Integrated Informatics Analysis of Cancer-Related Variants

Pagel, Kymberleigh A.; Kim, Rick; Moad, Kyle; Busby, Ben; Zheng, Lily; Tokheim, Collin; Ryan, Michaël; Karchin, Rachel

doi:10.1200/cci.19.00132

Cited by 77 publications

(60 citation statements)

References 24 publications

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“…Major structural variants (SVs) were inferred with Manta 0.27.1 [ 58 ]. The annotation and further filtering of Strelka quality-passed SNVs and indels were done based on two different platforms, i.e., OpenCravat [ 59 ] and Gemini-Seave pipeline [ 60 ]. Mutational signatures were determined for each specimen as per the method described by Mueller et al [ 18 ].…”

Section: Methodsmentioning

confidence: 99%

Comprehensive Mutational and Phenotypic Characterization of New Metastatic Cutaneous Squamous Cell Carcinoma Cell Lines Reveal Novel Drug Susceptibilities

Perry

Ashford

Thind

et al. 2020

IJMS

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Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer. Most patients who develop metastases (2–5%) present with advanced disease that requires a combination of radical surgery and adjuvant radiation therapy. There are few effective therapies for refractory disease. In this study, we describe novel patient-derived cell lines from cSCC metastases of the head and neck (designated UW-CSCC1 and UW-CSCC2). The cell lines genotypically and phenotypically resembled the original patient tumor and were tumorogenic in mice. Differences in cancer-related gene expression between the tumor and cell lines after various culturing conditions could be largely reversed by xenografting and reculturing. The novel drug susceptibilities of UW-CSCC1 and an irradiated subclone UW-CSCC1-R to drugs targeting cell cycle, PI3K/AKT/mTOR, and DNA damage pathways were observed using high-throughput anti-cancer and kinase-inhibitor compound libraries, which correlate with either copy number variations, targetable mutations and/or the upregulation of gene expression. A secondary screen of top hits in all three cell lines including PIK3CA-targeting drugs supports the utility of targeting the PI3K/AKT/mTOR pathway in this disease. UW-CSCC cell lines are thus useful preclinical models for determining targetable pathways and candidate therapeutics.

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Section: Methodsmentioning

confidence: 99%

Comprehensive Mutational and Phenotypic Characterization of New Metastatic Cutaneous Squamous Cell Carcinoma Cell Lines Reveal Novel Drug Susceptibilities

Perry

Ashford

Thind

et al. 2020

IJMS

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“…To prioritize cancer-related genes in AA ESCC, we employed a combination of analyses in Opencravat 25 . We identified 23 missense and splice site mutations and 34 noncoding or synonymous variants previously described in ESCC in COSMIC database (Supplementary Table S4 ).…”

Section: Resultsmentioning

confidence: 99%

Exome sequencing identifies novel somatic variants in African American esophageal squamous cell carcinoma

Erkizan¹,

Sukhadia

Natarajan³

et al. 2021

Sci Rep

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Esophageal cancer has a strikingly low survival rate mainly due to the lack of diagnostic markers for early detection and effective therapies. In the U.S., 75% of individuals diagnosed with esophageal squamous cell carcinoma (ESCC) are of African descent. African American ESCC (AA ESCC) is particularly aggressive, and its biological underpinnings remain poorly understood. We sought to identify the genomic abnormalities by conducting whole exome sequencing of 10 pairs of matched AA esophageal squamous cell tumor and control tissues. Genomic analysis revealed diverse somatic mutations, copy number alterations (SCNAs), and potential cancer driver genes. Exome variants created two subgroups carrying either a high or low tumor mutation burden. Somatic mutational analysis based on the Catalog of Somatic Mutations in Cancer (COSMIC) detected SBS16 as the prominent signature in the high mutation rate group suggesting increased DNA damage. SBS26 was also detected, suggesting possible defects in mismatch repair and microsatellite instability. We found SCNAs in multiple chromosome segments, encoding MYC on 8q24.21, PIK3CA and SOX2 on 3q26, CCND1, SHANK2, CTTN on 11q13.3, and KRAS on 12p12. Amplifications of EGFRvIII and EGFRvIVa mutants were observed in two patients, representing a novel finding in ESCC that has potential clinical relevance. This present exome sequencing, which to our knowledge, represents the first comprehensive exome analysis exclusively in AA ESCC, and highlights novel mutated loci that might explain the aggressive nature of AA ESCC and lead to the development of diagnostic and prognostic markers as well as therapeutic targets.

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“…For CanDrA+, we used the default prediction categories [ 27 ]. Predictions for CHASMplus and CanDrA+ were obtained from the OpenCRAVAT web server [ 55 ] and executable packages published by Mao et al [ 27 ]. Two ensemble techniques were used to combine the outputs produced by different mutation effect predictors.…”

Section: Methodsmentioning

confidence: 99%

Sequence Neighborhoods Enable Reliable Prediction of Pathogenic Mutations in Cancer Genomes

Banerjee

Raman

Ravindran

2021

Cancers

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Identifying cancer-causing mutations from sequenced cancer genomes hold much promise for targeted therapy and precision medicine. “Driver” mutations are primarily responsible for cancer progression, while “passengers” are functionally neutral. Although several computational approaches have been developed for distinguishing between driver and passenger mutations, very few have concentrated on using the raw nucleotide sequences surrounding a particular mutation as potential features for building predictive models. Using experimentally validated cancer mutation data in this study, we explored various string-based feature representation techniques to incorporate information on the neighborhood bases immediately 5′ and 3′ from each mutated position. Density estimation methods showed significant distributional differences between the neighborhood bases surrounding driver and passenger mutations. Binary classification models derived using repeated cross-validation experiments provided comparable performances across all window sizes. Integrating sequence features derived from raw nucleotide sequences with other genomic, structural, and evolutionary features resulted in the development of a pan-cancer mutation effect prediction tool, NBDriver, which was highly efficient in identifying pathogenic variants from five independent validation datasets. An ensemble predictor obtained by combining the predictions from NBDriver with three other commonly used driver prediction tools (FATHMM (cancer), CONDEL, and MutationTaster) significantly outperformed existing pan-cancer models in prioritizing a literature-curated list of driver and passenger mutations. Using the list of true positive mutation predictions derived from NBDriver, we identified a list of 138 known driver genes with functional evidence from various sources. Overall, our study underscores the efficacy of using raw nucleotide sequences as features to distinguish between driver and passenger mutations from sequenced cancer genomes.

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Integrated Informatics Analysis of Cancer-Related Variants

Cited by 77 publications

References 24 publications

Comprehensive Mutational and Phenotypic Characterization of New Metastatic Cutaneous Squamous Cell Carcinoma Cell Lines Reveal Novel Drug Susceptibilities

Comprehensive Mutational and Phenotypic Characterization of New Metastatic Cutaneous Squamous Cell Carcinoma Cell Lines Reveal Novel Drug Susceptibilities

Exome sequencing identifies novel somatic variants in African American esophageal squamous cell carcinoma

Sequence Neighborhoods Enable Reliable Prediction of Pathogenic Mutations in Cancer Genomes

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