GENIPAC: A Genomic Information Portal for Head and Neck Cancer Cell Systems

2018 ◽  
Vol 97 (8) ◽  
pp. 909-916 ◽  
Author(s):  
B.K.B. Lee ◽  
C.P. Gan ◽  
J.K. Chang ◽  
J.L. Tan ◽  
M.Z. Fadlullah ◽  
...  
Keyword(s):  
Head And Neck Cancer ◽  
Head And Neck ◽  
Exome Sequencing ◽  
Cell Lines ◽  
Copy Number ◽  
Rna Seq ◽  
Copy Number Alterations ◽  
Genomic Information ◽  
Genomic Alterations ◽  
Whole Exome

Head and neck cancer (HNC)–derived cell lines represent fundamental models for studying the biological mechanisms underlying cancer development and precision therapies. However, mining the genomic information of HNC cells from available databases requires knowledge on bioinformatics and computational skill sets. Here, we developed a user-friendly web resource for exploring, visualizing, and analyzing genomics information of commonly used HNC cell lines. We populated the current version of GENIPAC with 44 HNC cell lines from 3 studies: ORL Series, OPC-22, and H Series. Specifically, the mRNA expressions for all the 3 studies were derived with RNA-seq. The copy number alterations analysis of ORL Series was performed on the Genome Wide Human Cytoscan HD array, while copy number alterations for OPC-22 were derived from whole exome sequencing. Mutations from ORL Series and H Series were derived from RNA-seq information, while OPC-22 was based on whole exome sequencing. All genomic information was preprocessed with customized scripts and underwent data validation and correction through data set validator tools provided by cBioPortal. The clinical and genomic information of 44 HNC cell lines are easily assessable in GENIPAC. The functional utility of GENIPAC was demonstrated with some of the genomic alterations that are commonly reported in HNC, such as TP53, EGFR, CCND1, and PIK3CA. We showed that these genomic alterations as reported in The Cancer Genome Atlas database were recapitulated in the HNC cell lines in GENIPAC. Importantly, genomic alterations within pathways could be simultaneously visualized. We developed GENIPAC to create access to genomic information on HNC cell lines. This cancer omics initiative will help the research community to accelerate better understanding of HNC and the development of new precision therapeutic options for HNC treatment. GENIPAC is freely available at http://genipac.cancerresearch.my/ .

Abstract 3931: Whole genome and whole exome sequencing of head and neck cancer

2011 ◽  
Author(s):  
Nicolas Stransky ◽  
Ann Marie Egloff ◽  
Aaron Tward ◽  
Daniel Auclair ◽  
Kristian Cibulskis ◽  
...  
Keyword(s):  
Head And Neck Cancer ◽  
Head And Neck ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Neck Cancer ◽  
Whole Genome ◽  
Whole Exome

scholarly journals Whole-exome sequencing of cervical carcinomas identifies activating ERBB2 and PIK3CA mutations as targets for combination therapy

2019 ◽  
Vol 116 (45) ◽  
pp. 22730-22736 ◽  
Author(s):  
Luca Zammataro ◽  
Salvatore Lopez ◽  
Stefania Bellone ◽  
Francesca Pettinella ◽  
Elena Bonazzoli ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Cell Lines ◽  
Copy Number ◽  
Mtor Pathway ◽  
In Vivo Models ◽  
Whole Exome

The prognosis of advanced/recurrent cervical cancer patients remains poor. We analyzed 54 fresh-frozen and 15 primary cervical cancer cell lines, along with matched-normal DNA, by whole-exome sequencing (WES), most of which harboring Human-Papillomavirus-type-16/18. We found recurrent somatic missense mutations in 22 genes (including PIK3CA, ERBB2, and GNAS) and a widespread APOBEC cytidine deaminase mutagenesis pattern (TCW motif) in both adenocarcinoma (ACC) and squamous cell carcinomas (SCCs). Somatic copy number variants (CNVs) identified 12 copy number gains and 40 losses, occurring more often than expected by chance, with the most frequent events in pathways similar to those found from analysis of single nucleotide variants (SNVs), including the ERBB2/PI3K/AKT/mTOR, apoptosis, chromatin remodeling, and cell cycle. To validate specific SNVs as targets, we took advantage of primary cervical tumor cell lines and xenografts to preclinically evaluate the activity of pan-HER (afatinib and neratinib) and PIK3CA (copanlisib) inhibitors, alone and in combination, against tumors harboring alterations in the ERBB2/PI3K/AKT/mTOR pathway (71%). Tumors harboring ERBB2 (5.8%) domain mutations were significantly more sensitive to single agents afatinib or neratinib when compared to wild-type tumors in preclinical in vitro and in vivo models (P = 0.001). In contrast, pan-HER and PIK3CA inhibitors demonstrated limited in vitro activity and were only transiently effective in controlling in vivo growth of PIK3CA-mutated cervical cancer xenografts. Importantly, combinations of copanlisib and neratinib were highly synergistic, inducing long-lasting regression of tumors harboring alterations in the ERBB2/PI3K/AKT/mTOR pathway. These findings define the genetic landscape of cervical cancer, suggesting that a large subset of cervical tumors might benefit from existing ERBB2/PIK3CA/AKT/mTOR-targeted drugs.

