scholarly journals The utility of homologous recombination deficiency biomarkers across cancer types

2021 ◽  
Author(s):  
Shiro Takamatsu ◽  
J.B. Brown ◽  
Ken Yamaguchi ◽  
Junzo Hamanishi ◽  
Koji Yamanoi ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Cancer Cell Line ◽  
Parp Inhibitors ◽  
The Cancer Genome Atlas ◽  
Clinical Samples ◽  
Repair Deficiency ◽  
Dna Repair Deficiency ◽  
Cancer Genome Atlas ◽  
Cancer Types ◽  
Recombination Pathway

AbstractBackgroundGenomic alterations in BRCA1/2 and genomic scar signatures are associated with homologous recombination DNA repair deficiency (HRD) and serve as therapeutic biomarkers for platinum and PARP inhibitors in breast and ovarian cancers. However, the clinical significance of these biomarkers in other homologous recombination repair-related genes or other cancer types is not fully understood.ResultsWe analyzed the datasets of all solid cancers from The Cancer Genome Atlas and Cancer Cell Line Encyclopedia, and found that the association between biallelic alterations in the homologous recombination pathway genes and genomic scar signatures differed greatly depending on gender and the presence of somatic TP53 mutation. Additionally, HRD cases identified by a combination of these indicators showed higher sensitivity to DNA-damaging drugs than non-HRD cases both in clinical samples and cell lines.ConclusionOur work provides novel proof of the utility of HRD analysis for all cancer types and will improve the precision and efficacy of chemotherapy selection in clinical oncology.

scholarly journals Frequency and prognostic value of mutations associated with the homologous recombination DNA repair pathway in a large pan cancer cohort

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Daniel R. Principe ◽  
Matthew Narbutis ◽  
Regina Koch ◽  
Ajay Rana
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Synthetic Lethality ◽  
Parp Inhibitors ◽  
The Cancer Genome Atlas ◽  
Parp Inhibition ◽  
Repair Pathway ◽  
Wide Range ◽  
Recombination Pathway ◽  
Pan Cancer

AbstractPARP inhibitors have shown remarkable efficacy in the clinical management of several BRCA-mutated tumors. This approach is based on the long-standing hypothesis that PARP inhibition will impair the repair of single stranded breaks, causing synthetic lethality in tumors with loss of high-fidelity double-strand break homologous recombination. While this is now well accepted and has been the basis of several successful clinical trials, emerging evidence strongly suggests that mutation to several additional genes involved in homologous recombination may also have predictive value for PARP inhibitors. While this notion is supported by early clinical evidence, the mutation frequencies of these and other functionally related genes are largely unknown, particularly in cancers not classically associated with homologous recombination deficiency. We therefore evaluated the mutation status of 22 genes associated with the homologous recombination DNA repair pathway or PARP inhibitor sensitivity, first in a pan-cancer cohort of 55,586 patients, followed by a more focused analysis in The Cancer Genome Atlas cohort of 12,153 patients. In both groups we observed high rates of mutations in a variety of HR-associated genes largely unexplored in the setting of PARP inhibition, many of which were associated also with poor clinical outcomes. We then extended our study to determine which mutations have a known oncogenic role, as well as similar to known oncogenic mutations that may have a similar phenotype. Finally, we explored the individual cancer histologies in which these genomic alterations are most frequent. We concluded that the rates of deleterious mutations affecting genes associated with the homologous recombination pathway may be underrepresented in a wide range of human cancers, and several of these genes warrant further and more focused investigation, particularly in the setting of PARP inhibition and HR deficiency.

scholarly journals Comparing cancer cell lines and tumor samples by genomic profiles

2015 ◽  
Author(s):  
Rileen Sinha ◽  
Nikolaus Schultz ◽  
Chris Sander
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Cancer Cell Lines ◽  
Response To Therapy ◽  
Computational Method ◽  
The Cancer Genome Atlas ◽  
Cancer Genome Atlas ◽  
Cancer Types ◽  
Tumor Material

