scholarly journals Small-molecule binding sites to explore protein–protein interactions in the cancer proteome

2016 ◽  
Vol 12 (10) ◽  
pp. 3067-3087 ◽  
Author(s):  
David Xu ◽  
Shadia I. Jalal ◽  
George W. Sledge ◽  
Samy O. Meroueh
Keyword(s):  
Small Molecule ◽  
Protein Interactions ◽  
Binding Sites ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Mrna Levels ◽  
Protein Protein Interactions ◽  
Poor Survival ◽  
Cancer Genome Atlas ◽  
Genome Atlas

The Cancer Genome Atlas (TCGA) offers an unprecedented opportunity to identify small-molecule binding sites on proteins with overexpressed mRNA levels that correlate with poor survival.

Mutational oncogenic signatures on structurally resolved protein interacting interfaces

2015 ◽  
Author(s):  
Luz Garcia-Alonso ◽  
Joaquin Dopazo
Keyword(s):  
Cancer Patients ◽  
Protein Interactions ◽  
Three Dimensional ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Protein Protein Interactions ◽  
Cancer Occurrence ◽  
Domain Interactions ◽  
Cancer Mutations ◽  
Cancer Genome Atlas

The importance of the context of interactions in the proteins mutated in cancer is long known. However, our knowledge on how mutations affecting to protein-protein interactions (PPIs) are related to cancer occurrence and progression is still poor. Here, we extracted the missense somatic mutations from 5920 cancer patients of 33 different cancer types, taken from the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), and mapped them onto a structurally resolved interactome, which integrates three-dimensional atomic-level models of domain-domain interactions with experimentally determined PPIs, involving a total of 7580 unique interacting domains that participate in 13160 interactions connecting 4996 proteins. We observed that somatic nonsynonymous mutations tend to concentrate in ordered regions of the affected proteins and, within these, they have a clear preference for the interacting interfaces. Also, we have identified more than 250 interacting interfaces candidate to drive cancer. Examples demonstrate how mutations in the interacting interfaces are strongly associated with patient survival time, while similar mutations in other areas of the same proteins lack this association. Our results suggest that the perturbation caused by cancer mutations in protein interactions is an important factor in explaining the heterogeneity between cancer patients.

scholarly journals L1CAM is an independent predictor of poor survival in endometrial cancer — An analysis of The Cancer Genome Atlas (TCGA)

2016 ◽  
Vol 141 (2) ◽  
pp. 336-340 ◽  
Author(s):  
Thanh H. Dellinger ◽  
David D. Smith ◽  
Ching Ouyang ◽  
Charles D. Warden ◽  
John C. Williams ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Independent Predictor ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Poor Survival ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Indoleamine 2,3-dioxygenase (IDO1), PD-L1, and overall survival (OS) of patients diagnosed with esophageal cancer.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 50-50 ◽  
Author(s):  
Ari Rosenberg ◽  
Derek Wainwright ◽  
Alfred Rademaker ◽  
Carlos Galvez ◽  
Matthew Genet ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Survival Data ◽  
Human Cancer ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Mrna Levels ◽  
Exact Test ◽  
Kaplan Meier ◽  
Cancer Genome Atlas ◽  
Genome Atlas

50 Background: Immune checkpoint inhibition of PD-L1 is emerging as an important therapeutic target for patients with advanced esophageal cancer. However, response rates to therapy remain low. IDO1 is a rate-limiting immunosuppressive enzyme that has emerged as an important immunotherapeutic target in human cancer. The role, expression pattern, and relevance of IDO1 in esophageal cancer are currently unknown. Here, we utilize gene expression analysis of the cancer genome atlas and quantitative immunohistochemistry (IHC) to understand whether IDO1 contributes to a poor esophageal cancer patient prognosis. Methods: mRNA expression was assessed using Hi-RNA sequencing in an esophageal squamous cell carcinoma (SCC) cohort of 87 patients and an adenocarcinoma (AC) cohort of 97 patients. Survival data was obtained from the Cancer Genome Atlas. Patient survival was analyzed by the Kaplan-Meier Method. IHC for a second cohort of 93 cases of esophageal SCC were stained for IDO1, PD-L1, and CD3ε, followed by light microscopic immunoscoring analysis. Correlation between markers was analyzed using Fisher’s exact test. Results: The median OS for high versus low IDO1 mRNA levels was 15.9 months vs 41.5 months, respectively (p =0.02) in the SCC cohort. The median OS was 20.1 months and 58.6 months in the high vs low IDO1 mRNA levels, respectively (p = 0.036) in the esophageal AC cohort. High co-expression for IDO1 and PD-L1 vs low co-expression of these markers, demonstrated a median OS of 15.1 months and 41.5 months, respectively, in the SCC cohort, and 13.7 months and 41.5 months, respectively, in the AC cohort. IHC for IDO1 SCC showed a significant correlation with PD-L1 (p = < 0.0001) and CD3ε (p = < 0.0001). PD-L1 expression also significantly correlated with CD3ε expression (p = < 0.0001). Conclusions: Esophageal cancer with high IDO1 and PD-L1 levels is associated with significantly decreased survival. The expression of IDO1 and PD-L1 is significantly enhanced by the coincident intratumoral increase of T cells. These data suggest that combinatorial approaches for combination therapies that simultaneously inhibit IDO1 and PD-(L)1 may enhance T-cell mediated control of esophageal cancer in patients.

scholarly journals Exceptional Chemotherapy Response in Metastatic Colorectal Cancer Associated With Hyper-Indel–Hypermutated Cancer Genome and Comutation of POLD1 and MLH1

2017 ◽  
pp. 1-12
Author(s):  
Manish R. Sharma ◽  
James T. Auman ◽  
Nirali M. Patel ◽  
Juneko E. Grilley-Olson ◽  
Xiaobei Zhao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Somatic Mutation ◽  
Mutation Rate ◽  
Germ Line ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Response To Chemotherapy ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Purpose A 73-year-old woman with metastatic colon cancer experienced a complete response to chemotherapy with dose-intensified irinotecan that has been durable for 5 years. We sequenced her tumor and germ line DNA and looked for similar patterns in publicly available genomic data from patients with colorectal cancer. Patients and Methods Tumor DNA was obtained from a biopsy before therapy, and germ line DNA was obtained from blood. Tumor and germline DNA were sequenced using a commercial panel with approximately 250 genes. Whole-genome amplification and exome sequencing were performed for POLE and POLD1. A POLD1 mutation was confirmed by Sanger sequencing. The somatic mutation and clinical annotation data files from the colon (n = 461) and rectal (n = 171) adenocarcinoma data sets were downloaded from The Cancer Genome Atlas data portal and analyzed for patterns of mutations and clinical outcomes in patients with POLE- and/or POLD1-mutated tumors. Results The pattern of alterations included APC biallelic inactivation and microsatellite instability high (MSI-H) phenotype, with somatic inactivation of MLH1 and hypermutation (estimated mutation rate > 200 per megabase). The extremely high mutation rate led us to investigate additional mechanisms for hypermutation, including loss of function of POLE. POLE was unaltered, but a related gene not typically associated with somatic mutation in colon cancer, POLD1, had a somatic mutation c.2171G>A [p.Gly724Glu]. Additionally, we noted that the high mutation rate was largely composed of dinucleotide deletions. A similar pattern of hypermutation (dinucleotide deletions, POLD1 mutations, MSI-H) was found in tumors from The Cancer Genome Atlas. Conclusion POLD1 mutation with associated MSI-H and hyper-indel–hypermutated cancer genome characterizes a previously unrecognized variant of colon cancer that was found in this patient with an exceptional response to chemotherapy.

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