All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.

/pdf/signatures-of-mutational-processes-in-human-cancer-j3duru54oq.pdf

Signatures of mutational processes in human cancer

Immune checkpoint inhibitors, which unleash a patient’s own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used whole-exome sequencing of non–small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti–PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shapes response to anti–PD-1 therapy.

https://science.sciencemag.org/content/sci/early/2015/03/11/science.aaa1348.full.pdf

Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer

AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore

PL02-05 

All cancers are due to abnormalities in DNA. The availability of the human genome sequence has led to the proposal that resequencing of cancer genomes will reveal the full complement of somatic mutations and hence all the cancer genes. To explore the nature of the information that will be derived from cancer genome sequencing we have sequenced the coding exons of the family of 518 protein kinases, ~1.3Mb DNA per cancer sample, in 210 cancers of diverse histological types. Despite the screen being directed toward the coding regions of a gene family that has previously been strongly implicated in oncogenesis, the results indicate that the majority of somatic mutations detected are “passengers”. There is considerable variation in the number and pattern of these mutations between individual cancers, indicating substantial diversity of processes of molecular evolution between cancers. The imprints of exogenous mutagenic exposures, mutagenic treatment regimes and DNA repair defects can all be seen in the distinctive mutational signatures of individual cancers. This systematic mutation screen and others have previously yielded a number of cancer genes that are frequently mutated in one or more cancer types and which are now anticancer drug targets (for example BRAF , PIK3CA , and EGFR ). However, detailed analyses of the data from our screen additionally suggest that there exist a large number of additional “driver” mutations which are distributed across a substantial number of genes. It therefore appears that cells may be able to utilise mutations in a large repertoire of potential cancer genes to acquire the neoplastic phenotype. However, many of these genes are employed only infrequently. These findings may have implications for future anticancer drug development.

Patterns of Somatic Mutation in Human Cancer Genomes

NA damage has emerged as a major culprit in cancer and many diseases related to aging. The stability of the genome is supported by an intricate machinery of repair, damage tolerance, and checkpoint pathways that counteracts DNA damage. In addition, DNA damage and other stresses can trigger a highly conserved, anticancer, antiaging survival response that suppresses metabolism and growth and boosts defenses that maintain the integrity of the cell. Induction of the survival response may allow interventions that improve health and extend the life span. Recently, the first candidate for such interventions, rapamycin (also known as sirolimus), has been identified. 1 Compromised repair systems in tumors also offer opportunities for intervention, making it possible to attack malignant cells in which maintenance of the genome has been weakened. Time-dependent accumulation of damage in cells and organs is associated with gradual functional decline and aging. 2 The molecular basis of this phenomenon is unclear, 3-5 whereas in cancer, DNA alterations are the major culprit. In this review, I present evidence that cancer and diseases of aging are two sides of the DNAdamage problem. An examination of the importance of DNA damage and the systems of genome maintenance in relation to aging is followed by an account of the derailment of genome guardian mechanisms in cancer and of how this cancerspecific phenomenon can be exploited for treatment.

DNA Damage, Aging, and Cancer

https://repub.eur.nl/pub/55808/1-s2.0-S0092867412005284-main.pdf

Mutational Processes Molding the Genomes of 21 Breast Cancers

Tumor-driving mutations in the TP53 gene occur frequently in human cancers. These inactivating mutations arise predominantly from a single-point mutation in the DNA-binding domain of this tumor suppressor gene (i.e., exons 4–9). The human p53 knock-in (Hupki) mouse model was constructed using gene-targeting technology to create a mouse strain that harbors human wild-type TP53 DNA sequences in both copies of the mouse TP53 gene. Replacement of exons 4–9 of the endogenous mouse TP53 alleles in the Hupki mouse with the homologous normal human TP53 gene sequences has offered a humanized replica of the TP53 gene in a murine genetic environment. The Hupki mouse model system has proven to be an invaluable research tool for studying the underlying mechanisms of human TP53 mutagenesis. The utility of the Hupki mouse model system for exploring carcinogen-induced TP53 mutagenesis has been demonstrated in both in vivo animal experiments and in vitro cell culture experiments. Here, we highlight applications of the Hupki mouse model system for investigating mutagenesis induced by a variety of environmental carcinogens, including sunlight ultraviolet radiation, benzo[a]pyrene (a tobacco smoke-derived carcinogen), 3-nitrobenzanthrone (an urban air pollutant), aristolochic acid (a component of Chinese herbal medicine), and aflatoxin B1 (a food contaminant). We summarize the salient findings of the respective studies and discuss their relevance to human cancer etiology.—Besaratinia, A., Pfeifer, G. P. Applications of the human p53 knock-in (Hupki) mouse model for human carcinogen testing.

