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DNA polymerase ? mutational signatures are found in a variety of different types of cancer.

ABSTRACT: DNA polymerase (pol) ? is a specialized error-prone polymerase with at least two quite different and contrasting cellular roles: to mitigate the genetic consequences of solar UV irradiation, and promote somatic hypermutation in the variable regions of immunoglobulin genes. Misregulation and mistargeting of pol ? can compromise genome integrity. We explored whether the mutational signature of pol ? could be found in datasets of human somatic mutations derived from normal and cancer cells. A substantial excess of single and tandem somatic mutations within known pol ? mutable motifs was noted in skin cancer as well as in many other types of human cancer, suggesting that somatic mutations in A:T bases generated by DNA polymerase ? are a common feature of tumorigenesis. Another peculiarity of pol ?mutational signatures, mutations in YCG motifs, led us to speculate that error-prone DNA synthesis opposite methylated CpG dinucleotides by misregulated pol ? in tumors might constitute an additional mechanism of cytosine demethylation in this hypermutable dinucleotide.

SUBMITTER: Rogozin IB

PROVIDER: S-EPMC5914734 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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DNA polymerase η mutational signatures are found in a variety of different types of cancer.

Rogozin Igor B IB Goncearenco Alexander A Lada Artem G AG De Subhajyoti S Yurchenko Vyacheslav V Nudelman German G Panchenko Anna R AR Cooper David N DN Pavlov Youri I YI

Cell cycle (Georgetown, Tex.) 20180215 3

DNA polymerase (pol) η is a specialized error-prone polymerase with at least two quite different and contrasting cellular roles: to mitigate the genetic consequences of solar UV irradiation, and promote somatic hypermutation in the variable regions of immunoglobulin genes. Misregulation and mistargeting of pol η can compromise genome integrity. We explored whether the mutational signature of pol η could be found in datasets of human somatic mutations derived from normal and cancer cells. A subst ...[more]

PMID: 29139326

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Project description:BACKGROUND:Synonymous mutations have been identified to play important roles in cancer development, although they do not modify the protein sequences. However, relatively little research has specifically delineated the functionality of synonymous mutations in cancer. RESULTS:We investigated the nucleotide-based and amino acid-based features of synonymous mutations across 15 cancer types from The Cancer Genome Atlas (TCGA), and revealed novel driver candidates by identifying hotspot mutations. Firstly, synonymous mutations were analyzed between TCGA and 1000 Genomes Project at nucleotide and amino acid levels. We found that C:G → T:A transitions were the most frequent single-base substitutions, and leucine underwent the largest number of synonymous mutations in TCGA due to prevalent C → T transition, which induced the transformation between optimal and non-optimal codons. Next, 97 synonymous hotspot mutations in 86 genes were nominated as candidate drivers with potential cancer risk by considering the mutational rates across different sequence contexts. We observed that non-CpG-island GC transition sequence context was positively selected across most of cancer types, and different sequence contexts under which hotspot mutations occur could be significance for genetic differences and functional features. We also found that the hotspots were more conserved than neutral mutations of hotspot-mutation-containing-genes and frequently happened at leucine. In addition, we mapped hotspots, neutral and non-hotspot mutations of hotspot-mutation-containing-genes to their respective protein domains and found ion transport domain was the most frequent one, which could mediate the cell interaction and had relevant implication for tumor therapy. And the signatures of synonymous hotspots were qualitatively similar with those of harmful missense variants. CONCLUSIONS:We illustrated the preferences of cancer associated synonymous mutations, especially hotspots, and laid the groundwork for understanding the synonymous mutations act as drivers in cancer.

Dataset Information

DNA polymerase ? mutational signatures are found in a variety of different types of cancer.

Publications

DNA polymerase η mutational signatures are found in a variety of different types of cancer.

Similar Datasets

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