Cancer cell lines are often used in laboratory experiments as models of tumors, although they can have substantially different genetic and epigenetic profiles compared to tumors. We have developed a general computational method, TumorComparer, to systematically quantify similarities and differences between tumor material when detailed genetic and molecular profiles are available. The comparisons can be flexibly tailored to a particular biological question by placing a higher weight on functional alterations of interest (weighted similarity). In a first pan-cancer application, we have compared 260 cell lines from the Cancer Cell Line Encyclopaedia (CCLE) and 1914 tumors of six different cancer types from The Cancer Genome Atlas (TCGA), using weights to emphasize genomic alterations that frequently recur in tumors. We report the potential suitability of particular cell lines as tumor models and identify apparently unsuitable outlier cell lines, some of which are in wide use, for each of the six cancer types. In future, this weighted similarity method may be generalized for use in a clinical setting to compare patient profiles consisting of genomic patterns combined with clinical attributes, such as diagnosis, treatment and response to therapy.

scholarly journals Integrated mutational landscape analysis of uterine leiomyosarcomas

2021 ◽  
Vol 118 (15) ◽  
pp. e2025182118
Author(s):  
Jungmin Choi ◽  
Aranzazu Manzano ◽  
Weilai Dong ◽  
Stefania Bellone ◽  
Elena Bonazzoli ◽  
...  
Keyword(s):  
Copy Number ◽  
Muscle Layer ◽  
The Cancer Genome Atlas ◽  
Repair Deficiency ◽  
Whole Exome ◽  
Genetic Landscape ◽  
Dna Repair Deficiency ◽  
Number Variation ◽  
Fresh Frozen ◽  
Cancer Genome Atlas

Uterine leiomyosarcomas (uLMS) are aggressive tumors arising from the smooth muscle layer of the uterus. We analyzed 83 uLMS sample genetics, including 56 from Yale and 27 from The Cancer Genome Atlas (TCGA). Among them, a total of 55 Yale samples including two patient-derived xenografts (PDXs) and 27 TCGA samples have whole-exome sequencing (WES) data; 10 Yale and 27 TCGA samples have RNA-sequencing (RNA-Seq) data; and 11 Yale and 10 TCGA samples have whole-genome sequencing (WGS) data. We found recurrent somatic mutations in TP53, MED12, and PTEN genes. Top somatic mutated genes included TP53, ATRX, PTEN, and MEN1 genes. Somatic copy number variation (CNV) analysis identified 8 copy-number gains, including 5p15.33 (TERT), 8q24.21 (C-MYC), and 17p11.2 (MYOCD, MAP2K4) amplifications and 29 copy-number losses. Fusions involving tumor suppressors or oncogenes were deetected, with most fusions disrupting RB1, TP53, and ATRX/DAXX, and one fusion (ACTG2-ALK) being potentially targetable. WGS results demonstrated that 76% (16 of 21) of the samples harbored chromoplexy and/or chromothripsis. Clinically actionable mutational signatures of homologous-recombination DNA-repair deficiency (HRD) and microsatellite instability (MSI) were identified in 25% (12 of 48) and 2% (1 of 48) of fresh frozen uLMS, respectively. Finally, we found olaparib (PARPi; P = 0.002), GS-626510 (C-MYC/BETi; P < 0.000001 and P = 0.0005), and copanlisib (PIK3CAi; P = 0.0001) monotherapy to significantly inhibit uLMS-PDXs harboring derangements in C-MYC and PTEN/PIK3CA/AKT genes (LEY11) and/or HRD signatures (LEY16) compared to vehicle-treated mice. These findings define the genetic landscape of uLMS and suggest that a subset of uLMS may benefit from existing PARP-, PIK3CA-, and C-MYC/BET-targeted drugs.

scholarly journals Rapid advancement in cancer genomic big data in the pursuit of precision oncology

2021 ◽  
Author(s):  
Tiara Bunga Mayang Permata ◽  
Sri Mutya Sekarutami ◽  
Endang Nuryadi ◽  
Angela Giselvania ◽  
Soehartati Gondhowiardjo
Keyword(s):  
Big Data ◽  
Open Access ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Genomic Data ◽  
The Cancer Genome Atlas ◽  
Clinical Samples ◽  
Precision Oncology ◽  
Cancer Data ◽  
User Friendly

In the current big data era, massive genomic cancer data are available for open access from anywhere in the world. They are obtained from popular platforms, such as The Cancer Genome Atlas, which provides genetic information from clinical samples, and Cancer Cell Line Encyclopedia, which offers genomic data of cancer cell lines. For convenient analysis, user-friendly tools, such as the Tumor Immune Estimation Resource (TIMER), which can be used to analyze tumor-infiltrating immune cells comprehensively, are also emerging. In clinical practice, clinical sequencing has been recommended for patients with cancer in many countries. Despite its many challenges, it enables the application of precision medicine, especially in medical oncology. In this review, several efforts devoted to accomplishing precision oncology and applying big data for use in Indonesia are discussed. Utilizing open access genomic data in writing research articles is also described.

