Genome-scale mutational signatures of aflatoxin in cells, mice and human tumors

Mi, Huang; Yu, Willie; Teoh, Wei Wei; Ardin, Maude; Jusakul, Apinya; Ng, Alvin Wei Tian; Boot, Arnoud; Abedi‐Ardekani, Behnoush; Villar, Stéphanie; Myint, Swe Swe; Othman, Rashidah; Poon, Song Ling; Heguy, Adriana; Olivier, Magalí; Hollstein, Monica; Tan, Patrick; Teh, Bin Tean; Sabapathy, Kanaga; Zavadil, Jiří; Rozen, Steven G.

doi:10.1101/130179

Cited by 28 publications

(31 citation statements)

References 59 publications

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“…2D, p= 9.50×10 -41 , 6.33×10 -91 and 5.69×10 -33 respectively, Chi-squared tests). Furthermore, TC-NER proficiency decreases with increasing distance to the transcription start site (Conaway and Conaway 1999;Huang et al 2017;Boot et al 2018). Consistent with this, T>A, T>C and T>G mutations all showed decreased transcriptional strand bias towards the 3' end of transcripts ( Fig.…”

Section: T>n Mutations Att>act Mutationssupporting

confidence: 77%

Identification of novel mutational signatures in Asian oral squamous cell carcinomas associated with bacterial infections

Boot

et al. 2018

Preprint

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Mutational signatures can reveal the history of mutagenic processes that cells were exposed to prior to and during tumourigenesis. We expect that as-yet-undiscovered mutational processes will shed further light on mutagenesis leading to carcinogenesis. With this in mind, we analyzed the mutational spectra of 36 Asian oral squamous cell carcinomas. The mutational spectra of two samples from patients who presented with oral bacterial infections, showed novel mutational signatures. One of these novel signatures, SBS_AnT, is characterized by a preponderance of thymine mutations, strong transcriptional strand bias, and striking enrichment for adenines in the 4 base pairs 5’ of mutation sites. Examination of publicly available sequencing data revealed SBS_AnT in 25 tumours from several mucosal tissue types, all of which harbour human symbionts or are adjacent to tissues that harbour symbionts. Data in a preprint released while this manuscript was in revision strongly suggest that the bacterial compound colibactin causes SBS_AnT.

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Section: T>n Mutations Att>act Mutationssupporting

confidence: 77%

Identification of novel mutational signatures in Asian oral squamous cell carcinomas associated with bacterial infections

Boot

et al. 2018

Preprint

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“…This finding 422 suggests that the mutational processes that underlie these signatures are only active after 423 oncogenic transformation, or that mutagen exposure in liver cancer (progenitor) cells is 424 different from in vivo mouse ASCs and in vitro human ASCs. Liver cancer-specific Signature 425 24, for example, is associated with Aflatoxin intake(Huang et al 2017), a substance to 426 which our mice and organoids were not exposed. In addition, Signature 1 and Signature 5,427 which have been previously associated with age (Blokzijl et al 2016; Alexandrov et al 428 2015), did not have an increased contribution in the ASCs of progeroid Ercc1 -/Δ mice.…”

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confidence: 99%

Deficiency of nucleotide excision repair explains mutational signature observed in cancer

Jager

Blokzijl

Kuijk

et al. 2017

Preprint

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Nucleotide excision repair (NER) is one of the main DNA repair pathways that protect cells against genomic damage. Disruption of this pathway can contribute to the development of cancer and accelerate aging. Tumors deficient in NER are more sensitive to cisplatin treatment. Characterization of the mutational consequences of NER-deficiency may therefore provide important diagnostic opportunities. Here, we analyzed the somatic mutational profiles of adult stem cells (ASCs) from NER-deficient Ercc1-/Δ mice, using whole-genome sequencing analysis of clonally derived organoid cultures. Our results indicate that NER-deficiency increases the base substitution load in liver, but not in small intestinal ASCs, which coincides with a tissue-specific aging-pathology observed in these mice. The mutational landscape changes as a result of NER-deficiency in ASCs of both tissues and shows an increased contribution of Signature 8 mutations, which is a pattern with unknown etiology that is recurrently observed in various cancer types. The scattered genomic distribution of the acquired base substitutions indicates that deficiency of global-genome NER (GG-NER) is responsible for the altered mutational landscape. In line with this, we observed increased Signature 8 mutations in a GG-NER-deficient human organoid culture in which XPC was deleted using CRISPR-Cas9 gene-editing. Furthermore, genomes of NER-deficient breast tumors show an increased contribution of Signature 8 mutations compared with NER-proficient tumors. Elevated levels of Signature 8 mutations may therefore serve as a biomarker for NER-deficiency and could improve personalized cancer treatment strategies.

