Dataset Information

Curation of cancer hallmark-based genes and pathways for in silico characterization of chemical carcinogenesis.

ABSTRACT: Exposure to toxic substances in the environment is one of the most important causes of cancer. However, the time-consuming process for the identification and characterization of carcinogens is not applicable to a huge amount of testing chemicals. The data gaps make the carcinogenic risk uncontrollable. An efficient and effective way of prioritizing chemicals of carcinogenic concern with interpretable mechanism information is highly desirable. This study presents a curation work for genes and pathways associated with 11 hallmarks of cancer (HOCs) reported by the Halifax Project. To demonstrate the usefulness of the curated HOC data, the interacting HOC genes and affected HOC pathways of chemicals of the three carcinogen lists from IARC, NTP and EPA were analyzed using the in silico toxicogenomics ChemDIS system. Results showed that a higher number of affected HOCs were observed for known carcinogens than the other chemicals. The curated HOC data is expected to be useful for prioritizing chemicals of carcinogenic concern. Database URL: The HOC database is available at https://github.com/hocdb-KMU-TMU/hocdb and the website of Database journal as Supplementary Data.

SUBMITTER: Liang PI

PROVIDER: S-EPMC7294774 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Curation of cancer hallmark-based genes and pathways for in silico characterization of chemical carcinogenesis.

Liang Peir-In PI Wang Chia-Chi CC Cheng Hsien-Jen HJ Wang Shan-Shan SS Lin Ying-Chi YC Lin Pinpin P Tung Chun-Wei CW

Database : the journal of biological databases and curation 20200101

Exposure to toxic substances in the environment is one of the most important causes of cancer. However, the time-consuming process for the identification and characterization of carcinogens is not applicable to a huge amount of testing chemicals. The data gaps make the carcinogenic risk uncontrollable. An efficient and effective way of prioritizing chemicals of carcinogenic concern with interpretable mechanism information is highly desirable. This study presents a curation work for genes and pat ...[more]

PMID: 32539087

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Project description:Cancer is sometimes depicted as a reversion to single cell behavior in cells adapted to live in a multicellular assembly. If this is the case, one would expect that mutation in cancer disrupts functional mechanisms that suppress cell-level traits detrimental to multicellularity. Such mechanisms should have evolved with or after the emergence of multicellularity. This leads to two related, but distinct hypotheses: 1) Somatic mutations in cancer will occur in genes that are younger than the emergence of multicellularity (1000 million years [MY]); and 2) genes that are frequently mutated in cancer and whose mutations are functionally important for the emergence of the cancer phenotype evolved within the past 1000 million years, and thus would exhibit an age distribution that is skewed to younger genes. In order to investigate these hypotheses we estimated the evolutionary ages of all human genes and then studied the probability of mutation and their biological function in relation to their age and genomic location for both normal germline and cancer contexts. We observed that under a model of uniform random mutation across the genome, controlled for gene size, genes less than 500 MY were more frequently mutated in both cases. Paradoxically, causal genes, defined in the COSMIC Cancer Gene Census, were depleted in this age group. When we used functional enrichment analysis to explain this unexpected result we discovered that COSMIC genes with recessive disease phenotypes were enriched for DNA repair and cell cycle control. The non-mutated genes in these pathways are orthologous to those underlying stress-induced mutation in bacteria, which results in the clustering of single nucleotide variations. COSMIC genes were less common in regions where the probability of observing mutational clusters is high, although they are approximately 2-fold more likely to harbor mutational clusters compared to other human genes. Our results suggest this ancient mutational response to stress that evolved among prokaryotes was co-opted to maintain diversity in the germline and immune system, while the original phenotype is restored in cancer. Reversion to a stress-induced mutational response is a hallmark of cancer that allows for effectively searching "protected" genome space where genes causally implicated in cancer are located and underlies the high adaptive potential and concomitant therapeutic resistance that is characteristic of cancer.

Dataset Information

Curation of cancer hallmark-based genes and pathways for in silico characterization of chemical carcinogenesis.

Publications

Curation of cancer hallmark-based genes and pathways for in silico characterization of chemical carcinogenesis.

Similar Datasets

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