scholarly journals Whole-Exome Sequencing Characterizes the Landscape of Somatic Mutations and Copy Number Alterations in Adrenocortical Carcinoma

2015 ◽  
Vol 100 (3) ◽  
pp. E493-E502 ◽  
Author(s):  
C. Christofer Juhlin ◽  
Gerald Goh ◽  
James M. Healy ◽  
Annabelle L. Fonseca ◽  
Ute I. Scholl ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Adrenocortical Carcinoma ◽  
Copy Number ◽  
Somatic Mutations ◽  
Copy Number Alterations ◽  
Whole Exome

scholarly journals Case Report: Exome sequencing reveals recurrent RETSAT mutations and a loss-of-function POLDIP2 mutation in a rare undifferentiated tongue sarcoma

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 499 ◽  
Author(s):  
Jason Y. K. Chan ◽  
Peony Hiu Yan Poon ◽  
Yong Zhang ◽  
Cherrie W. K. Ng ◽  
Wen Ying Piao ◽  
...  
Keyword(s):  
Head And Neck Cancer ◽  
Head And Neck ◽  
Exome Sequencing ◽  
Mutation Rate ◽  
Neck Cancer ◽  
Genetic Profile ◽  
Rare Cancer ◽  
Undifferentiated Sarcoma ◽  
Whole Exome ◽  
Recurrent Mutations

Soft tissue sarcoma of the tongue represents a very rare head and neck cancer with connective tissue features, and the genetics underlying this rare cancer are largely unknown. There are less than 20 cases reported in the literature thus far. Here, we reported the first whole-exome characterization (>×200 depth) of an undifferentiated sarcoma of the tongue in a 31-year-old male. Even with a very good sequencing depth, only 19 nonsynonymous mutations were found, indicating a relatively low mutation rate of this rare cancer (lower than that of human papillomavirus (HPV)-positive head and neck cancer). Yet, among the few genes that are somatically mutated in this HPV-negative undifferentiated tongue sarcoma, a noticeable deleterious frameshift mutation (with a very high allele frequency of >93%) of a gene for DNA replication and repair, namelyPOLDIP2(DNA polymerase delta interacting protein 2), and two recurrent mutations of the adipogenesis and adipocyte differentiation geneRETSAT(retinol saturase), were identified. Thus, somatic events likely affecting adipogenesis and differentiation, as well as potential stem mutations toPOLDIP2, may be implicated in the formation of this rare cancer. This identified somatic whole-exome sequencing profile appears to be distinct from that of other reported adult sarcomas from The Cancer Genome Atlas, suggesting a potential unique genetic profile for this rare sarcoma of the tongue. Interestingly, this low somatic mutation rate is unexpectedly found to be accompanied by multiple tumor protein p53 andNOTCH1germline mutations of the patient’s blood DNA. This may explain the very early age of onset of head and neck cancer, with likely hereditary predisposition. Our findings are, to our knowledge, the first to reveal a unique genetic profile of this very rare undifferentiated sarcoma of the tongue.

scholarly journals 935 Attraction of immune cells by head and neck cancer cell lines and primary tumor-conditioned supernatants

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A981-A981
Author(s):  
Tara Muijlwijk ◽  
Naomi Remkes ◽  
Jos Poell ◽  
René Leemans ◽  
Ruud Brakenhoff ◽  
...  
Keyword(s):  
Head And Neck Cancer ◽  
Head And Neck ◽  
Cell Lines ◽  
Immune Cells ◽  
Copy Number ◽  
Immune Cell ◽  
Cd8 T Cell ◽  
Squamous Cell Carcinomas ◽  
Immune Cell Migration ◽  
Hnscc Cell