Applications of the human p53 knock-in (Hupki) mouse model for human carcinogen testing

In response to the growing public health concern regarding the risks or benefits of electronic cigarettes (e-cig) use relative to smoking, the National Institute on Drug Abuse (NIDA) has recently introduced the first standardized- and well- characterized e-cig device to the research community (see, https://www.drugabuse.gov/funding/supplemental-information-nida-e-cig ). E-cig are promoted as safe alternatives to conventional tobacco cigarettes and/or as aides to smoking cessation. E-cig are highly popular among cigarette smokers who are unable/unwilling to quit but are willing to switch to putatively less-harmful tobacco substitutes. E-cig are also becoming increasingly popular among youth who have never experimented with combustible cigarettes. However, chemical analyses of e-cig juices (both in liquid form and after being heated into vapor) have shown that many carcinogens present in cigarette smoke are also found in a range of e-cig products. To date, the cancer-causing potential of e-cig has not been investigated in e-cig users (i.e., vapers). Use of e-cig without a prior history of smoking is currently a rare phenomenon in adults, but is increasingly common among youth. Consequently, investigating the carcinogenic potential of e-cig in nonsmoking youth provides a unique opportunity to verify the health impact of e-cig use, without the confounding effects of cigarette smoking. Within this context, the availability of the NIDA Standard Research e-cig offers a unique research opportunity with tremendous public health implications. Comparing and contrasting the cancer-causing potentials of standard vaping and smoking in youth will help determine the health risks or benefits of e-cig use relative to cigarette smoking. This information will be instrumental in making scientifically based decisions on the development and evaluation of policies and regulations on e-cig manufacture, marketing, and distribution. Ultimately, evidence-based guidelines and legislations on e-cig will help reduce the burden of tobacco-related diseases, particularly on minors and vulnerable populations.

/pdf/an-opportune-and-unique-research-to-evaluate-the-public-3b19mo9a89.pdf

An opportune and unique research to evaluate the public health impact of electronic cigarettes

https://escholarship.org/content/qt7zw4x31f/qt7zw4x31f.pdf?t=qgghfg

Vaping: A growing global health concern.

The formation and repair of DNA damage at specific locations in the genome is modulated by DNA sequence context, by DNA cytosine-5 methylation patterns, by the transcriptional status of the locus and by proteins associated with the DNA. The only method currently available to allow precise sequence mapping of DNA lesions in mammalian cells is the ligation-mediated polymerase chain reaction (LM-PCR) technique. We provide an update on technical details of LM-PCR. LM-PCR can be used, for example, for mapping of ultraviolet (UV) light-induced DNA photoproducts such as cyclobutane pyrimidine dimers.

/pdf/measuring-the-formation-and-repair-of-uv-damage-at-the-dna-32vjij3kr7.pdf

Measuring the formation and repair of UV damage at the DNA sequence level by ligation-mediated PCR.

Aromatic amines are a widespread class of environmental contaminants present in various occupational settings and tobacco smoke. Exposure to aromatic amines is a major risk factor for bladder cancer development. The etiologic involvement of aromatic amines in the genesis of bladder cancer is attributable to their ability to form DNA-adducts, which upon eluding repair and causing mispairing during replication, may initiate mutagenesis. We have investigated the induction of DNA-adducts in relation to mutagenesis in bladder and various non-target organs of transgenic Big Blue® mice treated weekly (i.p.) with a representative aromatic-amine compound, 4-aminobiphenyl (4-ABP), for six weeks, followed by a six-week recovery period. We demonstrate an organ-specificity of 4-ABP in inducing repair-resistant DNA-adducts in bladder, kidney and liver of carcinogen-treated animals, which accords with the bioactivation pathway of this chemical in the respective organs. In confirmation, we show a predominant and sustained mutagenic effect of 4-ABP in bladder, and much weaker but significant mutagenicity of 4-ABP in the kidney and liver of carcinogen-treated mice, as reflected by the elevation of background cII mutant frequency in the respective organs. The spectrum of mutations produced in bladder of 4-ABP-treated mice matches the known mutagenic properties of 4-ABP-DNA-adducts, as verified by the preponderance of induced mutations occurring at G:C basepairs (82.9%), with the vast majority being G:C→T:A transversions (47.1%). Our data support a possible etiologic role of 4-ABP in bladder carcinogenesis, and provide a mechanistic view on how DNA-adduct-driven mutagenesis, specifically targeted to bladder urothelium, may account for organ-specific tumorigenicity of this chemical.

https://cancerpreventionresearch.aacrjournals.org/content/canprevres/early/2011/11/14/1940-6207.CAPR-11-0309.full.pdf

Ahmad Besaratinia

Papers

Applications of the human p53 knock-in (Hupki) mouse model for human carcinogen testing

An opportune and unique research to evaluate the public health impact of electronic cigarettes

Vaping: A growing global health concern.

Measuring the formation and repair of UV damage at the DNA sequence level by ligation-mediated PCR.

Organ specificity of the bladder carcinogen 4-aminobiphenyl in inducing DNA damage and mutation in mice.