Mutational signatures of DNA mismatch repair deficiency in C. elegans and human cancers

Abstract

Throughout their lifetime, cells are subject to extrinsic and intrinsic mutational processes leaving behind characteristic signatures in the genome. DNA mismatch repair (MMR) deficiency leads to hypermutation and is found in different cancer types. Although it is possible to associate mutational signatures extracted from human cancers with possible mutational processes, the exact causation is often unknown. Here, we use genome sequencing of and knockouts to reveal the mutational patterns linked to MMR deficiency and their dependency on endogenous replication errors and errors caused by deletion of the polymerase ε subunit Signature extraction from 215 human colorectal and 289 gastric adenocarcinomas revealed three MMR-associated signatures, one of which closely resembles the MMR spectrum and strongly discriminates microsatellite stable and unstable tumors (AUC = 98%). A characteristic difference between human and MMR deficiency is the lack of elevated levels of NG > NTG mutations in likely caused by the absence of cytosine (CpG) methylation in worms The other two human MMR signatures may reflect the interaction between MMR deficiency and other mutagenic processes, but their exact cause remains unknown. In summary, combining information from genetically defined models and cancer samples allows for better aligning mutational signatures to causal mutagenic processes.

Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer

“…It is hence likely that the dMMR-phenotype also contributes to the generation of signature 1 mutations. This is further supported by 9-10% of the subclonal mutations in Tumours 1-3 and 36% in Tumour 4 showing signature 1 and consistent with a recently suggested role of the MMR-system in the repair of deamination defects 27 . A total of 10.5% of the ubiquitous mutations in Tumour 3 showed signature 14, which has been described in dMMR cancers that are also POLE or POLD1 mutant 28 .…”

Extreme intratumour heterogeneity and driver evolution in mismatch repair deficient gastro-oesophageal cancer

“…It is hence likely that the dMMR phenotype also contributes to the generation of signature 1 mutations. This is further supported by 9-10% of the subclonal mutations in Tumours 1-3 and 36% in Tumour 4 showing signature 1 and consistent with a recently suggested role of the MMR system in the repair of deamination defects 28 . No other mutational signatures contributed substantially to the heterogeneous mutations, confirming that the MSIphenotype remains active during cancer progression and is the primary mechanism generating these large numbers of subclonal mutations.…”

Limiting oxidative DNA damage reduces microbe-induced colitis-associated colorectal cancer

“…This phenomenon was irrespective of whether one copy of the Msh2 gene was disrupted or both alleles are removed. We hypothesize that the effects on CRC of reducing oxidative DNA damage in Lynch syndrome models is being masked by the tenfold increase mutation rate in Msh2 −/− colon epithelial cells compared to controls 21 , which is largely due to an inability to repair replication errors 33 . Unrepaired 8-oxoG leads to C:G > A:T transversion mutations, which account for onlỹ 10% of all mutations in Msh2 −/− cells 33,34 .…”

“…We hypothesize that the effects on CRC of reducing oxidative DNA damage in Lynch syndrome models is being masked by the tenfold increase mutation rate in Msh2 −/− colon epithelial cells compared to controls 21 , which is largely due to an inability to repair replication errors 33 . Unrepaired 8-oxoG leads to C:G > A:T transversion mutations, which account for onlỹ 10% of all mutations in Msh2 −/− cells 33,34 . Hence, in MMRdeficient mice, replication errors and spontaneous cytidine deamination dominate over the effects of oxidative damage 33,34 , which might explain why antioxidants do not reduce CRC in Lynch syndrome models.…”

“…Unrepaired 8-oxoG leads to C:G > A:T transversion mutations, which account for onlỹ 10% of all mutations in Msh2 −/− cells 33,34 . Hence, in MMRdeficient mice, replication errors and spontaneous cytidine deamination dominate over the effects of oxidative damage 33,34 , which might explain why antioxidants do not reduce CRC in Lynch syndrome models. Another possibility is that polyposis in Apc min/+ MMR-heterozygous mice is purely affected by Apc loss of heterozygosity, and therefore any effects of antioxidants could be masked by Apc loss independent of oxidative DNA damage.…”