Mutational signatures are markers of drug sensitivity of cancer cells

Somatic mutations are an inevitable component of ageing and the most important cause of cancer. The rates and types of somatic mutation vary across individuals, but relatively few inherited influences on mutation processes are known. We perform a gene-based rare variant association study with diverse mutational processes, using human cancer genomes from over 11,000 individuals of European ancestry. By combining burden and variance tests, we identify 207 associations involving 15 somatic mutational phenotypes and 42 genes that replicated in an independent data set at a false discovery rate of 1%. We associate rare inherited deleterious variants in genes such as MSH3, EXO1, SETD2, and MTOR with two phenotypically different forms of DNA mismatch repair deficiency, and variants in genes such as EXO1, PAXIP1, RIF1, and WRN with deficiency in homologous recombination repair. In addition, we identify associations with other mutational processes, such as APEX1 with APOBEC-signature mutagenesis. Many of the genes interact with each other and with known mutator genes within cellular sub-networks. Considered collectively, damaging variants in the identified genes are prevalent in the population. We suggest that rare germline variation in diverse genes commonly impacts mutational processes in somatic cells.

show abstract

“…gdc.cancer.gov/] (dbGaP accession ID phs000178) and processed as described in ref. 113 . Copy numbers were identified with the tool FACETS 114 .…”

Section: Extraction Of Somatic Mutational Features and Somatic Compon...mentioning

confidence: 99%

The impact of rare germline variants on human somatic mutation processes

2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…Our analyses revealed that only COSMIC signatures SBS18 and SBS36 (SBS18/36), both previously attributed to reactive oxygen species 61,62 , were found to be operative in all irradiated MEF and HFF cells. It should be noted that ROS signatures SBS18 and SBS36 have cosine similarity of 0.914 ( Figure 7 a ), which, in many cases, makes them hard to distinguish from one another and these signatures are commonly reported together as SBS18/36 35,63,64 . Our analyses revealed that SBS18/36 were the only signatures enriched in irradiated HFF and MEF samples when compared to controls ( Figure 7 b-c ; q-values<0.05; Mann-Whitney tests).…”

Section: Resultsmentioning

confidence: 99%

DNA damage and somatic mutations in mammalian cells after irradiation with a nail polish dryer

Zhivagui¹,

Valenzuela²,

Yeh³

et al. 2021

Preprint

View full text Add to dashboard Cite

Ultraviolet A light (UVA) is commonly emitted by nail polish dryers with recent reports suggesting that long-term use of UV-nail polish dryers may increase the risk for developing skin cancer. However, no experimental evaluation has been conducted to reveal the effect of radiation emitted by UV-nail polish dryers on mammalian cells. Here, we examine the pre-mutagenic and mutagenic changes imprinted on the genomes of human and murine primary cell models due to irradiation by a UV-nail dryer. Our findings demonstrate that radiation from UV-nail devices is cytotoxic and genotoxic. Importantly, high levels of reactive oxygen species were observed in all irradiated samples. Analysis of somatic mutations revealed a dose-dependent increase of C:G>A:T substitutions in irradiated samples with a pattern consistent to the one of COSMIC signature 18, a mutational signature attributed to reactive oxygen species. Examination of previously generated skin cancer genomics data revealed that signature 18 is ubiquitously present in melanoma and that it accounts for ~12% of the observed driver mutations. In summary, this study demonstrates that radiation emitted by UV-nail polish dryers can both damage DNA and can permanently imprint somatic mutations on the genomes of mammalian cells. These results have far reaching implications in regard to public health and to preventing skin cancer due to occupational- or consumer-based exposure to ultraviolet light from artificial sources.

show abstract

“…their mutational consequences such as microsatellite expansion) might turn out to be a more robust therapeutic approach than targeting the primary DDR defect itself, given it is difficult to understand how the mutational consequences of many DDR defects could be easily reversed. Whilst this might be theoretically possible with WRN inhibitors in cancers with expanded TA repeats, approaches that target cancers with different types of mutational signature are not known but could be identified (an attempt to identify these is described here [172]). For example, in experimental models, though a BRCA2 reversion is able to restore HR and cause PARPi resistance, it does not restore a normal diploid genome to tumour cells; PARPi‐resistant BRCA2 ‐revertant cells retain a highly disordered genome and are still p53 mutant [173].…”

Section: Targeting Ddr Inhibitor Resistancementioning

confidence: 99%

Resistance to DNA repair inhibitors in cancer

et al. 2022

View full text Add to dashboard Cite

The DNA damage response (DDR) represents a complex network of proteins which detect and repair DNA damage, thereby maintaining the integrity of the genome and preventing the transmission of mutations and rearranged chromosomes to daughter cells. Faults in the DDR are a known driver and hallmark of cancer. Furthermore, inhibition of DDR enzymes can be used to treat the disease. This is exemplified by PARP inhibitors (PARPi) used to treat cancers with defects in the homologous recombination DDR pathway. A series of novel DDR targets are now also under pre-clinical or clinical investigation, including inhibitors of ATR kinase, WRN helicase or the DNA polymerase/helicase Polh (Pol-Theta). Drug resistance is a common phenomenon that impairs the overall effectiveness of cancer treatments and there is already some understanding of how resistance to PARPi occurs. Here, we discuss how an understanding of PARPi resistance could inform how resistance to new drugs targeting the DDR emerges. We also discuss potential strategies that could limit the impact of these therapy resistance mechanisms in cancer.Abbreviations ATR, Ataxia telangiectasia and Rad3 related gene; BRCA1, BRCA1 DNA repair-associated gene; BRCA2, BRCA2 DNA repair-associated gene; ctDNA, circulating tumour DNA; DDR, DNA damage response network; HR, homologous recombination; MMR, mismatch DNA repair; NAD+, nicotinamide adenine dinucleotide; PAR, poly-ADP-ribose; PARP1, poly-(ADP-ribose) polymerase 1 gene; PARPi, PARP inhibitor; POLQ, DNA polymerase theta gene, protein known as Polh; RS, replication stress; SWI/SNF, SWItch/sucrose non-fermentable chromatin remodelling complex; TMEJ, theta-mediated end joining; VEGF, vascular endothelial growth factor; WGR, protein domain containing tryptophan (W), glycine (G), arginine (R); WRN, Werner syndrome ATP-dependent helicase gene; ZnF, Zinc Finger protein domain.

show abstract

Mutational signatures are markers of drug sensitivity of cancer cells

Cited by 38 publications

References 107 publications

The impact of rare germline variants on human somatic mutation processes

The impact of rare germline variants on human somatic mutation processes

DNA damage and somatic mutations in mammalian cells after irradiation with a nail polish dryer

Resistance to DNA repair inhibitors in cancer

Contact Info

Product

Resources

About