Comprehensive Characterization of Cancer Driver Genes and Mutations

Bailey, Matthew H.; Tokheim, Collin; Porta-Pardo, Eduard; Sengupta, Sohini; Bertrand, Denis; Weerasinghe, Amila; Colaprico, Antonio; Wendl, Michael C.; Kim, Jaegil; Reardon, Brendan; Ng, Patrick Kwok-Shing; Jeong, Kang Jin; Cao, Song; Wang, Zixing; Gao, Jianjiong; Gao, Qingsong; Fan, Huihui; Liu, Eric Minwei; Mularoni, Loris; Rubio-Pérez, Carlota; Nagarajan, Niranjan; Cortés-Ciriano, Isidro; Zhou, Daniel Cui; Liang, Wen-Wei; Hess, Julian M.; Yellapantula, Venkata; Tamborero, David; González-Pérez, Abel; Suphavilai, Chayaporn; Ko, Jia Yu; Khurana, Ekta; Park, Peter J.; Allen, Eliezer M. Van; Liang, Han; Lawrence, Michael S.; Godzik, Adam; Stuart, Joshua M.; Wheeler, David A.; Getz, Gad; Chen, Ken; Lazar, Alexander J.; Mills, Gordon B.; Karchin, Rachel; Li, Ding

doi:10.1016/j.cell.2018.02.060

Cited by 1,857 publications

(1,742 citation statements)

References 90 publications

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“…Mutation hotspots were assigned according to Chang et al (2016). CTNNB1 mutation frequencies were assessed in 10 100 common cancers from The Cancer Genome Atlas (TCGA) (Bailey et al, 2018;Gao et al, 2013), including 175 pancreatic ADCs. In addition, mutational data from 8 SPNs from Wu et al (2011) and 344 non-SPN pancreatic tumors, including 23 acinar cell carcinomas from Jiao et al (2014), 98 PNETs from Scarpa et al (2017), and 24 cystic tumors of the pancreas Wu et al (2011).…”

Section: Whole-exome Sequencing Analysismentioning

confidence: 99%

Solid pseudopapillary neoplasms of the pancreas are dependent on the Wnt pathway

et al. 2019

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Solid pseudopapillary neoplasms (SPNs) are rare and relatively indolent tumors of the pancreas. While primary SPN s can be surgically resected, there are currently no therapies available for patients with advanced stage disease. Given that these tumors frequently carry CTNNB 1 hotspot (recurrently mutated loci in a gene) mutations resulting in β‐catenin nuclear accumulation, it has been speculated that the Wnt pathway may be a driver in this disease. Here, we present a comprehensive “multi‐omics” study where the genome, transcriptome, and methylome of SPN s were analyzed. We found that SPN s are characterized by a low‐complexity genome where somatic mutations in CTNNB 1 , present in 100% of the cases, are the only actionable genomic lesions. Compared to more common subtypes of pancreatic tumors (adenocarcinomas and pancreatic neuroendocrine tumors), SPN s show high expression levels of genes belonging to the Wnt pathway. Their methylome was consistent with an epithelial cell origin and a general upregulation of Wnt pathway genes. Clinical studies to evaluate the exquisite sensitivity of SPN s to inhibitors of the Wnt pathway are warranted.

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Section: Whole-exome Sequencing Analysismentioning

confidence: 99%

Solid pseudopapillary neoplasms of the pancreas are dependent on the Wnt pathway

et al. 2019

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“…Pan-cancer efforts by The Cancer Genome Atlas (TCGA) and others have shown that cancers originating from different tissues share similar genomic signatures (Bailey et al, 2018; Hoadley et al, 2018). Certain breast and bladder cancers display a basal-like molecular profile characterized by p63 activation and the expression of specific basal cell cytokeratins (Damrauer et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

A Human Adult Stem Cell Signature Marks Aggressive Variants across Epithelial Cancers

et al. 2018

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Cancer progression to an aggressive phenotype often co-opts aspects of stem cell biology. Here, we developed gene signatures for normal human stem cell populations to understand the relationship between epithelial cancers and stem cell transcriptional programs. Using a pan-cancer approach, we reveal that aggressive epithelial cancers are enriched for a transcriptional signature shared by epithelial adult stem cells. The adult stem cell signature selected for epithelial cancers with worse overall survival and alterations of oncogenic drivers. Lethal small cell neuroendocrine lung, prostate, and bladder cancers transcriptionally converged onto the adult stem cell signature and not other stem cell signatures tested. We found that DNA methyltransferase expression correlated with adult stem cell signature status and was enriched in small cell neuroendocrine cancers. DNA methylation analysis uncovered a shared epigenomic profile between small cell neuroendocrine cancers. These pan-cancer findings establish a molecular link between human adult stem cells and aggressive epithelial cancers.

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“…13 Meanwhile, these tumors have significant high level expressions of immune checkpoint proteins, including PD-1 and PD-L1, enabling them to survive from immune eradication. 14,15 However, the TIL and tumor molecular features remains largely unknown in CRC. Therefore, understanding the expression and clinical patterns of immunologic molecules will be critical in characterizing and selecting patient populations to benefit from their application in CRC.…”

Section: Introductionmentioning

confidence: 99%

The comprehensive molecular landscape of the immunologic co-stimulator B7 and TNFR ligand receptor families in colorectal cancer: immunotherapeutic implications with microsatellite instability

Tang

Liu

et al. 2018

OncoImmunology

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Immunotherapy is reportedly effective in a subset of colorectal cancers (CRCs) with high microsatellite instability (MSI-H). Exploring the expression patterns and clinical values of immunologic molecules is critical in defining the specific responsive candidates. Here, we performed comprehensive molecular profiling of the B7 and TNFR family genes across 6 CRC datasets with over 1,000 patients’ details using cBioPortal TCGA data. About 20% of patients had B7 and TNFR family gene alterations. The frequency of B7 gene mutations (2.2%–5%) were similar to copy number alterations (0.53%–5.46%). TNFR amplifications were relatively more common (5.45–11.32%) than that of B7 (0.09–2.73%). B7 and TNFR gene mRNAs were upregulated in 26% of cases (102/379) and 16% of cases (61/379), respectively. The mRNA levels of B7 and TNFR genes were inversely correlated with promoter methylation status. Clinically, both B7-H3 and TNFSF7 mRNA overexpression were associated with unfavorable clinical outcomes, and the B7-H3 expression was increased gradually in cases with gene amplifications. Moreover, patients with MSI-H had significantly higher PD-L1 or PD-1 expression. Most importantly, in MSI-H group, patients with PD-L1 or PD-1 upregulation had poorer survivals than those with PD-L1/PD-1 downregulation. This is the first study drawing the immune landscapes of the co-stimulator B7 and TNFR families in CRC and showing that MSI-H patients with PD-1/PD-L1 upregulation are associated with poor clinical outcomes, providing potential markers to stratify patients responsive to immune checkpoint therapy.

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Comprehensive Characterization of Cancer Driver Genes and Mutations

Cited by 1,857 publications

References 90 publications

Solid pseudopapillary neoplasms of the pancreas are dependent on the Wnt pathway

Solid pseudopapillary neoplasms of the pancreas are dependent on the Wnt pathway

A Human Adult Stem Cell Signature Marks Aggressive Variants across Epithelial Cancers

The comprehensive molecular landscape of the immunologic co-stimulator B7 and TNFR ligand receptor families in colorectal cancer: immunotherapeutic implications with microsatellite instability

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