Synthetic lethality is defined as a type of genetic interaction where the combination of two genetic events results in cell death or death of an organism.^[1] Although the foregoing explanation is wider than this, it is common when referring to synthetic lethality to mean the situation arising by virtue of a combination of deficiencies of two or more genes leading to cell death (whether by means of apoptosis or otherwise), whereas a deficiency of only one of these genes does not.^[2] In a synthetic lethalgenetic screen, it is necessary to begin with a mutation that does not result in cell death, although the effect of that mutation could result in a differingphenotype (slow growth for example), and then systematically test other mutations at additional loci to determine which, in combination with the first mutation, causes cell death arising by way of deficiency or abolition of expression.

Synthetic lethality has utility for purposes of molecular targeted cancer therapy. The first example of a molecular targeted therapeutic agent, which exploited a synthetic lethal approach, arose by means of an inactivatedtumor suppressor gene (BRCA1 and 2), a treatment which received FDA approval in 2016 (PARP inhibitor).^[3] A sub-case of synthetic lethality, where vulnerabilities are exposed by the deletion of passenger genes rather than tumor suppressor is the so-called "collateral lethality".^[4]

The phenomenon of synthetic lethality was first described byCalvin Bridges in 1922, who noticed that some combinations of mutations in the model organismDrosophila melanogaster (the common fruit fly) confer lethality.^[1]Theodore Dobzhansky coined the term "synthetic lethality" in 1946 to describe the same type of genetic interaction in wildtype populations ofDrosophila.^[5] If the combination of genetic events results in a non-lethal reduction in fitness, the interaction is called synthetic sickness. Although inclassical genetics the term synthetic lethality refers to the interaction between two genetic perturbations, synthetic lethality can also apply to cases in which the combination of a mutation and the action of a chemical compound causes lethality, whereas the mutation or compound alone are non-lethal.^[6]

Synthetic lethality is a consequence of the tendency of organisms to maintain buffering schemes (i.e. backup plans) which engender phenotypic stability notwithstanding underlying genetic variations, environmental changes or other random events, such as mutations. Thisgenetic robustness is the result of parallel redundant pathways and"capacitor" proteins that camouflage the effects of mutations so that important cellular processes do not depend on any individual component.^[7] Synthetic lethality can help identify these buffering relationships, and what type of disease or malfunction that may occur when these relationships break down, through the identification of gene interactions that function in either the same biochemical process or pathways that appear to be unrelated.^[8]

High-throughput synthetic lethal screens may help illuminate questions about how cellular processes work without previous knowledge of gene function or interaction. Screening strategy must take into account the organism used for screening, the mode of genetic perturbation, and whether the screen isforward orreverse. Many of the first synthetic lethal screens were performed inSaccharomyces cerevisiae. Budding yeast has many experimental advantages in screens, including a small genome, fastdoubling time, both haploid and diploid states, and ease of genetic manipulation.^[9] Gene ablation can be performed using aPCR-based strategy and complete libraries of knockout collections for all annotated yeast genes are publicly available.Synthetic genetic array (SGA), synthetic lethality by microarray (SLAM), and genetic interaction mapping (GIM) are three high-throughput methods for analyzing synthetic lethality in yeast. A genome scale genetic interaction map was created by SGA analysis inS. cerevisiae that comprises about 75% of all yeast genes.^[10]

Collateral lethality is a sub-case of synthetic lethality in personalized cancer therapy, where vulnerabilities are exposed by the deletion of passenger genes rather than tumor suppressor genes, which are deleted by virtue of chromosomal proximity to major deleted tumor suppressor loci.^[4]

Mutations in genes employed inDNA mismatch repair (MMR) cause a high mutation rate.^[11][12] In tumors, such frequent subsequent mutations often generate "non-self" immunogenic antigens. A human Phase II clinical trial, with 41 patients, evaluated one synthetic lethal approach for tumors with or without MMR defects.^[13] In the case of sporadic tumors evaluated, the majority would be deficient in MMR due to epigenetic repression of an MMR gene.(SeeDNA mismatch repair) The product of genePD-1 ordinarily represses cytotoxic immune responses. Inhibition of this gene allows a greater immune response. In this Phase II clinical trial with 47 patients, when cancer patients with a defect in MMR in their tumors were exposed to an inhibitor of PD-1, 67% - 78% of patients experienced immune-relatedprogression-free survival. In contrast, for patients without defective MMR, addition of PD-1 inhibitor generated only 11% of patients with immune-related progression-free survival. Thus inhibition of PD-1 is primarily synthetically lethal with MMR defects.

