ON 146040 The advent of next generation sequencing

The advent of next-generation sequencing (NGS) has shown that considerable variation in human genome is still undiscovered and therefore a considerable number of rare variations that are related to disease susceptibility may still be unknown. NGS has allowed to strengthen the association between loss of function mutation in DNA glycosylases and cancer in the two human syndromes identified up to now. Genetic analysis of colon carcinomas and adenomas in the nthl1 mutated patients showed a non-hypermutated profile enriched for C>T transitions that are expected on the basis of the mutation spectra observed in nthl1/neil1 double ko mice [78]. Similarly, analysis of the somatic mutational landscape of adenomas of patients affected by MUTYH-associated polyposis revealed a moderate mutator phenotype (5 times higher than in FAP adenomas) and as dominant signature G>T transversions that are typically associated with the failure to remove misincorporated adenines opposite 8-oxoG [215]. NGS applied to tumor genome profiling has revealed that DNA damage response genes are often mutated in all cancer types. Inherited polymorphisms as well as inherited and somatic mutations or epigenetic changes can disrupt the cell capacity to respond to damages constantly caused by normal metabolic products and environmental factors and genes mutations are rapidly accumulated. Large scale studies performed by the Cancer Genome Atlas and the International Cancer Genome Consortium researchers have generated comprehensive catalogues of genomic abnormalities in 50 different cancer types and sub-types that show how among the hundreds of mutations accumulated by cancer ON 146040 only a few are driver mutations and point out how defects inactivating DNA repair genes constitute a clear cancer-specific signature. Interestingly, whereas homologous recombination alterations are diffused in most cancer types (breast, ovarian, colorectal and prostate), MMR is typically impaired in colorectal and endometrial cancer, NER in prostate cancer and Fanconi Anemia genes in ovarian cancer [216]. The BER pathway does not present a specific cancer-signature but it is frequently mutated (>15% of patients analysed for each cancer type) in cancer such as bladder, colon, liver, lung and ovaries (data from [217]). It is of note that these are the cancer types most frequently associated with SNPs in DNA glycosylases (Table 2). Although it is outside of the topics of our review, it should be mentioned that DNA repair gene alterations are often the result of epigenetic modifications in cancer. Inactivation, reduced expression by promoter methylation as well as increased expression by unmethylation of DNA repair genes are early events driving neoplastic transformation and can also confer resistance to chemotherapeutic treatments (reviewed in [218]). For instance promoter hypermethylation of mbd4 is recognized as an early event in tumorigenesis of sporadic colorectal cancer [219] and aberrant promoter methylation of neil1 has been reported in head and neck squamous cell carcinoma [220]. Finally, over the last decade defects in components of several DNA repair pathways have been recognized as etiopathological factors of novel disorders other than cancers such as immunological disorders, metabolic disease and neurodegenerative disorders. The variety of the BER-associated diseases that also emerges from the DNA glycosylase SNPs-disease association studies (Table 2) indicates the need of studying genomic variations in DNA repair pathways in a broader spectrum of diseases than cancer.
Acknowledgements This work has been partially supported by AIRC, Italy (IG No. 13320 to ED) and has received funding from the European Union's Seventh Programme for Research, Technological Development and Demonstration under Grant agreement No 603946 (Health and Environment-wide Associations via Large population Surveys, HEALS).
Introduction