scholarly journals Spontaneous mutations in the single TTN gene represent high tumor mutation burden

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Ji-Hye Oh ◽  
Se Jin Jang ◽  
Jihun Kim ◽  
Insuk Sohn ◽  
Ji-Young Lee ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Diagnostic Accuracy ◽  
Single Gene ◽  
External Validation ◽  
Area Under The Curve ◽  
Targeted Sequencing ◽  
Diagnostic Model ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Pan Cancer

AbstractTumor mutation burden (TMB) is an emerging biomarker, whose calculation requires targeted sequencing of many genes. We investigated if the measurement of mutation counts within a single gene is representative of TMB. Whole-exome sequencing (WES) data from the pan-cancer cohort (n = 10,224) of TCGA, and targeted sequencing (tNGS) and TTN gene sequencing from 24 colorectal cancer samples (AMC cohort) were analyzed. TTN was identified as the most frequently mutated gene within the pan-cancer cohort, and its mutation number best correlated with TMB assessed by WES (rho = 0.917, p < 2.2e-16). Colorectal cancer was one of good candidates for the application of this diagnostic model of TTN-TMB, and the correlation coefficients were 0.936 and 0.92 for TMB by WES and TMB by tNGS, respectively. Higher than expected TTN mutation frequencies observed in other FLAGS (FrequentLy mutAted GeneS) are associated with late replication time. Diagnostic accuracy for high TMB group did not differ between TTN-TMB and TMB assessed by tNGS. Classification modeling by machine learning using TTN-TMB for MSI-H diagnosis was constructed, and the diagnostic accuracy was 0.873 by area under the curve in external validation. TTN mutation was enriched in samples possessing high immunostimulatory signatures. We suggest that the mutation load within TTN represents high TMB status.

Learning relevant H&E slide morphologies for prediction of colorectal cancer tumor mutation burden using weakly supervised deep learning.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15244-e15244
Author(s):  
Rohan P. Joshi ◽  
Andrew J. Kruger ◽  
Lingdao Sha ◽  
Madhavi Kannan ◽  
Aly A. Khan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Deep Learning ◽  
High Performance ◽  
Cross Validation ◽  
Area Under The Curve ◽  
Multiple Instance Learning ◽  
Tumor Mutation Burden ◽  
Synonymous Mutations ◽  
Mutation Burden ◽  
Weakly Supervised

e15244 Background: Tumor mutation burden (TMB) is the number of non-synonymous mutations present in a cancer exome. In colorectal cancer (CRC), high TMB is associated with microsatellite instability (MSI), POLE mutations, and response to immunotherapy. TMB prediction from whole-slide images (WSIs) could aid workflows that determine MSI and POLE status. Deep learning has previously been used to predict MSI status from WSIs. This approach assumed the morphologies of all regions within the tumor are equally associated with MSI. Here, we predict TMB using a weakly supervised deep learning framework that relaxes this assumption and automatically learns relevant regions within the tumor that are most associated with TMB, potentially uncovering morphological associations. Methods: Weakly supervised learning methods facilitate classification of samples that contain many individual instances, only some of which are related to the sample label. Here, a given WSI has a single TMB-high or -low label and contains individual regions that may or may not be associated with TMB status. We implemented a ResNet18 attention-based, multiple-instance learning (MIL), convolutional neural network to simultaneously learn which tiles are important for prediction of the slide-level TMB and the tile features that are associated TMB-high and -low. We determined performance through 8-fold cross-validation within a Tempus dataset using a 75%-12.5%-12.5% split of ~940 WSIs for training, validation, and testing folds. Results: In the cross-validation, we observed a receiver operating characteristic area under the curve of 0.854 (95% CI 0.776-0.932), an average precision of 0.723 (95% CI 0.580-0.865), and an accuracy of 0.889 (95% CI 0.833-0.945) in the held-out test sets. Morphologies predicted as irrelevant for TMB include adipose tissue and WSI artifacts. Visualizations of model weights show morphologies determined to be most associated with TMB-high and -low, such as high tumor/lymphocyte content and vasculature/red blood cells, respectively. Conclusions: Attention-MIL shows high performance for the prediction of TMB in CRC from H&E images and potentially reveals the morphologies of CRC that are most associated with TMB. Future directions include further investigation of morphological associations, generalizing this model beyond Tempus acquired data, and re-training on the entire Tempus dataset.