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“…Indeed, non-human cell lines are known to differ in DNA damage susceptibility (MacRae et al 2015), e.g. exposing aflatoxin to cell lines, mouse tumors and human tumors results in great diversity in mutation profiles (Huang et al 2017). Likewise, cisplatin signatures characterized with cell lines of different model organisms (Szikriszt et al 2016;Meier et al 2014) do not recapitulate the cisplatin patterns recently found in human cancer L.…”

Section: Discussionmentioning

confidence: 99%

5-Fluorouracil treatment induces characteristic T>G mutations in human cancer

Christensen

Roest

Besselink

et al. 2019

Preprint

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5-Fluorouracil (5-FU) is a chemotherapeutic drug component that is commonly used for the treatment of solid cancers. It is proposed that 5-FU possesses anticancer properties via the interference with nucleotide synthesis and incorporation into DNA. As both mechanisms may have a mutational impact on both surviving tumor and healthy cells, we treated intestinal organoids with 5-FU followed by whole genome sequencing analysis and uncovered a highly characteristic mutational pattern that is dominated by T>G substitutions in a CTT context. Analysis of tumor whole genome sequencing data confirmed that this signature can also be identified in vivo in colorectal and breast cancer patients that have undergone treatment with 5-FU. We also found that more 5-FU mutations are induced in TP53 null backgrounds which may be of clinical relevance. Taken together, our results demonstrate that 5-FU is mutagenic and may drive tumor evolution and increase the risk of secondary malignancies. Furthermore, the identified signature shows a strong resemblance to COSMIC signature 17, the hallmark signature of treatment-naive esophageal and gastric tumors, which indicates that distinct endogenous and exogenous triggers can converge onto highly similar mutational signatures. The use of 5-Fluorouracil (5-FU) as an anticancer agent became routine practice soon after its primary synthesis in 1957, and remains essential in many chemotherapeutic regimens today (Longley, Harkin, and Johnston 2003). The fluoropyrimidines, especially 5-FU, capecitabine, tegafur and cytarabine, are currently the third most commonly used anticancer drug in the treatment of solid cancers, including colorectal and breast cancers, and over two million patients are estimated to be treated with fluoropyrimidines each year (Ezzeldin and Diasio 2004). Response rates of 5-FU as a single drug are 10-15%, but increase drastically (>50% response) when given in combination therapies with leucovorin together with oxaliplatin or irinotecan (i.e. FOLFOX and FOLFIRI, respectively) (de Gramont et al. 2000;Boige et al. 2010;Cameron, Gabra, and Leonard 1994).The antifolate property of fluoropyrimidines is thought to be the principal mechanism of action. Fluoropyrimidines are intracellularly converted into the antifolate 5-fluorodeoxyuridine monophosphate (5-FdUMP) that can form a covalent intermediate with the folate-dependent enzyme thymidylate synthase (TYMS) (Sommer and Santi 1974). Consequently, the formation of dTMP from dUMP is inhibited which results in an imbalance of the nucleotide pool that affects DNA synthesis, possibly through incorporation of uracil, and impairs genome replication, with negative consequences for rapidly dividing cells such as cancer cells. Moreover, it has been proposed that 5-fluorodeoxyuridine triphosphate (5-FdUTP) can be directly incorporated into genomic DNA as well (Pettersen et al. 2011;Huehls et al. 2016). Considering these properties, it is conceivable that fluoropyrimidines have mutagenic potential, although the mutational consequences of 5-FU tr...

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Genome-scale mutational signatures of aflatoxin in cells, mice and human tumors

Cited by 28 publications

References 59 publications

Identification of novel mutational signatures in Asian oral squamous cell carcinomas associated with bacterial infections

Identification of novel mutational signatures in Asian oral squamous cell carcinomas associated with bacterial infections

Deficiency of nucleotide excision repair explains mutational signature observed in cancer

5-Fluorouracil treatment induces characteristic T>G mutations in human cancer

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