Somatic mutation burden in cancer samples determined by targeted next generation sequencing.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 15-15
Author(s):  
Dinesh Cyanam ◽  
Adam Broomer ◽  
David Mandelman ◽  
Ruchi Chaudhary ◽  
Paul D Williams ◽  
...  
Keyword(s):  
Somatic Mutation ◽  
The Cancer Genome Atlas ◽  
Single Nucleotide Variants ◽  
Sequencing Platform ◽  
Targeted Next Generation Sequencing ◽  
Mutation Burden ◽  
Cancer Genome Atlas ◽  
Advance Research ◽  
Ion Torrent Sequencing ◽  
Using Data

15 Background: High somatic mutation burden in tumor tissues is associated with the presentation of neoantigens that promote immune responses particularly in the context of immune checkpoint therapies. Herein, we characterize the ability of targeted cancer research panels to generate estimates of somatic mutation burden. Methods: Somatic mutation data from > 8000 cancer samples obtained from The Cancer Genome Atlas (TCGA) was curated and standardized, and the number of single nucleotide variants (SNVs) in exonic regions of each sample determined. Next, the number of SNVs associated with target regions of two Ion AmpliSeq cancer panels (Oncomine Comprehensive Assay [OCA, 146 genes, 0.35 MB]; Comprehensive Cancer Panel [CCP, 409 genes, 1.7 MB]) was likewise determined and the frequency of mutation counts in the exome and the panel target regions was compared. Mutation counts of samples containing truncating mutations in mismatch repair (MMR) and other DNA repair genes were characterized. A facile workflow with less than 60 minutes of hands-on time was developed to estimate mutation counts for a batch of 8 samples using the Ion Chef for automated library preparation and templating followed by sequencing on the Ion S5. Results: The sensitivity of targeted panels in estimating somatic mutation burden was positively correlated with panel size. The area under the Receiver Operating Characteristic (ROC) curve showed that CCP had > 90% sensitivity and > 95% specificity to differentiate high and low mutation burden based on informatics analysis of TCGA data. As expected, truncating mutations in MMR genes were associated with higher somatic mutation counts in colorectal tumor tissue. Using data generated from OCA and CCP, we characterized a set of filters that provided a good estimate of somatic mutation counts when applied to a tumor-only workflow. Conclusions: A simple workflow was developed on the Ion Torrent sequencing platform to estimate somatic mutation burden in cancer samples. The methods described herein will help advance research in immuo-oncology.

Comprehensive assessment of PD-L1 and PD-L2 dysregulation in gastrointestinal cancers

Epigenomics ◽  
2020 ◽  
Author(s):  
Qijie Zhao ◽  
Jinan Guo ◽  
Yueshui Zhao ◽  
Jing Shen ◽  
Parham Jabbarzadeh Kaboli ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Signaling Pathways ◽  
Underlying Mechanism ◽  
Comprehensive Analysis ◽  
The Cancer Genome Atlas ◽  
Gastrointestinal Cancers ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Background: PD-L1 and PD-L2 are ligands of PD-1. Their overexpression has been reported in different cancers. However, the underlying mechanism of PD-L1 and PD-L2 dysregulation and their related signaling pathways are still unclear in gastrointestinal cancers. Materials & methods: The expression of PD-L1 and PD-L2 were studied in The Cancer Genome Atlas and Genotype-Tissue Expression databases. The gene and protein alteration of PD-L1 and PD-L2 were analyzed in cBioportal. The direct transcription factor regulating PD-L1/ PD-L2 was determined with ChIP-seq data. The association of PD-L1/PD-L2 expression with clinicopathological parameters, survival, immune infiltration and tumor mutation burden were investigated with data from The Cancer Genome Atlas. Potential targets and pathways of PD-L1 and PD-L2 were determined by protein enrichment, WebGestalt and gene ontology. Results: Comprehensive analysis revealed that PD-L1 and PD-L2 were significantly upregulated in most types of gastrointestinal cancers and their expressions were positively correlated. SP1 was a key transcription factor regulating the expression of PD-L1. Conclusion: Higher PD-L1 or PD-L2 expression was significantly associated with poor overall survival, higher tumor mutation burden and more immune and stromal cell populations. Finally, HIF-1, ERBB and mTOR signaling pathways were most significantly affected by PD-L1 and PD-L2 dysregulation. Altogether, this study provided comprehensive analysis of the dysregulation of PD-L1 and PD-L2, its underlying mechanism and downstream pathways, which add to the knowledge of manipulating PD-L1/PD-L2 for cancer immunotherapy.