scholarly journals ctDNA Clearance and Radiographic Resolution of Disease in Response to Dual Checkpoint Inhibition in Metastatic Microsatellite Stable Colorectal Cancer with a High Tumor Mutation Burden

2021 ◽  
pp. 849-853
Author(s):  
Charles J. Schneider ◽  
Michael Krainock ◽  
Allyson Koyen Malashevich ◽  
Meenakshi Malhotra ◽  
Perry Olshan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lymph Node ◽  
Ct Scan ◽  
Circulating Tumor Dna ◽  
Therapeutic Benefit ◽  
Tumor Mutation Burden ◽  
Early Treatment Response ◽  
Mutation Burden ◽  
Disease Present

Immunotherapy (IO) has increasingly been demonstrated to provide therapeutic benefit to patients with metastatic colorectal cancer (mCRC). However, only a subset of mCRC tumors respond to IO. Monitoring response with tumor biomarkers like carcinoembryonic antigen (CEA) has been challenging in patients with microsatellite stable (MSS) mCRC due to low expression of CEA (CEA/lo). Noninvasive blood-based biomarkers such as circulating tumor DNA (ctDNA) can inform early treatment response and augment radiographic monitoring. We describe a case study of a patient with chemotherapy-refractory CEA/lo MSS mCRC, with metastatic disease present in a cardiophrenic lymph node. The patient was given 2 cycles of combination IO (ipilimumab/nivolumab). Response was monitored by ctDNA using a multiplex PCR next-generation sequencing assay, CEA, and CT scan. After IO administration, ctDNA levels rapidly declined, becoming undetectable. This was concurrent with radiographic resolution of the lymph node metastasis. Serial monitoring of CEA during this same period was uninformative, with no significant changes observed. Significant decline in ctDNA identified metastatic response to IO in a patient with CEA/lo, MSS mCRC and was concurrently validated by CT scan. This case study provides evidence that ctDNA can be used as a prospective surrogate for radiographic tumor response.

Tumor Mutation Burden Computation in Two Pan-Cancer Precision Medicine Next-Generation Sequencing Panels

2020 ◽  
Vol 27 (10) ◽  
pp. 1553-1560 ◽  
Author(s):  
Yongqian Shu ◽  
Xiaohong Wu ◽  
Jia Shen ◽  
Dongdong Luo ◽  
Xiang Li ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Precision Medicine ◽  
Next Generation ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Pan Cancer ◽  
Generation Sequencing

Efficacy of PD-1 Blockade in Refractory Microsatellite-Stable Colorectal Cancer With High Tumor Mutation Burden

2019 ◽  
Vol 18 (4) ◽  
pp. 307-309
Author(s):  
Jun Gong ◽  
Mandy D. Robertson ◽  
Edward Kim ◽  
Marwan Fakih ◽  
Alexa B. Schrock ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Mutation Burden ◽  
Mutation Burden

