Comprehensive genomic profiling (CGP) to assess mutational load in gastric and esophageal adenocarcinomas: Implications for immunotherapies.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 66-66
Author(s):  
Garrett Michael Frampton ◽  
Alexa Betzig Schrock ◽  
Zachary Rockow Chalmers ◽  
James Sun ◽  
Riley Ennis ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Checkpoint Inhibitors ◽  
Clinical Care ◽  
Mutational Load ◽  
Mismatch Repair Genes ◽  
Histologic Subtype ◽  
Dna Mismatch ◽  
Significant Difference ◽  
Comprehensive Genomic Profiling ◽  
Repair Genes

66 Background: Gastroesophageal cancer (GEC) present a management challenge, particularly when ERBB2 is not amplified and cytotoxic therapy has failed. Tumor mutational load is linked to predicted benefit from immune checkpoint inhibitors in advanced cancers. Using CGP we assessed the relationship between mutational burden and clinically relevant genomic alterations in GEC samples in the course of routine clinical care. Methods: DNA was extracted from 40 microns of FFPE sections from patients with GEC. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of greater than 500x for 236 or 315 cancer-related genes. Mutational load was characterized as the number of somatic base substitutions and short indels per megabase. Samples were stratified by histologic subtype, and presence or absence of therapeutically relevant receptor tyrosine kinase (RTK) alterations. The majority of samples were from patients with advanced disease. Results: The genomic profiles from a total of 736 gastric and 862 esophageal carcinomas were assessed. Median patient age was 57 for gastric and 60 for esophageal cases. There was no significant difference in mutational load between gastric and esophageal samples. 10th, 25th, median, 75th, and 90th percentiles of mutation load were 1.3, 2.7, 6.3, 11.3, and 20.0 for gastric cancers and 1.8, 3.6, 6.4, 11.3, and 17.5 for esophageal cancers. 27 (3.7%) gastric and 20 (2.3%) esophageal cases had alterations in mismatch repair genes MLH1, MSH2, MSH6 which was associated with ~2.5 fold increased mutational load. Mutational load was not significantly associated with the presence of RTK alterations, which occurred in 155 (21%) gastric and 355 (41%) esophageal cases. Conclusions: CGP in the course of clinical care can be used to assess mutational load in GEC. Alterations in RTKs were not exclusive of the high mutation subgroup, contrary to some previous reports. Mutations in DNA mismatch repair genes were associated with higher mutation burden as expected. Incorporation of CGP into ongoing prospective immunotherapy trials and clinical practice is needed to refine these relationships.

scholarly journals Tumor Mutational Burden and Other Immunotherapy Markers in Histiocytic Neoplasms Using Next Generation Sequencing

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1112-1112
Author(s):  
Gaurav Goyal ◽  
Robert Vassallo ◽  
Karen L Rech ◽  
Jay H Ryu ◽  
Caroline J Davidge-Pitts ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Checkpoint Inhibitors ◽  
Braf V600e ◽  
Mismatch Repair Genes ◽  
Gene Expressions ◽  
Dna Mismatch ◽  
Tumor Mutational Burden ◽  
Mismatch Repair Status ◽  
Repair Genes