scholarly journals Targeted sequencing reveals the somatic mutation landscape in a Swedish breast cancer cohort

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Argyri Mathioudaki ◽  
Viktor Ljungström ◽  
Malin Melin ◽  
Maja Louise Arendt ◽  
Jessika Nordin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Somatic Mutation ◽  
Age Of Onset ◽  
Single Nucleotide Variants ◽  
Modifying Genes ◽  
Dna Mismatch ◽  
Targeted Next Generation Sequencing ◽  
Estrogen Receptor Positive ◽  
Underlying Mechanisms ◽  
Swedish Cohort

Abstract Breast cancer (BC) is a genetically heterogeneous disease with high prevalence in Northern Europe. However, there has been no detailed investigation into the Scandinavian somatic landscape. Here, in a homogeneous Swedish cohort, we describe the somatic events underlying BC, leveraging a targeted next-generation sequencing approach. We designed a 20.5 Mb array targeting coding and regulatory regions of genes with a known role in BC (n = 765). The selected genes were either from human BC studies (n = 294) or from within canine mammary tumor associated regions (n = 471). A set of predominantly estrogen receptor positive tumors (ER +  85%) and their normal tissue counterparts (n= 61) were sequenced to ~ 140 × and 85 × mean target coverage, respectively. MuTect2 and VarScan2 were employed to detect single nucleotide variants (SNVs) and copy number aberrations (CNAs), while MutSigCV (SNVs) and GISTIC (CNAs) algorithms estimated the significance of recurrent somatic events. The significantly mutated genes (q ≤ 0.01) were PIK3CA (28% of patients), TP53 (21%) and CDH1 (11%). However, histone modifying genes contained the largest number of variants (KMT2C and ARID1A, together 28%). Mutations in KMT2C were mutually exclusive with PI3KCA mutations (p ≤ 0. 001) and half of these affect the formation of a functional PHD domain. The tumor suppressor CDK10 was deleted in 80% of the cohort while the oncogene MDM4 was amplified. Mutational signature analyses pointed towards APOBEC deaminase activity (COSMIC signature 2) and DNA mismatch repair (COSMIC signature 6). We noticed two significantly distinct patterns related to patient age; TP53 being more mutated in the younger group (29% vs 9% of patients) and CDH23 mutations were absent from the older group. The increased somatic mutation prevalence in the histone modifying genes KMT2C and ARID1A distinguishes the Swedish cohort from previous studies. KMT2C regulates enhancer activation and assists tumor proliferation in a hormone-rich environment, possibly pointing to a role in ER + BC, especially in older cases. Finally, age of onset appears to affect the mutational landscape suggesting that a larger age-diverse population incorporating more molecular subtypes should be studied to elucidate the underlying mechanisms.

scholarly journals Exceptional Chemotherapy Response in Metastatic Colorectal Cancer Associated With Hyper-Indel–Hypermutated Cancer Genome and Comutation of POLD1 and MLH1