Correlation of negative PD-L1 expression with TMB-H and MSI-H rates.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13162-e13162
Author(s):  
Jun Dong ◽  
Xiaoni Zhang ◽  
Hongyue Qu ◽  
Shifu Chen ◽  
Ziyang Zhu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Protein Expression ◽  
Cancer Colorectal ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Sequencing Library ◽  
Expression Evaluation ◽  
L1 Protein ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

e13162 Background: PD-L1 protein expression, tumor mutation burden (TMB) and microsatellite instability (MSI) are majorbiomarkers for PD-1/PD-L1 blockade therapy for solid tumors. We designed a study to evaluate the relevance of these biomarkers. Methods: From April 2018 to December 2018, 197 patients with lung cancer, colorectal cancer, andgastric cancer wereprospectivelyenrolled.Foreachpatient, afreshfrozentissuesampleor FFPE sample wascollected. Each sample was dividedinto3parts for next-generation sequencing (NGS), PD-L1 protein expression evaluation and MSI evaluation. The sequencing library was captured using a 605-gene panel and sequenced at~5,000×coverage.Mutationsinthe NGS datawereidentified,andTMB was then calculated. The PD-L1 protein expression was analyzedby immunohistochemistry, and the MSI was evaluated using a multiplex PCR comprising 5 loci(NR27, NR21, NR24, BAT25, and BAT26). Results: 18.78% (37/197) were detected with high PD-L1 expression (positive tumor cells ≥50%); 5.08% (10/197) ofpatientswere diagnosed as MSI-H; 4.06% (8/197) of patients had a TMB-H (TMB > 20 mutations/Mb). Among the 37 PD-L1 positive patients, only one patientwith TMB-Hwas detected, and 3patients were MSI-H. In contrast, among the 14 patients with PD-L1 expression less than 1%, 8patients (57.14%) were detected with TMB-H or MSI-H (3 with TMB-H only, 3 with MSI-H only, and 2 with both). In addition, among all the 10patients with MSI-H, 4patients had TMB-H, indicating that MSI-H may be partly associatedwith high TMB. Conclusions: From our preliminary result, PD-L1 protein expression negative patients tend to have higher rates of TMB-H and MSI-H. For patients with negative PD-L1 expression, it issuggested to evaluate its TMB level and MSI status. This study is ongoing, and more data will be collected to verify these findings.

scholarly journals MUC4 mutation correlates with tumor mutation burden and the immune microenvironment in colorectal cancer

2020 ◽  
Author(s):  
Ting Li ◽  
Wenjia Hui ◽  
Halina Halike ◽  
Feng Gao
Keyword(s):  
Colorectal Cancer ◽  
Immune Response ◽  
T Cells ◽  
Immune Cells ◽  
Gene Mutations ◽  
Cancer Genome ◽  
Immune Microenvironment ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Mutant Genes

Abstract Background: Immunotherapy is a new strategy for Colorectal cancer (CRC) treatment. Tumor mutation burden (TMB) may act as an emerging biomarker for predicting responses to immunotherapy. Nevertheless, no studies investigate if these gene mutations correlate to TMB and tumor-infiltrating immune cells. Methods: Somatic mutation data for CRC samples were obtained from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) datasets. Then, we investigated the relationship between these mutant genes, TMB and overall survival outcomes. GSEA analysis was performed to explore the underlying mechanism of mutant gene. Finally, we further verified the connection between gene mutations and immune response.Results: We identified 17 common mutant genes shared by both two cohorts. Further analysis found that MUC4 mutation was strongly related to higher TMB and predicted a poorer prognosis. Moreover, functional enrichment analysis of samples with MUC4 mutation revealed that they were involved in regulating the natural killer cell mediated cytotoxicity signaling pathway. Significant changes in the proportion of the immune cells of CD8 T cells, activated NK cells, M1 macrophages and resting memory CD4 T cells were observed using the CIBERSORT algorithm. Conclusions: Our research revealed that MUC4 mutation significantly correlated with increased TMB, a worse prognosis and modulating the immune microenvironment, which may be considered a biomarker to predict the outcome of the immune response in colorectal cancer.