scholarly journals Integrated Dissection of lncRNA-Perturbated Triplets Reveals Novel Prognostic Signatures Across Cancer Types

2020 ◽  
Vol 21 (17) ◽  
pp. 6087
Author(s):  
Yunzhen Wei ◽  
Limeng Zhou ◽  
Yingzhang Huang ◽  
Dianjing Guo
Keyword(s):  
Cancer Biology ◽  
Noncoding Rna ◽  
The Cancer Genome Atlas ◽  
Dynamic Changes ◽  
Computational Framework ◽  
Potential Biomarker ◽  
Cancer Genome Atlas ◽  
Cancer Types ◽  
Tcga Dataset ◽  
Pan Cancer

Long noncoding RNA (lncRNA)/microRNA(miRNA)/mRNA triplets contribute to cancer biology. However, identifying significative triplets remains a major challenge for cancer research. The dynamic changes among factors of the triplets have been less understood. Here, by integrating target information and expression datasets, we proposed a novel computational framework to identify the triplets termed as “lncRNA-perturbated triplets”. We applied the framework to five cancer datasets in The Cancer Genome Atlas (TCGA) project and identified 109 triplets. We showed that the paired miRNAs and mRNAs were widely perturbated by lncRNAs in different cancer types. LncRNA perturbators and lncRNA-perturbated mRNAs showed significantly higher evolutionary conservation than other lncRNAs and mRNAs. Importantly, the lncRNA-perturbated triplets exhibited high cancer specificity. The pan-cancer perturbator OIP5-AS1 had higher expression level than that of the cancer-specific perturbators. These lncRNA perturbators were significantly enriched in known cancer-related pathways. Furthermore, among the 25 lncRNA in the 109 triplets, lncRNA SNHG7 was identified as a stable potential biomarker in lung adenocarcinoma (LUAD) by combining the TCGA dataset and two independent GEO datasets. Results from cell transfection also indicated that overexpression of lncRNA SNHG7 and TUG1 enhanced the expression of the corresponding mRNA PNMA2 and CDC7 in LUAD. Our study provides a systematic dissection of lncRNA-perturbated triplets and facilitates our understanding of the molecular roles of lncRNAs in cancers.

scholarly journals Epstein-Barr Virus-Positive Cancers Show Altered B-Cell Clonality

mSystems ◽  
2018 ◽  
Vol 3 (5) ◽  
Author(s):  
Sara R. Selitsky ◽  
David Marron ◽  
Lisle E. Mose ◽  
Joel S. Parker ◽  
Dirk P. Dittmer
Keyword(s):  
B Cells ◽  
B Cell ◽  
Epstein Barr Virus ◽  
The Cancer Genome Atlas ◽  
Barr Virus ◽  
Cancer Genome Atlas ◽  
Cancer Types ◽  
Epstein Barr ◽  
Tumor Types ◽  
Genome Atlas

ABSTRACTEpstein-Barr virus (EBV) is convincingly associated with gastric cancer, nasopharyngeal carcinoma, and certain lymphomas, but its role in other cancer types remains controversial. To test the hypothesis that there are additional cancer types with high prevalence of EBV, we determined EBV viral expression in all the Cancer Genome Atlas Project (TCGA) mRNA sequencing (mRNA-seq) samples (n= 10,396) from 32 different tumor types. We found that EBV was present in gastric adenocarcinoma and lymphoma, as expected, and was also present in >5% of samples in 10 additional tumor types. For most samples, EBV transcript levels were low, which suggests that EBV was likely present due to infected infiltrating B cells. In order to determine if there was a difference in the B-cell populations, we assembled B-cell receptors for each sample and found B-cell receptor abundance (P≤ 1.4 × 10−20) and diversity (P≤ 8.3 × 10−27) were significantly higher in EBV-positive samples. Moreover, diversity was independent of B-cell abundance, suggesting that the presence of EBV was associated with an increased and altered B-cell population.IMPORTANCEAround 20% of human cancers are associated with viruses. Epstein-Barr virus (EBV) contributes to gastric cancer, nasopharyngeal carcinoma, and certain lymphomas, but its role in other cancer types remains controversial. We assessed the prevalence of EBV in RNA-seq from 32 tumor types in the Cancer Genome Atlas Project (TCGA) and found EBV to be present in >5% of samples in 12 tumor types. EBV infects epithelial cells and B cells and in B cells causes proliferation. We hypothesized that the low expression of EBV in most of the tumor types was due to infiltration of B cells into the tumor. The increase in B-cell abundance and diversity in subjects where EBV was detected in the tumors strengthens this hypothesis. Overall, we found that EBV was associated with an increased and altered immune response. This result is not evidence of causality, but a potential novel biomarker for tumor immune status.

