Abstract 5293: A method to identify somatic mutations from tumor samples in the absence of matched normal tissue

AbstractThe colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions leading to cancer. As for most cancer types, however, understanding of the earliest phases of colorectal neoplastic change, which may occur in morphologically normal tissue, is comparatively limited because of the difficulty of detecting somatic mutations in normal cells. Each colorectal crypt is a small clone of cells derived from a single recently-existing stem cell. Here, we whole genome sequenced hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed, some ubiquitous and continuous, others only found in some individuals, in some crypts or during some phases of the cell lineage from zygote to adult cell. Likely driver mutations were present in ∼1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium.

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PD30. Identification of novel somatic mutations and structural variations in tongue cancer, matched leukoplakia and normal tissue by genome sequencing

Oral Oncology ◽

10.1016/j.oraloncology.2011.06.060 ◽

2011 ◽

Vol 47 ◽

pp. S13

Author(s):

M. Abraham Kuriakose ◽

B. Panda ◽

S. Pattnaik ◽

R. Pait Choudhury ◽

A. Suresh ◽

...

Keyword(s):

Genome Sequencing ◽

Normal Tissue ◽

Somatic Mutations ◽

Tongue Cancer ◽

Structural Variations

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TNscope: Accurate Detection of Somatic Mutations with Haplotype-based Variant Candidate Detection and Machine Learning Filtering

10.1101/250647 ◽

2018 ◽

Cited By ~ 11

Author(s):

Donald Freed ◽

Renke Pan ◽

Rafael Aldana

Keyword(s):

Machine Learning ◽

Normal Tissue ◽

Structural Variation ◽

Somatic Mutations ◽

Variant Calling ◽

Somatic Variant ◽

Accurate Detection ◽

Machine Learning Model ◽

Early Engineering ◽

Somatic Mutation Calling

AbstractDetection of somatic mutations in tumor samples is important in the clinic, where treatment decisions are increasingly based upon molecular diagnostics. However, accurate detection of these mutations is difficult, due in part to intra-tumor heterogeneity, contamination of the tumor sample with normal tissue and pervasive structural variation. Here, we describe Sentieon TNscope, a haplotype-based somatic variant caller with increased accuracy relative to existing methods. An early engineering version of TNscope was used in our submission to the most recent ICGC-DREAM Somatic Mutation calling challenge. In that challenge, TNscope is the leader in accuracy for SNVs, indels and SVs. To further improve variant calling accuracy, we combined the improvements in the variant caller with machine learning. We benchmarked TNscope using in-silico mixtures of well-characterized Genome in a Bottle (GIAB) samples. TNscope displays higher accuracy than the other benchmarked tools and the accuracy is substantially improved by the machine learning model.

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Identification of Five Cytotoxicity-Related Genes Involved in the Progression of Triple-Negative Breast Cancer

Frontiers in Genetics ◽

10.3389/fgene.2021.723477 ◽

2022 ◽

Vol 12 ◽

Author(s):

Yan Zhang ◽

Gui-hui Tong ◽

Xu-Xuan Wei ◽

Hai-yang Chen ◽

Tian Liang ◽

...

Keyword(s):

Breast Cancer ◽

T Cell ◽

Signaling Pathway ◽

Therapeutic Efficacy ◽

Normal Tissue ◽

R Package ◽

Rna Seq ◽

Matched Normal Tissue ◽

M1 Macrophage ◽

Key Genes

Background: Breast cancer is one of the deadly tumors in women, and its incidence continues to increase. This study aimed to identify novel therapeutic molecules using RNA sequencing (RNA-seq) data of breast cancer from our hospital.Methods: 30 pairs of human breast cancer tissue and matched normal tissue were collected and RNA sequenced in our hospital. Differentially expressed genes (DEGs) were calculated with raw data by the R package “edgeR”, and functionally annotated using R package “clusterProfiler”. Tumor-infiltrating immune cells (TIICs) were estimated using a website tool TIMER 2.0. Effects of key genes on therapeutic efficacy were analyzed using RNA-seq data and drug sensitivity data from two databases: the Cancer Cell Line Encyclopedia (CCLE) and the Cancer Therapeutics Response Portal (CTRP).Results: There were 2,953 DEGs between cancerous and matched normal tissue, as well as 975 DEGs between primary breast cancer and metastatic breast cancer. These genes were primarily enriched in PI3K-Akt signaling pathway, calcium signaling pathway, cAMP signaling pathway, and cell cycle. Notably, CD8+ T cell, M0 macrophage, M1 macrophage, regulatory T cell and follicular helper T cell were significantly elevated in cancerous tissue as compared with matched normal tissue. Eventually, we found five genes (GALNTL5, MLIP, HMCN2, LRRN4CL, and DUOX2) were markedly corelated with CD8+ T cell infiltration and cytotoxicity, and associated with therapeutic response.Conclusion: We found five key genes associated with tumor progression, CD8+ T cell and therapeutic efficacy. The findings would provide potential molecular targets for the treatment of breast cancer.

