrichard A, Şenbabaoğlu Y, Hakimi AA, Makarov V, et al. Pan-cancer analysis of intratumor heterogeneity as a prognostic determinant of survival. Oncotarget 2016;7(9):10051–63.GDC. [cited 2021Jul28]. Available from: https://portal.gdc.cancer.gov/cBioPortal for cancer genomics [Internet]. cBioPortal for Cancer Genomics. [cited 2021Jul28]. Available from: https://www.cbioportal.org/Roth A, Khattra J, Yap D, Wan A, Laks E, Biele J, et al. PyClone: Statistical inference of CLONAL population structure in cancer. Nature Methods 2014;11(4):396–8.GenePattern [Internet]. GenePattern sign in. [cited 2021Jul28]. Available from: https://cloud.genepattern.org/gp/pages/index.jsfTamborero D, Gonzalez-Perez A, Lopez-Bigas N. OncodriveCLUST: Exploiting the Positional clustering of somatic mutations to identify CANCER GENES. Bioinformatics. 2013;29(18):2238–44.Mayakonda A, Lin D-C, Assenov Y, Plass C, Koeffler HP. Maftools: Efficient and comprehensive analysis of somatic variants in cancer. Genome Research 2018;28(11):1747–56.Ethics ApprovalN/AConsentN/A

scholarly journals DACH1 mutation frequency in endometrial cancer is associated with high tumor mutation burden

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0244558
Author(s):  
McKayla J. Riggs ◽  
Nan Lin ◽  
Chi Wang ◽  
Dava W. Piecoro ◽  
Rachel W. Miller ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Microsatellite Instability ◽  
Information Exchange ◽  
P Value ◽  
Tumor Mutation Burden ◽  
Prognostic Features ◽  
Oncology Research ◽  
Mutational Burden ◽  
Mutation Burden ◽  
Tumor Mutational Burden

Objective DACH1 is a transcriptional repressor and tumor suppressor gene frequently mutated in melanoma, bladder, and prostate cancer. Loss of DACH1 expression is associated with poor prognostic features and reduced overall survival in uterine cancer. In this study, we utilized the Oncology Research Information Exchange Network (ORIEN) Avatar database to determine the frequency of DACH1 mutations in patients with endometrial cancer in our Kentucky population. Methods We obtained clinical and genomic data for 65 patients with endometrial cancer from the Markey Cancer Center (MCC). We examined the clinical attributes of the cancers by DACH1 status by comparing whole-exome sequencing (WES), RNA Sequencing (RNASeq), microsatellite instability (MSI), and tumor mutational burden (TMB). Results Kentucky women with endometrial cancer had an increased frequency of DACH1 mutations (12/65 patients, 18.5%) compared to The Cancer Genome Atlas (TCGA) endometrial cancer population (25/586 patients, 3.8%) with p-value = 1.04E-05. DACH1 mutations were associated with increased tumor mutation count in both TCGA (median 65 vs. 8972, p-value = 7.35E-09) and our Kentucky population (490 vs. 2160, p-value = 6.0E-04). DACH1 mutated patients have a higher tumor mutation burden compared to DACH1 wild-type (24 vs. 6.02, p-value = 4.29E-05). DACH1 mutations showed significant gene co-occurrence patterns with POLE, MLH1, and PMS2. DACH1 mutations were not associated with an increase in microsatellite instability at MCC (MSI-H) (p-value = 0.1342). Conclusions DACH1 mutations are prevalent in Kentucky patients with endometrial cancer. These mutations are associated with high tumor mutational burden and co-occur with genome destabilizing gene mutations. These findings suggest DACH1 may be a candidate biomarker for future trials with immunotherapy, particularly in endometrial cancers.

Tumor Mutational Burden and Survival in Papillary Renal Cell Carcinoma Patients

2021 ◽  
Author(s):  
Haiyang Ding ◽  
Shu Yan ◽  
Yuying Han ◽  
Zhenguo Ji ◽  
Peiqian Yang
Keyword(s):  
Renal Cell Carcinoma ◽  
Prognostic Factor ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Immune Cell ◽  
Papillary Renal Cell Carcinoma ◽  
High Expression ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Checkpoint Genes