PD-1 antibody combined with COX inhibitor in MSI-h/dMMR or high TMB colorectal cancer: A single arm phase II study.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. TPS729-TPS729
Author(s):  
Zehua Wu ◽  
Yanhong Deng ◽  
Jianwei Zhang ◽  
Huabin Hu ◽  
Yue Cai ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase Ii ◽  
Objective Response ◽  
Progression Free Survival ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Cox Inhibitor ◽  
Duration Of Response ◽  
Colorectal Cancer Patients ◽  
To Receive

TPS729 Background: Programmed death protein 1 (PD-1) antibody has been to approved in patients with MSI-H/dMMR colorectal cancer and has achieved significant efficacy. It's also reported that tumor mutation burden (TMB) may be another biomarker of response to PD-1 therapy. But there were about 50-60% of patients with MSI-H/dMMR were insensitive to PD-1 antibody. Cyclooxygenase (COX) inhibitor has been proved to prevent adenomas in colorectal and it is safe for most of the patients. Preclinical data demonstrate that inhibition of COX synergizes with anti-PD-1 blockade in inducing eradication of tumors. Methods: This single arm, phase II trial will assess the efficacy and safety of combination of PD-1 antibody and COX inhibitor in patients with MSI-H/dMMR or high tumor mutation burden colorectal cancer. Patients diagnosed with MSI-H/dMMR or high tumor mutation burden colorectal cancer which was unresectable and had at least one lines of chemotherapy fail or refuse to receive chemotherapy were eligible. Eligible patients were assigned to receive BAT1306 (100 mg once every three weeks) plus COX inhibitor (aspirin 200 mg every day or Celebrex 400 mg every day). Chest/abdomen/pelvic CT with IV contrast will be performed to assess clinical response. The primary endpoint is objective response rate (ORR). Secondary endpoints include progression-free survival (PFS), overall survival (OS), disease control rate (DCR), safety and duration of response. Adverse events are graded per NCI CTCAE v4.03 and will be monitored for 30 days after treatment. Patients will be followed for survival. Planned enrollment is 54 patients. Clinical trial information: NCT03638297.

Analysis of mutation detection of POLD1/pole in pan-cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3142-3142
Author(s):  
Gao Yang ◽  
Jian'An Huang ◽  
Yukun Zu ◽  
Yan Zhang ◽  
Pingping Dai ◽  
...  
Keyword(s):  
Driver Mutation ◽  
Driver Mutations ◽  
Base Substitution ◽  
Tumor Mutation Burden ◽  
Target Capture ◽  
Mutation Burden ◽  
Substitution Mutations ◽  
High Level ◽  
Pan Cancer ◽  
Generation Sequencing

3142 Background: Previous studies proved that mutation of POLD1 and POLE elevates base-substitution mutations and lead to the elevation of tumor mutation burden (TMB). Other signature needs to explore to identify driver mutations in these two genes. Methods: Using gene-panel target-capture next generation sequencing, we analyzed the TMB and POLD1/POLE mutation in 17383 tumor tissue or plasma ctDNA samples from different patients. Results: Tumor mutation burdens were calculated of all the 17383 samples. According to the present research and our panel, we use 10 and 100 Mut/Mb to define hypermutation and ultra-hypermutation. Samples with hypermutation possessed 18.8% (n = 3268) and ultra-hypermutation possessed 0.3% (n = 58). In unselected, hypermutation and ultra-hypermutation group, POLD1 or/and POLE mutations were identified in 3.5% (n = 625), 56.1% (n = 32) and 87.9%(n = 372) samples. There were 0.5% (n = 81), 17.0% (n = 73) and 87.7%(n = 51) identified more than one mutation. These results showed that POLD1 or/and POLE mutations were enriched in samples with high TMB. We screened every known POLE and POLD1 driver mutations. There were 22 ultra-hypermutation samples identified these mutations, including A456P(3), P286R(10), V411L(6), M444K(1), S459F(1) in POLE and R1016H(1) in POLD1. Interestingly, all of them were identified in microsatellite stable (MSS) samples, which suggest that driver mutation may enriched in MSS samples. These already known driver mutation was not detect in 24 high-level microsatellite instability (MSI-H) and ultra-hypermutation samples. We further analyzed 10 POLD1/POLE mutations in other 5 MSS and ultra-hypermutation samples. POLE L424V was a pathogenic germline mutation but not defined as a driver mutation clearly before. POLE P286C had not been biochemically characterized but had different residue with P286R in the same position. Others had not been biochemically characterized (R232H, A234T, V945M, S1064I, Y467H in POLD1, D462N and R749Q, E1956D in POLE). These mutations were potential driver mutations and further research need to be support. Conclusions: We found that not only POLD1 or/and POLE mutations were enriched in samples with high TMB, but also driver mutations were enriched in microsatellite stable tumors. Further researches need to continue to identify more driver mutations of POLD1 and POLE.