2017 ◽  
pp. 1-12
Author(s):  
Manish R. Sharma ◽  
James T. Auman ◽  
Nirali M. Patel ◽  
Juneko E. Grilley-Olson ◽  
Xiaobei Zhao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Somatic Mutation ◽  
Mutation Rate ◽  
Germ Line ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Response To Chemotherapy ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Purpose A 73-year-old woman with metastatic colon cancer experienced a complete response to chemotherapy with dose-intensified irinotecan that has been durable for 5 years. We sequenced her tumor and germ line DNA and looked for similar patterns in publicly available genomic data from patients with colorectal cancer. Patients and Methods Tumor DNA was obtained from a biopsy before therapy, and germ line DNA was obtained from blood. Tumor and germline DNA were sequenced using a commercial panel with approximately 250 genes. Whole-genome amplification and exome sequencing were performed for POLE and POLD1. A POLD1 mutation was confirmed by Sanger sequencing. The somatic mutation and clinical annotation data files from the colon (n = 461) and rectal (n = 171) adenocarcinoma data sets were downloaded from The Cancer Genome Atlas data portal and analyzed for patterns of mutations and clinical outcomes in patients with POLE- and/or POLD1-mutated tumors. Results The pattern of alterations included APC biallelic inactivation and microsatellite instability high (MSI-H) phenotype, with somatic inactivation of MLH1 and hypermutation (estimated mutation rate > 200 per megabase). The extremely high mutation rate led us to investigate additional mechanisms for hypermutation, including loss of function of POLE. POLE was unaltered, but a related gene not typically associated with somatic mutation in colon cancer, POLD1, had a somatic mutation c.2171G>A [p.Gly724Glu]. Additionally, we noted that the high mutation rate was largely composed of dinucleotide deletions. A similar pattern of hypermutation (dinucleotide deletions, POLD1 mutations, MSI-H) was found in tumors from The Cancer Genome Atlas. Conclusion POLD1 mutation with associated MSI-H and hyper-indel–hypermutated cancer genome characterizes a previously unrecognized variant of colon cancer that was found in this patient with an exceptional response to chemotherapy.

scholarly journals Molecular basis of distinct oestrogen responses in endometrial and breast cancer

2019 ◽  
Vol 26 (1) ◽  
pp. 31-46 ◽  
Author(s):  
Eva Baxter ◽  
Karolina Windloch ◽  
Greg Kelly ◽  
Jason S Lee ◽  
Frank Gannon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcriptional Activation ◽  
The Cancer Genome Atlas ◽  
Breast Cancers ◽  
Oestrogen Receptor Alpha ◽  
Limited Success ◽  
Cancer Genome Atlas ◽  
Using Data ◽  
Oestrogen Signalling

Up to 80% of endometrial and breast cancers express oestrogen receptor alpha (ERα). Unlike breast cancer, anti-oestrogen therapy has had limited success in endometrial cancer, raising the possibility that oestrogen has different effects in both cancers. We investigated the role of oestrogen in endometrial and breast cancers using data from The Cancer Genome Atlas (TCGA) in conjunction with cell line studies. Using phosphorylation of ERα (ERα-pSer118) as a marker of transcriptional activation of ERα in TCGA datasets, we found that genes associated with ERα-pSer118 were predominantly unique between tumour types and have distinct regulators. We present data on the alternative and novel roles played by SMAD3, CREB-pSer133 and particularly XBP1 in oestrogen signalling in endometrial and breast cancer.

scholarly journals Exploring the Pathological Mechanism of Bladder Cancer Based on Tumor Mutational Burden Analysis

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Yao Ma ◽  
Xiao-Fei Feng ◽  
Wan-Xia Yang ◽  
Chong-Ge You
Keyword(s):  
Bladder Cancer ◽  
High Throughput Sequencing ◽  
The Cancer Genome Atlas ◽  
Bladder Neoplasm ◽  
Urinary Bladder Neoplasm ◽  
Related Data ◽  
Mutation Burden ◽  
Tumor Mutational Burden ◽  
Cancer Genome Atlas ◽  
Tumor Genome

Although immunotherapy has progressed in the treatment of bladder cancer, some patients still have poor prognosis. New therapeutic targets are eager to be discovered to improve the outcomes of bladder cancer. With the development of high-throughput sequencing and tumor profiling, potential tumor biomarkers were identified. Through the interpretation of related data from the Cancer Genome Atlas database (TCGA), some key genes have been discovered to drive the development and prognosis of urinary bladder neoplasm. On account of the success of immunotherapy in many cancer types, we established the relationship between tumor mutation burden and immune microenvironment of bladder cancer and found the changes of several immune cells in this disease. Based on the understanding of the bladder tumor genome and immune environment, this study is supposed to provide new therapies for the treatment of bladder neoplasm.

scholarly journals Spatial heterogeneity and organization of tumor mutation burden and immune infiltrates within tumors based on whole slide images correlated with patient survival in bladder cancer

2019 ◽  
Author(s):  
Hongming Xu ◽  
Sunho Park ◽  
Jean René Clemenceau ◽  
Jinhwan Choi ◽  
Nathan Radakovich ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Spatial Heterogeneity ◽  
Tumor Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
The Cancer Genome Atlas ◽  
Mutation Burden ◽  
Prognostic Utility ◽  
Cancer Genome Atlas ◽  
Infiltrating Lymphocytes ◽  
Whole Slide Images