Abstract Background: Papillary renal cell carcinoma (PRCC) is the second most prevalent subtype of renal cell carcinoma (RCC), accounting for 15% of all RCCs. Tumor mutational burden (TMB) is a promising prognostic factor in many types of cancers. The present study aimed to investigate the association between TMB and patient survival in PRCC patients.Methods: Genomic and clinical data of 281 PRCC patients were collected from The Cancer Genome Atlas. Overall survival (OS) was compared between patients with high and low TMB using the Kaplan-Meier method with log-rank tests. Gene expression comparison and immune cell fraction comparison were performed using Student’s t test or Wilcoxon’s rank-sum test. Results: Patients with high TMB tumors had longer OS than those with low TMB tumors. Among tumor-infiltrating immune cells, high TMB tumors were associated with high levels of CD4+ T-cell infiltration, which were further associated with better survival. Furthermore, low TMB tumors were associated with a high level of infiltration of regulatory T-cells and dendritic cells. Among immune checkpoint genes, low TMB tumors expressed high levels of CD274, PDCD1LG2, LAG3, and TGFB1, and these genes were associated with a poor prognosis in PRCC. Among cytokine-related genes, low TMB tumors were associated with a high expression of IL6, whereas high TMB tumors were associated with a high expression of IFNA1.Conclusions: High TMB indicated better survival outcomes in PRCC patients. High TMB was associated with anti-tumor immune cell infiltration, whereas low TMB was associated with high expression of checkpoint genes that indicated a worse prognosis in RCC. Moreover, TMB was associated with the expression of immune cytokines. Thus, TMB may be a novel prognostic factor in PRCC.

Correlation of the tumor mutational burden with the composition of the immune cell subpopulations in peripheral blood of triple-negative breast cancer patients undergoing neoadjuvant therapy with durvalumab: Results from the prospectively randomized GeparNuevo trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 588-588
Author(s):  
Barbara Seliger ◽  
Thomas Karn ◽  
Carsten Denkert ◽  
Andreas Schneeweiss ◽  
Claus Hanusch ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Neoadjuvant Therapy ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Immune Cell ◽  
Effector Memory ◽  
Cell Counts ◽  
Mutational Burden ◽  
Tumor Mutational Burden

588 Background: The GeparNuevo trial is a randomized, double-blind, multi-center phase II trial of neoadjuvant therapy in patients with early-stage triple negative breast cancer (TNBC) investigating the role of durvalumab, an anti-PD-L1 antibody, which blocks PD-L1 binding to PD1 and CD80, in addition to standard chemotherapy with nab-Paclitaxel (nab-Pac) followed by Epirubicin plus Cyclophosphamid (EC; Loibl S et al. ASCO 2018). Since the tumor mutational burden (TMB) has been suggested to be associated with a better outcome of patients undergoing immunotherapy and an increased T cell response, we determined whether there exists a link between TMB and immune cell composition, frequency and function in patients of the GeparNuevo trial. Methods: In order to determine possible predictive and / or prognostic biomarkers, tumor biopsies taken at recruitment from 149 patients out of the 174 enrolled patients underwent deep sequencing in order to determine the TMB. In addition, for 120 patients blood samples were taken at recruitment and during different time points of treatment (after durvalumab pre-treatment, after Nab-Pac and at surgery after EC) and evaluated using multicolor flow cytometry by monitoring the absolute cell counts of T cells, B cells and NK cells as well as the frequency, composition and functionality of different immune cell populations. Results: The TMB of the GeparNuevo cohort was in line with published data with a mean of 1.8 mutations/MB (range 0.02 – 7.65), respectively. Preliminary evaluation demonstrated a significant correlation of TMB with blood parameters, in particular with subsets of CD8+ T cells. Interestingly, the data suggest a negative correlation of TMB with the frequency of effector cells while a positive correlation exists with the effector memory cells at recruitment. In depth analyses of a correlation with treatment arm and clinical responses are currently performed. Conclusions: Using this approach we hope to identify biomarkers, which will allow a better selection of TNBC patients undergoing specific immunotherapies. Clinical trial information: NCT02685059.

scholarly journals A case of successful pembrolizumab monotherapy in a patient with advanced lung adenocarcinoma: Use of multiple biomarkers in combination for clinical practice

Open Medicine ◽  
2021 ◽  
Vol 17 (1) ◽  
pp. 53-60
Author(s):  
Hanfei Guo ◽  
Lei Qian ◽  
Xiao Chen ◽  
Yuguang Zhao ◽  
Wei Song ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Lung Adenocarcinoma ◽  
Driver Genes ◽  
Cancer Driver ◽  
Dna Mismatch ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Clinical Benefits ◽  
Hyperprogressive Disease ◽  
Low Expression