scholarly journals BET Proteins as Attractive Targets for Cancer Therapeutics

2021 ◽  
Vol 22 (20) ◽  
pp. 11102
Author(s):  
Joanna Sarnik ◽  
Tomasz Popławski ◽  
Paulina Tokarz
Keyword(s):  
Homologous Recombination ◽  
Transcriptional Control ◽  
Synthetic Lethality ◽  
Clinical Success ◽  
Predictive Biomarkers ◽  
Cancer Therapeutics ◽  
Parp Inhibitors ◽  
Novel Approach ◽  
Bet Inhibitors ◽  
Recombination Pathway

Transcriptional dysregulation is a hallmark of cancer and can be an essential driver of cancer initiation and progression. Loss of transcriptional control can cause cancer cells to become dependent on certain regulators of gene expression. Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that regulate the expression of multiple genes involved in carcinogenesis. BET inhibitors (BETis) disrupt BET protein binding to acetylated lysine residues of chromatin and suppress the transcription of various genes, including oncogenic transcription factors. Phase I and II clinical trials demonstrated BETis’ potential as anticancer drugs against solid tumours and haematological malignancies; however, their clinical success was limited as monotherapies. Emerging treatment-associated toxicities, drug resistance and a lack of predictive biomarkers limited BETis’ clinical progress. The preclinical evaluation demonstrated that BETis synergised with different classes of compounds, including DNA repair inhibitors, thus supporting further clinical development of BETis. The combination of BET and PARP inhibitors triggered synthetic lethality in cells with proficient homologous recombination. Mechanistic studies revealed that BETis targeted multiple essential homologous recombination pathway proteins, including RAD51, BRCA1 and CtIP. The exact mechanism of BETis’ anticancer action remains poorly understood; nevertheless, these agents provide a novel approach to epigenome and transcriptome anticancer therapy.

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 Higher prevalence of homologous recombination-deficiency in lung squamous carcinoma from African Americans

2019 ◽  
Author(s):  
Sanju Sinha ◽  
Khadijah A. Mitchell ◽  
Adriana Zingone ◽  
Elise Bowman ◽  
Neelam Sinha ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Copy Number ◽  
Squamous Carcinoma ◽  
The Cancer Genome Atlas ◽  
Multiple Cancer ◽  
Homologous Recombination Deficiency ◽  
Molecular Features ◽  
Incidence And Mortality ◽  
Cancer Types ◽  
Lung Squamous Carcinoma

AbstractTo improve our understanding of the longstanding disparities in incidence and mortality across multiple cancer types among minority populations, we performed a systematic comparative analysis of molecular features in tumors from African American (AA) and European American (EA) ancestry. Our pan-cancer analysis on the cancer genome atlas (TCGA) and a more focused analysis of genome-wide somatic copy number profiles integrated with tumor-normal RNA sequencing in a racially balanced cohort of 222 non-small cell lung cancers (NSCLC) reveals more aggressive genomic characteristics of AA tumors. In general, we find AA tumors exhibit higher genomic instability (GI), homologous recombination-deficiency (HRD) levels, and more aggressive molecular features such as chromothripsis across many cancer types, including lung squamous carcinoma (LUSC). GI and HRD levels are strongly correlated across AA tumors, indicating that HRD plays an important role in GI in these patients. The prevalence of germline HRD is higher in AA tumors, suggesting that the somatic differences observed have genetic ancestry origins. Finally, we identify AA-specific copy number-based arm, focal and gene level recurrent features in lung cancer, including a higher frequency of PTEN deletion and KRAS amplification and a lower frequency of CDKN2A deletion. These results highlight the importance of including minority and under-represented populations in genomics research and may have therapeutic implications.

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