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Comprehensive molecular and genomic characterization of pancreatic tropism in metastatic renal cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.633 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 633-633 ◽

Cited By ~ 1

Author(s):

Nirmish Singla ◽

Jacob Choi ◽

Oreoluwa Onabolu ◽

Layton Woolford ◽

Christina Stevens ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Normal Tissue ◽

Pancreatic Metastasis ◽

Matched Normal Tissue ◽

Pancreatic Metastases ◽

Metastatic Sites ◽

Pdx Models

633 Background: Patients with metastatic renal cell carcinoma (mRCC) involving the pancreas have been shown to exhibit a relatively indolent course, yet the biologic explanation is unclear. We sought to characterize the genomic landscape of patients with mRCC harboring pancreatic metastases to identify molecular drivers of pancreatic tropism. Methods: mRCC patients harboring pancreatic metastases from UTSW and Cleveland Clinic were identified. Clinicopathologic data and oncologic outcomes were analyzed. Samples were obtained from primary tumors, metastatic sites (including pancreatic or other distant metastases), and matched normal tissue. Whole exome (WES) and RNA sequencing of tumors was conducted. Patient-derived xenograft (PDX) models were generated from a subset of patients, and the engrafted tumors were analyzed. Results: 31 mRCC patients with pancreatic metastases were included with 54 tumor samples derived from the primary tumor or thrombus (24), pancreatic metastasis (21), or other metastatic sites (9). Median follow-up was 101 months. Clinicopathologic characteristics were similar between the two institutional cohorts, and all but one patient were favorable or intermediate IMDC risk. All patients had clear cell histology. 8 patients (26%) were metastatic at diagnosis, and median time to metastasis in the remaining patients was 74 months (IQR 32-120). Overall (OS) and cancer-specific (CSS) survival did not vary by IMDC risk group. Morphologically, tumors largely displayed low-grade acinar patterns. WES with matched normal tissue and RNAseq were completed with adequate quality for 48 and 30 samples, respectively. 14 PDX lines were generated, of which 5 (36%) engrafted stably (≥2 passages). WES from 2 tumorgraft specimens revealed preservation of specific mutations in the corresponding human samples. Conclusions: mRCC patients with pancreatic metastases exhibit remarkably favorable survival outcomes. The relatively indolent biology of these tumors is reflected histologically and genomically and can be recapitulated in PDX models. Understanding tumor heterogeneity may help refine prognostic models for mRCC and hold implications for improved personalization of therapy.

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Gene expression profiling of multiple leiomyomata uteri and matched normal tissue from a single patient

Fertility and Sterility ◽

10.1016/j.fertnstert.2008.03.071 ◽

2009 ◽

Vol 91 (6) ◽

pp. 2650-2663 ◽

Cited By ~ 17

Author(s):

Irina K. Dimitrova ◽

Jennifer K. Richer ◽

Michael C. Rudolph ◽

Nicole S. Spoelstra ◽

Elaine M. Reno ◽

...

Keyword(s):

Gene Expression ◽

Gene Expression Profiling ◽

Expression Profiling ◽

Normal Tissue ◽

Single Patient ◽

Matched Normal Tissue

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Differential methylation relative to breast cancer subtype and matched normal tissue reveals distinct patterns

Breast Cancer Research and Treatment ◽

10.1007/s10549-013-2738-0 ◽

2013 ◽

Vol 142 (2) ◽

pp. 365-380 ◽

Cited By ~ 23

Author(s):

Sabrina A. Bardowell ◽

Joel Parker ◽

Cheng Fan ◽

Jamie Crandell ◽

Charles M. Perou ◽

...

Keyword(s):

Breast Cancer ◽

Normal Tissue ◽

Breast Cancer Subtype ◽

Differential Methylation ◽

Matched Normal Tissue ◽

Cancer Subtype

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Levels of Oxidative Damage in Thyroid Neoplasia

Otolaryngology ◽

10.1016/j.otohns.2008.05.496 ◽

2008 ◽

Vol 139 (2_suppl) ◽

pp. P91-P91

Author(s):

Orla G Young ◽

Jacintha N O'Sullivan ◽

Rohana O'Connell ◽

Crotty Thomas ◽

Aongus J. Curran

Keyword(s):

Oxidative Damage ◽

Normal Tissue ◽

Thyroid Neoplasms ◽

Tissue Microarrays ◽

Early Event ◽

P Values ◽

Matched Normal Tissue ◽

Normal Tissues ◽

Thyroid Neoplasia ◽

Subsequent Risk

Problem To assess levels of oxidative damage: DNA adduct (8 oxo dG) and lipid peroxidation (4HNE) in follicular carcinomas (FTC), papillary carcinomas (PTC) and follicular adenomas (FTA) and their corresponding matched normal tissue. Methods Using tissue microarrays and immunohistochemistry, we examined expression levels of nuclear and cytoplasmic (mitochondrial) 8 oxo dG and 4HNE in matched tumor and normal tissues from 16 FTC's, 15 PTC's and 39 FTA's. Results There were higher levels of mitochondrial 8 oxo dG expression in the FTA, FTC and PTC tissue compared to matched normal tissue (p values <0.001, <0.001, <0.03, respectively). This trend remained significant for the levels of mitochondrial 4HNE expression in these groups. (All p values < 0.01.) The levels of nuclear 4HNE expression were elevated in FTA and FTC compared to matched normal tissue (p values <0.001, <0.01, respectively). In contrast, the levels of nuclear 8 oxo dG expression was only statistically significant in the FTA group compared to matched normal tissue. Comparing all three groups to each other, there were higher levels of nuclear 8 oxo dG expression in FTA compared to FTC (p<0.01). This difference was not detected for 4HNE expression. Conclusion Oxidative stress is a key feature of benign and malignant thyroid neoplasms. Interestingly, levels of oxidative damage are higher in adenoma compared to the carcinoma groups. Significance The higher levels of oxidative damage in thyroid adenoma compared to carcinoma groups indicates the accumulation of this damage is an early event which could promote further genomic instability with subsequent risk of mutational events.

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