Abstract Clinical treatment is challenging for elderly patients with lung cancer who cannot tolerate chemotherapy, do not have cancer driver genes, and have low expression of PD-L1. Since these patients are usually excluded from clinical studies, evidence-based medicine supporting the use of immunotherapy is lacking. Considering the potentially limited clinical benefits and high associated risk of hyperprogressive disease, determining an appropriate treatment is an urgent clinical challenge. We report a 71 year-old male patient diagnosed with advanced lung adenocarcinoma lacking key driving genes (EGFR, ALK, and ROS-1), and low expression of PD-L1 on tumor cells (10–15%). The tumor tissue showed a low level of microsatellite instability, low tumor mutational burden, and no DNA mismatch repair deficiency on whole-exome sequencing (WES). However, a high blood tumor mutational burden was detected. After considering the biomarkers of therapeutic effect and ruling out the risk of hyperprogressive disease, pembrolizumab 200 mg was administered every 3 weeks for a year (17 cycles). The disease remained stable for >39 months, and adverse effects were mild and well-tolerated. Therefore, a comprehensive biomarker evaluation, especially in elderly patients lacking driving genes, is essential. Liquid biopsy technology and WES may be useful for overcoming the limitations of tissue biopsy.

Correlation of tumor mutational burden, tumor microenvironment and alterations of driver genes in patients with NSCLC: A retrospective analysis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20019-e20019
Author(s):  
Yao Yu ◽  
Rongbo Lin ◽  
Ning He ◽  
Yadong Yang ◽  
Ge Jin ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Cell Density ◽  
Driver Genes ◽  
Chi Square ◽  
Metastatic Nsclc ◽  
Tumor Infiltrating Lymphocyte ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Chi Square Test

e20019 Background: To investigate the correlation of tumor mutational burden, tumor microenvironment and alterations of driver genes in tumor tissue of patients with NSCLC. Methods: 79 patients with confirmed NSCLC admitted from January 2018 to January 2019 were included. Tumor DNA was isolated from FFPE samples or fresh tissue samples. Mutation profiles were obtained by targeted deep sequencing of 620 selected genes. Tumor mutational burden (TMB) was defined as the number of non-synonymous mutations per 1Mbp and divided into tertiles. PD-L1 expression, CD8+ T cell and tumor infiltrating lymphocyte density were evaluated by immunohistochemical analysis. The correlation coefficient of TMB, tumor microenvironment and alterations of driver genes was calculated by chi-square test. Results: Median TMB of these patients is 6.915 Muts/Mbp (4.22-9.44 Muts/Mbp). Prevalence of PD-L1 expression is 28.0% (n = 7/25) at a tumor proportion score cutoff of at least 5% evaluated by Dako 28-8 PharmDx Assay kit and prevalence of CD8+ T cell density is 95.8% (n = 23/24). TP53 mutations are the most common alteration (n = 49/79, 62.0%), followed by EGFR alterations (n = 31/79, 39.2%), CDKN2A alterations (n = 11/79, 13.9%), KRAS mutations (n = 10/79, 12.7%), STK11 mutations (n = 5/79, 6.3%), ALK fusions (n = 4/79, 5.1%) and POLE mutations (n = 4/79, 5.1%). According to results of chi-square test, squamous cell carcinoma has higher TMB (p= 0.023) than adenocarcinoma. Metastatic NSCLC has higher PD-L1 expression (p= 0.049) than non-metastatic NSCLC. Furthermore, EGFR alterations are associated with lower TMB (p=0.020) and POLE mutations are associated with higher TMB (p= 0.015). There are no correlations among CD8+ T cell density, tumor infiltrating lymphocyte density and other variants. Conclusions: Our study highlights the correlation of tumor mutational burden, tumor microenvironment and alterations of driver genes in patients with NSCLC. This result may be the reference of anti-PD-1 therapy.

scholarly journals Positive Association Between Location of Melanoma, Ultraviolet Signature, Tumor Mutational Burden, and Response to Anti–PD-1 Therapy

2021 ◽  
pp. 1821-1829
Author(s):  
Léa Dousset ◽  
Florence Poizeau ◽  
Caroline Robert ◽  
Sandrine Mansard ◽  
Laurent Mortier ◽  
...  
Keyword(s):  
Primary Melanoma ◽  
Sun Exposure ◽  
Positive Association ◽  
P Value ◽  
Multiple Cancer ◽  
Exposed Area ◽  
Metastatic Site ◽  
Mutational Burden ◽  
Metastatic Sample ◽  
Tumor Mutational Burden