AbstractHigh-TMB (TMB-H) could result in an increased number of neoepitopes from somatic mutations expressed by a patient’s own tumor cell which can be recognized and targeted by neighboring tumor-infiltrating lymphocytes (TILs). Deeper understanding of spatial heterogeneity and organization of tumor cells and their neighboring immune infiltrates within tumors could provide new insights into tumor progression and treatment response. Here we developed and applied computational approaches using digital whole slide images (WSIs) to investigate spatial heterogeneity and organization of regions harboring TMB-H tumor cells and TILs within tumors, and its prognostic utility. In experiments using WSIs from The Cancer Genome Atlas bladder cancer (BLCA), our findings show that WSI-based approaches can reliably predict patient-level TMB status and delineate spatial TMB heterogeneity and co-organization with TILs. TMB-H patients with low spatial heterogeneity enriched with high TILs show improved overall survival indicating a prognostic role of spatial TMB and TILs information in BLCA.

scholarly journals The tissue differentiation and cancer manifolds in gene and protein expression spaces

2021 ◽  
Author(s):  
J Nieves ◽  
A Gonzalez
Keyword(s):  
Protein Expression ◽  
Cancer Progression ◽  
Tissue Differentiation ◽  
The Cancer Genome Atlas ◽  
Normal Tissues ◽  
Gene And Protein Expression ◽  
Human Protein Atlas ◽  
Cancer Genome Atlas ◽  
Tissue Of Origin ◽  
Using Data

AbstractIt is well known that, for a particular tissue, the homeostatic and cancer attractors are well apart both in gene expression and in protein expression spaces. By using data for 15 tissues and the corresponding tumors from The Cancer Genome Atlas, and for 49 normal tissues and 20 tumors from The Human Protein Atlas, we show that the set of normal attractors are also well separated from the set of tumors. Roughly speaking, one may say that there is a cancer progression axis orthogonal to the normal tissue differentiation and cancer manifolds. This separation suggests that therapies targeting common genes, which define the cancer axis, may be effective, irrespective of the tissue of origin.

scholarly journals Cancer Type-Dependent Correlations betweenTP53Mutations and Antitumor Immunity

2019 ◽  
Author(s):  
Lin Li ◽  
Mengyuan Li ◽  
Xiaosheng Wang
Keyword(s):  
Antitumor Immunity ◽  
Colon Adenocarcinoma ◽  
Joint Effect ◽  
The Cancer Genome Atlas ◽  
Cancer Type ◽  
Mutation Burden ◽  
Cancer Genome Atlas ◽  
Negative Role ◽  
Stomach Adenocarcinoma ◽  
Cancer Types

AbstractMany studies have shown thatTP53mutations play a negative role in antitumor immunity. However, a few studies reported thatTP53mutations could promote antitumor immunity. To explain these contradictory findings, we analyzed five cancer cohorts from The Cancer Genome Atlas (TCGA) project. We found thatTP53-mutated cancers had significantly higher levels of antitumor immune signatures thanTP53-wildtype cancers in breast invasive carcinoma (BRCA) and lung adenocarcinoma (LUAD). In contrast,TP53-mutated cancers had significantly lower antitumor immune signature levels thanTP53-wildtype cancers in stomach adenocarcinoma (STAD), colon adenocarcinoma (COAD), and head and neck squamous cell carcinoma (HNSC). Moreover,TP53-mutated cancers likely had higher tumor mutation burden (TMB) and tumor aneuploidy level (TAL) thanTP53-wildtype cancers. However, the TMB differences were more marked betweenTP53-mutated andTP53-wildtype cancers than the TAL differences in BRCA and LUAD, and the TAL differences were more significant in STAD and COAD. Furthermore, we showed that TMB and TAL had a positive and a negative correlation with antitumor immunity and that TMB affected antitumor immunity more greatly than TAL did in BRCA and LUAD while TAL affected antitumor immunity more strongly than TMB in STAD and HNSC. These findings indicate that the distinct correlations betweenTP53mutations and antitumor immunity in different cancer types are a consequence of the joint effect of the altered TMB and TAL caused byTP53mutations on tumor immunity. Our data suggest that theTP53mutation status could be a useful biomarker for cancer immunotherapy response depending on cancer types.