Abstract Introduction Histiocytic neoplasms are rare hematological malignancies that have protean clinical manifestations and can pose significant management challenges. Recently, vemurafenib was approved by the US-FDA for treatment of BRAF-V600-mutant Erdheim-Chester disease (ECD). However, there is a lack of FDA-approved therapies for other histiocytic neoplasms such as Langerhans cell histiocytosis (LCH) and Rosai-Dorfman disease (RDD). Over the last 5 years, immune checkpoint inhibitors such as programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have shown significant improvement in outcomes among patients with several hematological and solid organ malignancies. In order to identify appropriate treatment candidates for these therapies, predictive biomarkers have been developed in various cancers. Evidence from solid tumors has suggested a favorable response to checkpoint inhibitor therapy with higher tumor mutational burden (TMB), defined as the number of mutations within a tumor genome. Next generation sequencing (NGS) of various tumors has shown an association between TMB of < 5 mutations/megabase (mut/Mb) to be associated with an absence of benefit from checkpoint inhibitors. In addition, high levels of PD-1/PD-L1 expression and microsatellite instability (MSI) are also correlated with response to therapy. The latter may be a result of somatic or germline alterations in DNA mismatch repair genes. In this study, we report the results for these biomarkers using NGS in patients with histiocytic neoplasms. Methods We utilized TempusTM NGS platform to analyze the tissue specimen of patients with histiocytic neoplasm. The Tempus xO Assay (Tempus Labs; Chicago, IL) combines a 1,711 gene targeted somatic and germline DNA sequencing panel with RNA-sequencing to detect both germline and somatic single nucleotide polymorphisms, indels, copy number variants, and gene rearrangements causing chimeric mRNA transcript expression in a wide array of solid tumor types. The assay utilizes formalin-fixed paraffin-embedded tumor samples and matched blood samples. TMB was calculated and reported as somatic mutations in tumor tissue per million base-pairs or mut/Mb. RNA sequencing was utilized to assess for PD-L1 and PD-1 gene expressions as compared to matched tumor and normal reference sets. Both PD-L1 and PD-1 gene expressions were reported as percentiles. DNA mismatch repair status was predicted by analysis of alterations in five common mismatch repair genes in somatic and germline DNA (MSH2, MSH6, MLH1, PMS2, and EPCAM). If there were no alterations identified in these genes, the mismatch repair status was predicted as microsatellite stable (MSS). Results A total of 13 patients with histiocytic neoplasms were included in the study. The distribution of individual histiocytic neoplasms was as follows: RDD (n=9), ECD (n=3), and LCH (n=1). The median TMB for RDD and ECD patients was 0.17 mut/Mb. For the one patient with LCH, the TMB level was 0.51 mut/Mb. Individual TMB levels are shown in figure 1. PD-L1 and PD-1 expression levels are depicted in table 1. Compared to normal reference sets, the PD-L1 expression was elevated in one patient each with RDD and ECD, and PD-1 expression was elevated in two patients each with RDD and ECD. For both ECD patients with higher PD-1 expression, NGS also showed presence of BRAF-V600E in the tumor tissue. The LCH patient had a low level of PD-L1 and PD-1 expression. For patients where evaluation of DNA mismatch repair was feasible on the tissue specimen (n=4), none showed related somatic or germline alterations. Conclusions In our series, the histiocytic neoplasms RDD, ECD, and LCH demonstrated low levels of TMB. None of the RDD and ECD patients were found to have alterations in DNA mismatch repair genes. Other markers of immunotherapy such as PD-L1/PD-1 expression appeared to be higher in ECD patients with BRAF-V600E, but in only a small subset of RDD patients. The low TMB seen in our study suggests that these histiocytic neoplasms may be less likely to respond to immune checkpoint inhibitors such as anti-PD-1 and anti-PD-L1 agents as compared to the tumors with high TMB. Disclosures No relevant conflicts of interest to declare.

scholarly journals Immune Checkpoint Inhibitors in pMMR Metastatic Colorectal Cancer: A Tough Challenge

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2317 ◽  
Author(s):  
Federica Marmorino ◽  
Alessandra Boccaccino ◽  
Marco Maria Germani ◽  
Alfredo Falcone ◽  
Chiara Cremolini
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Mismatch Repair ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Dna Mismatch Repair ◽  
Checkpoint Inhibitors ◽  
Favorable Effect ◽  
Mutational Load ◽  
Dna Mismatch

The introduction of checkpoint inhibitors provided remarkable achievements in several solid tumors but only 5% of metastatic colorectal cancer (mCRC) patients, i.e., those with bearing microsatellite instable (MSI-high)/deficient DNA mismatch repair (dMMR) tumors, benefit from this approach. The favorable effect of immunotherapy in these patients has been postulated to be due to an increase in neoantigens due to their higher somatic mutational load, also associated with an abundant infiltration of immune cells in tumor microenvironment (TME). While in patients with dMMR tumors checkpoint inhibitors allow achieving durable response with dramatic survival improvement, current results in patients with microsatellite stable (MSS or MSI-low)/proficient DNA mismatch repair (pMMR) tumors are disappointing. These tumors show low mutational load and absence of “immune-competent” TME, and are intrinsically resistant to immune checkpoint inhibitors. Modifying the interplay among cancer cells, TME and host immune system is the aim of multiple lines of research in order to enhance the immunogenicity of pMMR mCRC, and exploit immunotherapy also in this field. Here, we focus on the rationale behind ongoing clinical trials aiming at extending the efficacy of immunotherapy beyond the MSI-high/dMMR subgroup with particular regard to academic no-profit studies.

scholarly journals Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas

2011 ◽  
Vol 129 (3) ◽  
pp. 659-670 ◽  
Author(s):  
Jörg Felsberg ◽  
Niklas Thon ◽  
Sabina Eigenbrod ◽  
Bettina Hentschel ◽  
Michael C. Sabel ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Promoter Methylation ◽  
Dna Mismatch Repair ◽  
Mismatch Repair Genes ◽  
Dna Mismatch ◽  
Dna Mismatch Repair Genes ◽  
Repair Genes
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