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.

scholarly journals Prolonged Response to Anti–PD-1 Antibody Therapy in Chemotherapy-Refractory Cholangiocarcinoma With High Tumor Mutational Burden

2019 ◽  
Vol 17 (6) ◽  
pp. 644-648 ◽  
Author(s):  
Olumide Gbolahan ◽  
Neda Hashemi-Sadraei ◽  
Bert O’Neil
Keyword(s):  
Overall Survival ◽  
Clinical Symptoms ◽  
Checkpoint Inhibitors ◽  
Antibody Therapy ◽  
Tumor Mutation Burden ◽  
Mutational Burden ◽  
Mutation Burden ◽  
Tumor Mutational Burden ◽  
Tumor Genome ◽  
Prolonged Response

Management of advanced intrahepatic cholangiocarcinoma (iCCA) is challenging and overall survival is poor. Progress in the development of new therapeutic options for metastatic cholangiocarcinoma (CCA) has been slow; hence, to date, there are no approved second-line agents in this setting. Although the development of immune checkpoint inhibitors has significantly improved overall survival in a variety of malignancies, there has not been a clinically important impact in CCA. This report presents a 66-year-old patient with chemotherapy-refractory iCCA who experienced a prolonged response to immunotherapy. Tumor genome profiling revealed a high tumor mutation burden of 17 mutations per megabase in the absence of microsatellite instability. He was started on immunotherapy with nivolumab and has experienced an ongoing response for 16 months without clinical symptoms and only minimal radiologic disease.

PD-L1 expression landscape and its relationship with tumor mutation burden in Chinese cancer patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15267-e15267
Author(s):  
Haihua Yang ◽  
Longgang Cui ◽  
Yuzi Zhang ◽  
Zhengyi Zhao ◽  
Yuezong Bai ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Expression Profiles ◽  
Chinese Patients ◽  
Cancer Type ◽  
Tissue Samples ◽  
Tumor Mutation Burden ◽  
Mutational Burden ◽  
Mutation Burden ◽  
Tumor Mutational Burden ◽  
Chinese Cancer Patients

e15267 Background: Little is known about the pan-cancer PD-L1 expression landscape in Chinese patients although PD-L1 expression has been approved by FDA as a diagnosis for anti-PD-(L)1 therapy in several types of cancer. We did a cross-sectional analysis to assess the PD-L1 expression landscape in Chinese patients and its relationship with Tumor mutation burden (TMB). Methods: Tissue samples were collected from more than 8,000 consecutive cases in China between January, 2017, and August, 2019 and were analyzed by 3D Medicines, a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. The method for NGS sequencing and tumor mutational burden (TMB) measurement were described previously. Clinical data and PD-L1 expression profiles were obtained from 8,063 patients whose tissue samples assed quality control. IHC staining for PD-L1 expression was performed using PD-L1 IHC 22C3 pharmDx assay (Dako North America, Carpentaria, CA, U.S.) or Ventana PD-L1 SP263 assay (Ventana Medical Systems, Tucson, AZ, U.S.). PD-L1 expression was determined using Tumor Proportion Score (TPS), the percentage of viable tumor cells stained. Results: PD-L1 expression was examined for 8,063 tissue samples collected from more than 18 different types of solid tumors. There were 4,866 (60%) male and 3,197 (40%) female patients. Their median age was 59 (IQR range, 50-66) years. Given the significance of different cut-points of PD-L1 expression in predicting clinical outcomes, expression levels of PD-L1 were arranged into the following intervals: < 1%, 1%-5%, 5%-50% and ≥50% for each cancer type. Small cell lung cancer (SCLC) had the lowest and Squamous Carcinoma of Head and Neck (HNSC) had the highest levels of PD-L1 expression. Spearman correlation analysis indicated no correlation between PD-L1 and tumor mutational burden (TMB) for Chinese cancer patients (R = 0.1, P < 0.01), which is in line with the previous reports that PD-L1 and TMB were two independent predictors in immunotherapy. Conclusions: The landscape of PD-L1 expression among Chinese cancer population in this study will further assist the utilization of PD-L1 as a predictive biomarker in clinical practice.

Real-world patterns on tumor mutation burden testing in a pan-tumor population

2021 ◽  
Author(s):  
Santosh Gautam ◽  
Sumesh Kachroo ◽  
Richard W DeClue ◽  
Maxine D Fisher ◽  
Anirban Basu
Keyword(s):  
Real World ◽  
Clinical Characteristics ◽  
Tumor Mutation Burden ◽  
Mutational Burden ◽  
Mutation Burden ◽  
Black Patients ◽  
Study Results ◽  
Tumor Mutational Burden ◽  
Anticancer Treatment ◽  
World Information

Background: There is limited real-world information on use of tumor mutational burden (TMB) testing and characteristics of patients receiving it. Materials & methods: Patients ≥18 years old and diagnosed with advanced solid tumors between 1 January 2015 and 31 January 2019 with TMB testing (TMB cohort) and without it (non-TMB) were included in this retrospective, observational study. Results: The TMB cohort (n = 202) was younger than non-TMB (n = 212) (mean age 62.1 vs 65.6 at diagnosis; p = 0.005). There were more Black patients in the TMB cohort (21.3 vs 11.8% in non-TMB; p = 0.004). Clinical characteristics were comparable between the two cohorts; however, systemic anticancer treatment was higher among TMB cohort (91.6 vs 77.8% in non-TMB). Conclusion: Notable differences were observed between patients receiving TMB test and those not receiving it.

scholarly journals A next-generation sequencing-based strategy combining microsatellite instability and tumor mutation burden for comprehensive molecular diagnosis of advanced colorectal cancer