scholarly journals Cis-Compound Mutations are Prevalent in Triple Negative Breast Cancer and Can Drive Tumor Progression

2016 ◽  
Author(s):  
Nao Hiranuma ◽  
Jie Liu ◽  
Chaozhong Song ◽  
Jacob Goldsmith ◽  
Michael Dorschner ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Triple Negative ◽  
The Cancer Genome Atlas ◽  
Breast Cancers ◽  
Single Nucleotide Variants ◽  
Primary Tumors ◽  
Cancer Subtypes ◽  
Multiple Biopsies ◽  
Cancer Genome Atlas

About 16% of breast cancers fall into a clinically aggressive category designated triple negative (TNBC) due to a lack of ERBB2, estrogen receptor and progesterone receptor expression1-3. The mutational spectrum of TNBC has been characterized as part of The Cancer Genome Atlas (TCGA)4; however, snapshots of primary tumors cannot reveal the mechanisms by which TNBCs progress and spread. To address this limitation we initiated the Intensive Trial of OMics in Cancer (ITOMIC)-001, in which patients with metastatic TNBC undergo multiple biopsies over space and time5. Whole exome sequencing (WES) of 67 samples from 11 patients identified 426 genes containing multiple distinct single nucleotide variants (SNVs) within the same sample, instances we term Multiple SNVs affecting the Same Gene and Sample (MSSGS). We find that >90% of MSSGS result from cis-compound mutations (in which both SNVs affect the same allele), that MSSGS comprised of SNVs affecting adjacent nucleotides arise from single mutational events, and that most other MSSGS result from the sequential acquisition of SNVs. Some MSSGS drive cancer progression, as exemplified by a TNBC driven by FGFR2(S252W;Y375C). MSSGS are more prevalent in TNBC than other breast cancer subtypes and occur at higher-than-expected frequencies across TNBC samples within TCGA. MSSGS may denote genes that play as yet unrecognized roles in cancer progression.

scholarly journals Identification of ST7 Alteration Profile, Frequency of Alteration and Correlation with ST7-Related Genes using TCGA Data

2019 ◽  
Vol 16 (3) ◽  
pp. 217-230
Author(s):  
Nurdina CHARONG ◽  
Moltira PROMKAN
Keyword(s):  
Disease Free Survival ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Free Survival ◽  
Cancer Genome Atlas ◽  
Stomach Adenocarcinoma ◽  
Using Data ◽  
Liver Hepatocellular Carcinoma ◽  
Disease Free ◽  
Genome Atlas

ST7 (Suppression of Tumorigenicity 7) was reported as a protein playing a role in maintaining cellular structure. This study aims to investigate the ST7 alteration profiles and frequency of alteration in different cancers using data from The Cancer Genome Atlas (TCGA). The correlation between alterations of ST7 and angiogenesis-related genes, SERPINE1, MMP13, and VEGFA, was determined and the relation between ST7 and genes involved in suppression of ST7 transcription, PRMT5 and SMARCA4, were also analyzed. Data of 6 cancer groups from The Cancer Genome Atlas (TCGA) including ovarian serous cystadenocarcinoma (OSC), liver hepatocellular carcinoma (LHC), bladder urothelial adenocarcinoma (BUA), stomach adenocarcinoma (SC), prostate adenocarcinoma (PRAD) and glioblastoma multiforme (GBM) were downloaded for this study. The results indicated that 3 alteration patterns including amplification, missense mutation, and deletion were observed in 6 cancer studies. Gene pair between ST7 and SERPINE1 indicated the co-occurrent alteration in BUC, OSC and SC (p < 0.05). However, no association between alterations of these 2 genes and survival events in our study was observed. Shorter overall survival rate and disease-free survival were found in BUC patients with ST7, PRMT5, and  SMARCA4 alterations. These findings suggest that using TCGA data can target the potential genes involved in carcinogenesis. Combining ST7 with PRMT5 and SMARCA4 could be used as indicators for analyzing the patient survival in BUC patients and may serve as the potential therapeutic target for cancer in the future.

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