BackgroundHead and neck squamous cell carcinomas (HNSCC) are classified in human papillomavirus (HPV)-positive and HPV-negative tumors. In general, HPV-negative HNSCC are genetically characterized by many chromosomal gains and losses.1 Previously, we and others identified a HPV-negative subgroup with few or absent copy number alterations (CNA-silent), and a more favorable prognosis.2 3 Tumors with low copy number changes have generally been associated with high immune infiltration scores,4 but for CNA-silent versus CNA-high HPV-negative HNSCC such data are lacking.In this study we aim to unravel by functional assays immunological differences between HPV-negative and HPV-positive HNSCC, as well as between CNA-silent and CNA-high HPV-negative HNSCC. We analyzed the immune cell subsets attracted by HNSCC cell lines and by tumor-conditioned supernatants.MethodsEight HNSCC cell lines (3 HPV-positive, 3 HPV-negative CNA-high, 2 HPV-negative CNA-silent) and 24-hour supernatants of thirteen HNSCC biopsies were used to characterize their ability to attract immune cells in a transwell migration system. A chemokine mixture was used as a positive control, while medium alone was used to determine spontaneous migration. Peripheral blood mononuclear cells (PBMCs) of various healthy donors were plated in the upper compartment and after six hours the transwell migration was quantified by flow cytometry.ResultsMost HNSCC cell lines induced migration of monocytes, B cells and CD4+ T-cells up to maximal 12%, whereas CD8+ T-cells and conventional dendritic cells (cDCs) were not attracted, irrespective of the donor. Notably, one HPV-negative CNA-silent cell line induced significantly more migration compared to the negative control and other cell lines. Tumor-conditioned supernatants promoted immune cell migration with no apparent differences between tumor sites or HPV-status. Remarkably, up to 31% of monocytes migrated to these supernatants, 9x more than the chemokine control. Also cDC migration was induced, whereas lymphocytes were not attracted.ConclusionsHNSCC cell lines induced monocyte, B-lymphocyte and CD4+ T-lymphocyte migration, whereas tumor-conditioned supernatants attracted monocytes and cDCs only. No difference in immune cell attraction between HPV-positive and -negative HNSCC was observed. Interestingly, one HPV-negative CNA-silent cell line induced robust immune cell migration. Currently we perform a comprehensive chemokine analysis to explain the observed migration. The noted lack of CD8+ T-cell attraction may explain why current treatments with PD-1 inhibitors are effective in only a minority of HNSCC patients. Our data could provide a means to identify patients who might most likely respond to immune checkpoint blockade and to find clues to improve CD8+ T-cell attraction.ReferencesLeemans CR, Snijders PJF, Brakenhoff RH. The molecular landscape of head and neck cancer. Nat Rev Cancer 2018;18:269–82.Smeets SJ, Brakenhoff RH, Ylstra B, van Wieringen WN, van de Wiel MA, Leemans CR, et al. Genetic classification of oral and oropharyngeal carcinomas identifies subgroups with a different prognosis. Cell Oncol 2009;31:291–300.Cancer Genome Atlas N. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 2015;517:576–82.Davoli T, Uno H, Wooten EC, Elledge SJ. Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy. Science 2017;355.Ethics ApprovalWritten informed consent was obtained from all patients from whom fresh tumor biopsies were used for research, as part of the HNcol protocol at the Department of Otolaryngology|Head and Neck Surgery of Amsterdam UMC (VUmc) as approved by the Institutional Review Board (2008.071|A2016.035). Buffy coats, with written consent from the donors, were purchased from the Dutch blood bank (Sanquin) and used to isolate PBMC.

scholarly journals Copy-number alterations reshape the classification of diffuse intrinsic pontine gliomas. First exome sequencing results of the BIOMEDE trial.

2021 ◽  
Author(s):  
Thomas Kergrohen ◽  
David Castel ◽  
Gwenael Le Teuff ◽  
Arnault Tauziede-Espariat ◽  
Emmanuele Lechapt-Zalcman ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Copy Number ◽  
Copy Number Alteration ◽  
Present Report ◽  
Copy Number Alterations ◽  
Randomized Phase Ii ◽  
Whole Exome ◽  
Diffuse Intrinsic Pontine Gliomas ◽  
Made In

Diffuse intrinsic pontine gliomas (DIPG) is an incurable neoplasm occurring mainly in children for which no progress was made in the last decades. The randomized phase II BIOMEDE trial compared three drugs (everolimus, dasatinib, erlotinib) combined with irradiation. The present report describes whole exome sequencing (WES) results for the first 100 patients randomized. Copy-number-Alteration (CNA) unsupervised clustering identified four groups with different outcomes and biology. This classification improved prognostication compared to models based on known biomarkers (Histone H3 and TP53 mutations). The cluster presenting complex genomic rearrangements was associated with significantly worse outcome and TP53 dysfunction. Mutation and CNA signatures confirmed the frequent alteration in DNA repair machinery. With respect to potential targetable pathways, PI3K/AKT/mTOR activation occurred in all the samples through multiples mechanisms. In conclusion, WES at diagnosis was feasible in most patients and provides a better patient stratification and theranostic information for precision medicine.

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