The analysis of 630 human primary tumors in 11 tissues shows thatWRNpromoterhypermethylation (with loss of expression of WRN protein) is a common event in tumorigenesis.^[14] TheWRN gene promoter is hypermethylated in about 38% ofcolorectal cancers andnon-small-cell lung carcinomas and in about 20% or so ofstomach cancers,prostate cancers,breast cancers,non-Hodgkin lymphomas andchondrosarcomas, plus at significant levels in the other cancers evaluated. TheWRN helicase protein is important inhomologous recombinational DNA repair and also has roles innon-homologous end joining DNA repair andbase excision DNA repair.^[15]

Topoisomerase inhibitors are frequently used as chemotherapy for different cancers, though they cause bone marrow suppression, are cardiotoxic and have variable effectiveness.^[16] A 2006 retrospective study, with long clinical follow-up, was made of colon cancer patients treated with the topoisomerase inhibitoririnotecan. In this study, 45 patients hadhypermethylatedWRN genepromoters and 43 patients had unmethylatedWRN gene promoters.^[14] Irinitecan was more strongly beneficial for patients with hypermethylatedWRN promoters (39.4 months survival) than for those with unmethylatedWRN promoters (20.7 months survival). Thus, a topoisomerase inhibitor appeared to be synthetically lethal with deficient expression ofWRN. Further evaluations have also indicated synthetic lethality of deficient expression ofWRN and topoisomerase inhibitors.^{[17][18][19][20][21]}

As reviewed by Murata et al.,^[22] five different PARP1 inhibitors are now undergoingPhase I, II and III clinical trials, to determine if particular PARP1 inhibitors are synthetically lethal in a large variety of cancers, including those in the prostate, pancreas, non-small-cell lung tumors, lymphoma, multiple myeloma, and Ewing sarcoma. In addition, in preclinical studies using cells in culture or within mice, PARP1 inhibitors are being tested for synthetic lethality against epigenetic and mutational deficiencies in about 20 DNA repair defects beyond BRCA1/2 deficiencies. These include deficiencies inPALB2,FANCD2,RAD51,ATM,MRE11,p53,XRCC1 andLSD1.

ARID1A, a chromatin modifier, is required fornon-homologous end joining, a major pathway that repairs double-strand breaks in DNA,^[23] and also has transcription regulatory roles.^[24]ARID1A mutations are one of the 12 most common carcinogenic mutations.^[25] Mutation or epigenetically decreased expression^[26] ofARID1A has been found in 17 types of cancer.^[27] Pre-clinical studies in cells and in mice show that synthetic lethality for deficientARID1A expression occurs by either inhibition of the methyltransferase activity of EZH2,^[28][29] by inhibition of the DNA repair kinase ATR,^[30] or by exposure to the kinase inhibitor dasatinib.^[31]

There are two pathways forhomologous recombinational repair of double-strand breaks. The major pathway depends onBRCA1,PALB2 andBRCA2 while an alternative pathway depends on RAD52.^[32] Pre-clinical studies, involving epigenetically reduced or mutatedBRCA-deficient cells (in culture or injected into mice), show that inhibition of RAD52 is synthetically lethal withBRCA-deficiency.^[33]

Although treatments using synthetic lethality can stop or slow progression of cancers and prolong survival, each of the synthetic lethal treatments has some adverse side effects. For example, more than 20% of patients treated with an inhibitor of PD-1 encounter fatigue, rash,pruritus, cough, diarrhea, decreased appetite, constipation orarthralgia.^[34] Thus, it is important to determine which DDR deficiency is present, so that only an effective synthetic lethal treatment can be applied, and not unnecessarily subject patients to adverse side effects without a direct benefit.

• Synthetic genetic array
• Synthetic rescue
• Essential gene

• Data Repository of Yeast Genetic INteractions
• Saccharomyces Genome Deletion Project
• SynLethDB Database

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