Learning mutational signatures and their multidimensional genomic properties with TensorSignatures

Vöhringer, Harald; Gerstung, Moritz

doi:10.1101/850453

Cited by 20 publications

(24 citation statements)

References 48 publications

(52 reference statements)

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“…Using the trinucleotide context of each mutation, four single-base substitution reference to genomic context (11). It has been hypothesised that SBS7c and SBS7d may be due to translesion DNA synthesis by error-prone polymerases inserting T rather than A, or G rather than A, opposite UV damage respectively (10).…”

Section: Mutant Gene Selection and Mutational Signature Vary Across Tmentioning

confidence: 99%

Selection of Oncogenic Mutant Clones in Normal Human Skin Varies with Body Site

et al. 2021

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Skin cancer risk varies substantially across the body, yet how this relates to the mutations found in normal skin is unknown. Here we mapped mutant clones in skin from high and low risk sites. The density of mutations varied by location. The prevalence of NOTCH1 and FAT1 mutations in forearm, trunk and leg skin was similar to that in keratinocyte cancers. Most mutations were caused by ultraviolet (UV) light, but mutational signature analysis suggested differences in DNA repair processes between sites. 11 mutant genes were under positive selection, with TP53 preferentially selected in the head and FAT1 in the leg. Fine scale mapping revealed 10% of clones had copy number alterations. Analysis of hair follicles showed mutations in the upper follicle resembled adjacent skin, but the lower follicle was sparsely mutated. Normal skin is dense patchwork of mutant clones arising from competitive selection that varies by location. Statement of significance Mapping mutant clones across the body reveals normal skin is a dense patchwork of mutant cells. The variation in cancer risk between sites substantially exceeds that in mutant clone density. More generally, mutant genes cannot be assigned as cancer drivers until their prevalence in normal tissue is known.

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Section: Mutant Gene Selection and Mutational Signature Vary Across Tmentioning

confidence: 99%

Selection of Oncogenic Mutant Clones in Normal Human Skin Varies with Body Site

et al. 2021

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“…Thus, we might expect MMR deficiency to be associated with distinct mutational signatures, with mutation rates varying by specific base changes, indels, local sequence context and replication strand. To assess this, we extracted mutational signatures jointly for all microdissected samples, including both healthy and neoplastic, using the TensorSignatures algorithm (Vöhringer et al, 2020).…”

Section: Mmr Repairs Replication-dependent and Independent Dna Damagementioning

confidence: 99%

“…TensorSignatures (Vöhringer et al, 2020) (Pich et al, 2018). Clustered SBS were identified using a 2-state Hidden-Markov model (Vöhringer et al, 2020).…”

Section: Mutational Signature Extractionmentioning

confidence: 99%

Life without mismatch repair

Sanders

Vöhringer

Forster

et al. 2021

Preprint

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Mismatch repair (MMR) is a critical defence against mutation, but we lack quantification of its activity on different DNA lesions during human life. We performed whole-genome sequencing of normal and neoplastic tissues from individuals with constitutional MMR deficiency to establish the roles of MMR components, tissue type and disease state in somatic mutation rates. Mutational signatures varied extensively across genotypes, some coupled to leading-strand replication, some to lagging-strand replication and some independent of replication, implying that the various MMR components engage different forms of DNA damage. Loss of MSH2 or MSH6 (MutSα), but not MLH1 or PMS2 (MutLα), caused 5-methylcytosine-dependent hypermutation, indicating that MutSα is the pivotal complex for repairing spontaneous deamination of methylated cytosines in humans. Neoplastic change altered the distribution of mutational signatures, particularly accelerating replication-coupled indel signatures. Each component of MMR repairs 1-10 lesions/day per normal human cell, and many thousands of additional events during neoplastic transformation.

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“…For the transcription strand asymmetry, coding and template strand were obtained from a published study 53 and the asymmetry is reported as log2 ratio of (mutation count within template regions) / (mutation counts within coding regions).…”

Section: Methodsmentioning

confidence: 99%

Deficiency in DNA mismatch repair of methylation damage is a major mutational process in cancer

Zhu

et al. 2020

Preprint

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DNA mismatch repair (MMR) is essential for maintaining genome integrity with its deficiency predisposing to cancer1. MMR is well known for its role in the post-replicative repair of mismatched base pairs that escape proofreading by DNA polymerases following cell division2. Yet, cancer genome sequencing has revealed that MMR deficient cancers not only have high mutation burden but also harbour multiple mutational signatures3, suggesting that MMR has pleotropic effects on DNA repair. The mechanisms underlying these mutational signatures have remained unclear despite studies using a range of in vitro4,5 and in vivo6 models of MMR deficiency. Here, using mutation data from cancer genomes, we identify a previously unknown function of MMR, showing that the loss of non-canonical replication-independent MMR activity is a major mutational process in human cancers. MMR is comprised of the MutSα (MSH2/MSH6) and MutLα (MLH1/PMS2) complexes7. Cancers with deficiency of MutSα exhibit mutational signature contributions distinct from those deficient of MutLα. This disparity is attributed to mutations arising from the unrepaired deamination of 5-methylcytosine (5mC), i.e. methylation damage, as opposed to replicative errors by DNA polymerases induced mismatches. Repair of methylation damage is strongly associated with H3K36me3 chromatin but independent of binding of MBD4, a DNA glycosylase that recognise 5mC and can repair methylation damage. As H3K36me3 recruits MutSα, our results suggest that MutSα is the essential factor in mediating the repair of methylation damage. Cell line models of MMR deficiency display little evidence of 5mC deamination-induced mutations as their rapid rate of proliferation limits for the opportunity for methylation damage. We thus uncover a non-canonical role of MMR in the protection against methylation damage in non-dividing cells.

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Learning mutational signatures and their multidimensional genomic properties with TensorSignatures

Cited by 20 publications

References 48 publications

Selection of Oncogenic Mutant Clones in Normal Human Skin Varies with Body Site

Selection of Oncogenic Mutant Clones in Normal Human Skin Varies with Body Site

Life without mismatch repair

Deficiency in DNA mismatch repair of methylation damage is a major mutational process in cancer

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