28. Creation, maintenance, and utility of a comprehensive and informative pan-cancer gene list to aid in interpretation of whole genomes in cancer

Telomere shortening at chromosomal ends due to the constraints of the DNA replication process acts as a tumor suppressor by restricting the replicative potential in primary cells. Cancers evade that limitation primarily through rejuvenation of telomerase via different mechanisms. Mutations within the promoter of the telomerase reverse transcriptase (TERT) gene define a definite method for the ribonucleic enzyme regeneration predominantly in cancers that arise from tissues with low rates of self-renewal. The promoter mutations cause a moderate surge in TERT transcription and telomerase rejuvenation to the levels sufficient to delay replicative senescence but not prevent bulk telomere shortening and genomic instability. Since the discovery, a staggering number of studies and publications have resolved the discrete aspects, effects, and clinical relevance of the TERT promoter mutations. Those noncoding alterations link the TERT transcription with oncogenic pathways, associate with markers of poor outcome, and define patients with reduced survivals in several cancers. In this review, we discuss the occurrence and impact of the promoter mutations and highlight the mechanism of TERT activation. We further deliberate on the foundational question of the abundance of the TERT promoter mutations and a general dearth of functional mutations within noncoding sequences as evident from pan-cancer analysis of the whole-genomes. We posit that the favorable genomic constellation within the TERT promoter may be less than a common occurrence in other noncoding functional elements and the evolutionary constraints limit the functional fraction within the human genome, hence the lack of abundant mutations outside the coding sequences.

Download Full-text

DriverPower: Combined burden and functional impact tests for cancer driver discovery

10.1101/215244 ◽

2017 ◽

Cited By ~ 4

Author(s):

Shimin Shuai ◽

Steven Gallinger ◽

Lincoln Stein ◽

Keyword(s):

Driver Mutations ◽

Functional Interpretation ◽

Functional Impact ◽

Genomic Features ◽

Cancer Driver ◽

Mutational Burden ◽

Mutation Model ◽

Whole Genomes ◽

Cancer Genomes ◽

Pan Cancer

AbstractWe describe DriverPower, a software package that uses mutational burden and functional impact evidence to identify cancer driver mutations in coding and non-coding sites within cancer whole genomes. Using a total of 1,373 genomic features derived from public sources, DriverPower’s background mutation model explains up to 93% of the regional variance in the mutation rate across a variety of tumour types. By incorporating functional impact scores, we are able to further increase the accuracy of driver discovery. Testing across a collection of 2,583 cancer genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) project, DriverPower identifies 217 coding and 95 non-coding driver candidates. Comparing to six published methods used by the PCAWG Drivers and Functional Interpretation Group, DriverPower has the highest F1-score for both coding and non-coding driver discovery. This demonstrates that DriverPower is an effective framework for computational driver discovery.

Download Full-text

Diagnostic significance and carcinogenic mechanism of pan-cancer gene POU5F1 in liver hepatocellular carcinoma

10.21203/rs.3.rs-51170/v1 ◽

2020 ◽

Author(s):

Dingdong He ◽

Xiaokang Zhang ◽

Jiancheng Tu

Keyword(s):

Hepatocellular Carcinoma ◽

Meta Analysis ◽

Diagnostic Value ◽

Gene Set Enrichment Analysis ◽

Clinicopathological Parameters ◽

Cancer Gene ◽

Hub Genes ◽

Liver Hepatocellular Carcinoma ◽

The Impact ◽

Pan Cancer

Abstract Background The prognostic and clinicopathological significance of POU Class 5 Homeobox 1 (POU5F1) among various cancers is disputable heretofore. The diagnostic value and function mechanism of POU5F1 in liver hepatocellular carcinoma (LIHC) have not been studied thoroughly. Methods An integrative strategy of meta-analysis, bioinformatics and wet-lab approach was used to explore the diagnostic and prognostic significance of POU5F1 in various types of tumors, especially in LIHC. Meta-analysis was utilized to investigate the impact of POU5F1 on prognosis and clinicopathological parameters in various cancers. The expression level and diagnostic value of POU5F1 were assessed by qPCR in plasma collected from LIHC patients and controls. The correlation between POU5F1 and tumor infiltrating immune cells (TIICs) in LIHC was evaluated by CIBERSORT. Gene set enrichment analysis (GSEA) was performed based on TCGA. Hub genes and related pathways were identified on the basis of co-expression genes of POU5F1. Results Elevated POU5F1 was associated with poor OS, DFS, RFS and DSS in various cancers. POU5F1 was confirmed as an independent risk factor for LIHC and correlated with tumor occurrence, stage and invasion depth. The combination of POU5F1 and AFP in plasma was with high diagnostic validity (AUC = 0.902, P < 0.001). Specifically, the level of POU5F1 was correlated with infiltrating levels of B cells, T cells, dendritic cells and monocytes in LIHC. GSEA indicated POU5F1 participated in multiple cancer related pathways and cell proliferation pathways. Moreover, CBX3, CCHCR1 and NFYC were filtered as the central hub genes of POU5F1. Conclusions Our study identified POU5F1 as a pan-cancer gene could not only be a prognostic and diagnostic biomarker in various cancers, especially in LIHC, but functionally carcinogenic in LIHC.

Download Full-text

Diagnostic significance and carcinogenic mechanism of pan‐cancer gene POU5F1 in liver hepatocellular carcinoma

Cancer Medicine ◽

10.1002/cam4.3486 ◽

2020 ◽

Vol 9 (23) ◽

pp. 8782-8800

Author(s):

Dingdong He ◽

Xiaokang Zhang ◽

Jiancheng Tu

Keyword(s):

Hepatocellular Carcinoma ◽

Cancer Gene ◽

Diagnostic Significance ◽

Liver Hepatocellular Carcinoma ◽

Pan Cancer

Download Full-text

Comprehensive characterisation of intronic mis-splicing mutations in human cancers

Oncogene ◽

10.1038/s41388-020-01614-3 ◽

2021 ◽

Author(s):

Hyunchul Jung ◽

Kang Seon Lee ◽

Jung Kyoon Choi

Keyword(s):

Current Knowledge ◽

Telomere Maintenance ◽

Splice Sites ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

Splicing Silencer ◽

Splicing Mutations ◽

Whole Genomes ◽

Cryptic Splice Sites ◽

Pan Cancer

AbstractPrevious studies studying mis-splicing mutations were based on exome data and thus our current knowledge is largely limited to exons and the canonical splice sites. To comprehensively characterise intronic mis-splicing mutations, we analysed 1134 pan-cancer whole genomes and transcriptomes together with 3022 normal control samples. The ratio-based splicing analysis resulted in 678 somatic intronic mutations, with 46% residing in deep introns. Among the 309 deep intronic single nucleotide variants, 245 altered core splicing codes, with 38% activating cryptic splice sites, 12% activating cryptic polypyrimidine tracts, and 36% and 12% disrupting authentic polypyrimidine tracts and branchpoints, respectively. All the intronic cryptic splice sites were created at pre-existing GT/AG dinucleotides or by GC-to-GT conversion. Notably, 85 deep intronic mutations indicated gain of splicing enhancers or loss of splicing silencers. We found that 64 tumour suppressors were affected by intronic mutations and blood cancers showed higher proportion of deep intronic mutations. In particular, a telomere maintenance gene, POT1, was recurrently mis-spliced by deep intronic mutations in blood cancers. We validated a pseudoexon activation involving a splicing silencer in POT1 by CRISPR/Cas9. Our results shed light on previously unappreciated mechanisms by which noncoding mutations acting on splicing codes in deep introns contribute to tumourigenesis.

Download Full-text