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jian Xiao ◽  
Wenyun Li ◽  
Yan Huang ◽  
Mengli Huang ◽  
Shanshan Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Molecular Diagnosis ◽  
Checkpoint Inhibitors ◽  
The Cancer Genome Atlas ◽  
Immune Microenvironment ◽  
Mutational Burden ◽  
Immune Signatures ◽  
Mutation Burden ◽  
Tumor Mutational Burden

Abstract Background Mismatch repair (MMR)/microsatellite instability (MSI) and tumor mutational burden (TMB) are independent biomarkers that complement each other for predicting immune checkpoint inhibitors (ICIs) efficacy. Here we aim to establish a strategy that integrates MSI and TMB determination for colorectal cancer (CRC) in one single assay. Methods Surgical or biopsy specimens retrospectively collected from CRC patients were subjected to NGS analysis. Immunohistochemistry (IHC) and polymerase chain reaction (PCR) were also used to determine MMR/MSI for those having enough tissues. The NGS-MSI method was validated against IHC and PCR. The MSI-high (MSI-H) or microsatellite stable (MSS) groups were further stratified based on tumor mutational burden, followed by validation using the The Cancer Genome Atlas (TCGA) CRC dataset. Immune microenvironment was evaluated for each subgroup be profiling the expression of immune signatures. Results Tissues from 430 CRC patients were analyzed using a 381-gene NGS panel. Alterations in KRAS, NRAS, BRAF, and HER2 occurred at a significantly higher incidence among MSI-H tumors than in MSS patients (83.6% vs. 58.4%, p = 0.0003). A subset comprising 98 tumors were tested for MSI/MMR using all three techniques, where NGS proved to be 99.0 and 93.9% concordant with PCR and IHC, respectively. Four of the 7 IHC-PCR discordant cases had low TMB (1.1–8.1 muts/Mb) and were confirmed to have been misdiagnosed by IHC. Intriguingly, 4 of the 66 MSS tumors (as determined by NGS) were defined as TMB-high (TMB-H) using a cut-off of 29 mut/Mb. Likewise, 15 of the 456 MSS tumors in the TCGA CRC cohort were also TMB-H with a cut-off of 9 muts/Mb. Expression of immune signatures across subgroups (MSS-TMB-H, MSI-H-TMB-H, and MSS-TMB-L) confirmed that the microenvironment of the MSS-TMB-H tumors was similar to that of the MSI-H-TMB-H tumors, but significantly more immune-responsive than that of the MSS-TMB-L tumors, indicating that MSI combined with TMB may be more precise than MSI alone for immune microenvironment prediction. Conclusion This study demonstrated that NGS panel-based method is both robust and tissue-efficient for comprehensive molecular diagnosis of CRC. It also underscores the importance of combining MSI and TMB information for discerning patients with different microenvironment.

The landscape of POLE variants in colorectal and endometrial tumors: Correlation with microsatellite instability (MSI) and tumor mutation burden (TMB).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13538-e13538
Author(s):  
Sanjeevani Arora ◽  
Joanne Xiu ◽  
Davendra Sohal ◽  
Emil Lou ◽  
Richard M. Goldberg ◽  
...  
Keyword(s):  
Life Sciences ◽  
Mutation Rates ◽  
Chi Square ◽  
Tumor Mutation Burden ◽  
Pathogenic Variants ◽  
Mutational Burden ◽  
Mutation Burden ◽  
Tumor Mutational Burden ◽  
Polymerase Epsilon ◽  
Very High

e13538 Background: Polymerase epsilon (POLE) is a major replicative DNA polymerase. Somatic POLE pathogenic variants (PV) are prevalent in endometrial cancer (EC) and in germline predispose to colorectal cancer (CRC), EC, and possibly other cancers (CA). PVs in the exonuclease domain (ExoD) [amino acid (AA) 268-471] lead to CAs with exceptionally high TMB. PV and uncertain variants (VUS) outside ExoD are sometimes concurrent with an ExoD PV and/or MSI. We hypothesized that the presence of non-ExoD variants may further increase POLE-associated mutation rate and tumor mutational burden. Methods: We retrospectively examined 1870 CRC and 4481 EC genomic profiles conducted by Caris Life Sciences (6/2016-6/2019). All patients had a 592-targeted gene somatic panel. Profiles with a POLE variant (PV or VUS) were analyzed. Median TMB (TMB, in mutations/megabase) was dichotomized to low/intermed ( < 17) vs high (>17). Tumors were grouped by: single ExoD PV, ExoD PV plus another variant (PV or VUS), or no ExoD PV. Known CRC/EC ExoD PV drivers were identified (Campbell et al, Cell 2017): D275G, P286R, S297F/Y, F367C/L/V, V411L, L424F, P436R/S/Y, M444K/L, A456P, S459F/Y, S461L/P, A465V. Kruskal-Wallis and chi-square tests were used. Results: Overall 4.5% CRC (80/1870) and 6.5% EC (303/4481) samples had POLE variants (Table). High TMB was seen in 56.3% CRC and 53.3% EC. In both CRC/ECs, TMB was higher in tumors with an ExoD PV and a 2nd variant compared to those with a solitary ExoD PV or no ExoD PV (both p < 0.001). MSI was more prevalent in CRC and EC with high TMB but no ExoD PV vs those with either high TMB and an ExoD PV, or low/intermed TMB and no ExoD PV (both p < 0.001). In both CRC/ECs, several ExoD PV associated with very high TMB when non-ExoD regions of POLE contained recurrent variant clusters: AA 1906 (TMB 225); AA 1826-7 (TMB 243); AA 1380-2 (TMB 229). Conclusions: In CRC/ECs, POLE ExoD PV and MSI appear to drive TMB in distinct and largely non-overlapping ways. Non-ExoD POLE variants may synergize with ExoD PVs to further increase mutation rates. [Table: see text]

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

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