NTRK fusion positive colorectal cancer as a unique subset of CRC with high tumor mutation burden and microsatellite instability.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3544-3544
Author(s):  
Hui WANG ◽  
Qiuxiang Ou ◽  
Xue Wu ◽  
Misako Nagasaka ◽  
Sai-Hong Ignatius Ou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Neurotrophin Receptor ◽  
Driver Mutations ◽  
Fusion Partner ◽  
Tumor Mutation Burden ◽  
Targeted Next Generation Sequencing ◽  
Mutation Burden ◽  
Genetic Features ◽  
Colorectal Cancer Patients

3544 Background: Neurotrophin receptor tyrosine kinase ( NTRK) gene fusions are rare but actionable oncogenic drivers that are present in a wide variety of solid tumors. This study aims to identify the frequency and the clinicopathologic and genetic features of NTRK-driven colorectal cancers (CRC). Methods: Colonic and rectal tumor DNA specimen from colorectal cancer patients submitted for molecular profiling at a CLIA-certified genomics laboratory in China that performed NTRK1/2/3 fusion detection by hybridization-based targeted next generation sequencing (NGS) were retrospectively reviewed. Patients’ demographic, clinical characteristics, and treatment history were retrieved from the database for further evaluation. Results: A total of 2,519 unique Chinese colorectal cancer cases were profiled from April 2016 to May 2020, and 17 NTRK+ fusion events were identified (0.7%, 17/2,519) consisting of 14 cases of NTRK1+ and 3 cases of NTRK3+ fusions. Furthermore, thirteen out of 17 NTRK+ CRC tumors (76%) were microsatellite instability-high (MSI-H) tumors, a much higher rate than that of the molecularly unselected CRC population (8%) or NTRK+ non-CRC tumors ( < 1%). NTRK+ CRC patients also had increased tumor mutation burden (median TMB = 65 mut/MB) compared to that of non- NTRK+ CRC (median TMB = 7.7 mut/MB) or NTRK+ non-CRC tumors (median TMB = 4 mut/MB). POLE/POLD1 mutations were also enriched in NTRK+ CRC (8/17, 47%) relative to molecularly unstratified CRC patients (8%) with over half carrying concurrent POLE and POLD1 mutations. TPM3 was the most common fusion partner of NTRK1 (78%, N = 14), followed by LMNA and TRP. Three NTRK3+ CRC were identified (ETV6-NTRK3, RUNX1-NTRK3, CSNK1G1-NTRK3). RNF43 (71%) was the most frequently mutated gene and the aberrations of RNF43 and ARID1 were significantly enriched in MSI-positive NTRK+ tumors as compared to the MSS NTRK+ subgroup. TP53 (53%) and APC (35%) aberrations frequently co-occurred with NTRK fusions, whereas the majority of the NTRK+ cohort were RAS/BRAF wildtype, except in one case that an oncogenic KRAS Q61R variant co-occurred with RUNX1-NTRK3. Conclusions: NTRK+ colorectal cancer is rare. In addition to the absence of canonical driver mutations, NTRK+ tumors demonstrated increased tumor mutation burden, higher frequency of microsatellite instability, and an enrichment of POLE/POLD1 mutations relative to molecularly unselected CRC population.

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