PURPOSE Emerging evidence suggests a correlation between the tumor mutational burden (TMB) and the response to programmed cell death-1 protein (PD-1) monotherapy across multiple cancer types. In skin cancers, as high TMB is mostly because of ultraviolet (UV) exposure, we hypothesized a correlation between the primary melanoma cutaneous location according to sun exposure and response to anti–PD-1 monotherapy. METHODS The aim of this study was to analyze, in advanced melanoma, the relationship between TMB, locations according to sun exposure, and response to PD-1 inhibitors. We conducted a prospective multicentric analysis, by sequencing the most recent metastatic sample before PD-1 inhibitors using FoundationOne assay. RESULTS One hundred two patients were included, with TMB available for 94 cases. In univariate and multivariate linear regression, TMB was significantly associated with sun-exposed areas of the primary melanoma location and with age (coefficients of the association with log-TMB: non-UV location, –1.05; chronic sun-exposed area, 1.12; P value for the location, < 10–5; age, 0.021 per year, P value for age, .002). Molecular UV signature present on the metastatic site was associated with higher TMB ( P = .003). Melanomas bearing a high TMB had a higher probability of response to PD-1 inhibitors compared with melanomas with a low TMB, with a dose-dependent effect following an exponential curve and a negative odds ratio of 0.40 (95% CI, 0.20 to 0.72, P = .004) between log-TMB and 6-month progression. CONCLUSION Cumulative sun exposure related to skin location and molecular UV signature present on the metastatic site appear to be relevant biomarkers directly linked to TMB. Because TMB is not yet available to all for routine clinical use, the location of the primary melanoma in a sun-exposed area may play an important role in clinical decisions regarding therapeutic choice.

scholarly journals Estimating tumor mutational burden from RNA-sequencing without a matched-normal sample

2021 ◽  
Author(s):  
Rotem Katzir ◽  
Keren Yizhak
Keyword(s):  
Rna Sequencing ◽  
Somatic Mutations ◽  
Superior Performance ◽  
Normal Sample ◽  
Sequencing Data ◽  
Mutational Signatures ◽  
Driver Genes ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Matched Normal Sample

Detection of somatic point mutations using patients sequencing data has many clinical applications, including the identification of cancer driver genes, detection of mutational signatures, and estimation of tumor mutational burden (TMB). In a recent work we developed a tool for detection of somatic mutations using tumor RNA and matched-normal DNA. Here, we further extend it to detect somatic mutations from RNA sequencing data without a matched-normal sample. This is accomplished via a machine learning approach that classifies mutations as either somatic or germline based on various features. When applied to RNA-sequencing of >450 melanoma samples high precision and recall are achieved, and both mutational signatures and driver genes are correctly identified. Finally, we show that RNA-based TMB is significantly associated with patient survival, with similar or superior performance to DNA-based TMB. Our pipeline can be utilized in many future applications, analyzing novel and existing datasets where only RNA is available.

scholarly journals Assessing tumor heterogeneity: integrating tissue and circulating tumor DNA (ctDNA) analysis in the era of immuno-oncology - blood TMB is not the same as tissue TMB

2021 ◽  
Vol 9 (8) ◽  
pp. e002551
Author(s):  
Stanislav Fridland ◽  
Jaeyoun Choi ◽  
Myungwoo Nam ◽  
Samuel Joseph Schellenberg ◽  
Eugene Kim ◽  
...  
Keyword(s):  
Tumor Heterogeneity ◽  
Predictive Power ◽  
Composite Index ◽  
Circulating Tumor Dna ◽  
Small Cell Lung ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Ctdna Analysis ◽  
Tumor Dna ◽  
Predict Treatment Response

Tissue tumor mutational burden (tTMB) is calculated to aid in cancer treatment selection. High tTMB predicts a favorable response to immunotherapy in patients with non-small cell lung cancer. Blood TMB (bTMB) from circulating tumor DNA is reported to have similar predictive power and has been proposed as an alternative to tTMB. Across many studies not only are tTMB and bTMB not concordant but also as reported previously by our group predict conflicting outcomes. This implies that bTMB is not a substitute for tTMB, but rather a composite index that may encompass tumor heterogeneity. Here, we provide a thorough overview of the predictive power of TMB, discuss the use of tumor heterogeneity alongside TMB to predict treatment response and review several methods of tumor heterogeneity assessment. Furthermore, we propose a hypothetical method of estimating tumor heterogeneity and touch on its clinical implications.

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