Colorectal cancer (CRC) is one of the main causes of death of neoplasia. Demand for predictive and prognostic markers to reverse this trend is increasing. Long non-coding RNA HOTAIR (Homeobox Transcript Antisense Intergenic RNA) overexpression in tumors was previously associated with poor prognosis and higher mortality in different carcinomas. We analyzed HOTAIR expression levels in tumor and blood of incident sporadic CRC patients in relation to their overall survival with the aim to evaluate surrogate prognostic marker for CRC. Tissue donor group consisted of 73 CRC patients sampled for tumor and normal tissue. Blood donor group was represented by 84 CRC patients compared with 40 healthy controls. Patients were characterized for tumor-node-metastasis stage, tumor grade, microsatellite instability and tumor penetration by stromal cells. HOTAIR levels were assessed by real-time quantitative PCR. CRC patients had higher HOTAIR expression in blood than healthy controls (P = 0.0001), whereas there was no difference in HOTAIR levels between tumor and adjacent mucosa of CRC patients. HOTAIR levels positively correlated between blood and tumor (R = 0.43, P = 0.03). High HOTAIR levels in tumors were associated with higher mortality of patients [Cox's proportional hazard, hazard ratio = 4.4, 95% confidence interval: 1.0-19.2, P = 0.046]. The hazard ratio was even higher when blood HOTAIR levels were taken into account (hazard ratio = 5.9, 95% confidence interval: 1.3-26.1, P = 0.019). Upregulated HOTAIR relative expression in primary tumors and in blood of CRC patients is associated with unfavorable prognosis. Our data suggest that HOTAIR blood levels may serve as potential surrogate prognostic marker in sporadic CRC.

Cellular repair enzymes remove virtually all DNA damage before it is fixed; repair therefore plays a crucial role in preventing cancer. Repair studied at the level of transcription correlates poorly with enzyme activity, and so assays of phenotype are needed. In a biochemical approach, substrate nucleoids containing specific DNA lesions are incubated with cell extract; repair enzymes in the extract induce breaks at damage sites; and the breaks are measured with the comet assay. The nature of the substrate lesions defines the repair pathway to be studied. This in vitro DNA repair assay has been modified for use in animal tissues, specifically to study the effects of aging and nutritional intervention on repair. Recently, the assay was applied to different strains of Drosophila melanogaster proficient and deficient in DNA repair. Most applications of the repair assay have been in human biomonitoring. Individual DNA repair activity may be a marker of cancer susceptibility; alternatively, high repair activity may result from induction of repair enzymes by exposure to DNA-damaging agents. Studies to date have examined effects of environment, nutrition, lifestyle, and occupation, in addition to clinical investigations.

Targeted cancer therapies represent a milestone towards personalized treatment as they function via inhibition of cancer-specific alterations. Polymerase θ (POLQ), an error-prone translesion polymerase, also involved in DNA doublestrand break (DSB) repair, is often upregulated in cancer. POLQ is synthetic lethal with various DNA repair genes, including known cancer drivers such as BRCA1/2, making it essential in homologous recombination-deficient cancers. Thus, POLQ represents a promising target in cancer therapy and efforts for the development of POLQ inhibitors are actively underway with first clinical trials due to start in 2021. This review summarizes the journey of POLQ from a backup DNA repair enzyme to a promising therapeutic target for cancer treatment. POLQ: Exploiting a Cancer Vulnerability for TherapyTo increase efficiency and lower the burden of toxic side effects, a major goal of cancer therapy is to progress from a 'one-drug-fits-all' to an individualized treatment approach tailored to the tumor-specific molecular features. Two main targeted therapeutic strategies are currently utilized in cancer treatment, both exploiting cancer-specific vulnerabilities. In the first approach, therapeutic suppression of aberrantly upregulated oncogenes alleviates the growth advantage of cancer cells. The second approach is based on the phenomenon that genetic alterations acquired by tumor cells cause their dependency on other compensatory pathways, loss of which leads to synthetic lethality (see Glossary). Therefore, therapeutic inhibition of pathways that are synthetic lethal with a cancer-specific alteration evokes cellular death in tumor cells while leaving normal cells unharmed [1]. The recent advent of genome-wide genetic interaction studies has demonstrated the extensive number of synthetic lethal interactions in cancer, many of which can potentially be translated to targeted cancer therapies [2].Cancer cells frequently acquire mutations in DNA repair genes and respond by rewiring their DNA repair network to utilize compensatory pathways for survival. Dependency on compensatory DNA repair pathways opens room for the development of cancer-specific small molecule inhibitors. A group of successful drugs that use this mode of action are poly(ADP-ribose) polymerase (PARP) inhibitors, approved for the treatment of BRCA-deficient cancers. The essentiality of PARP for cancer cells with loss-of-function mutations in BRCA1/2 is remarkable as such cancer cells are up to 1000 times more sensitive to PARP inhibitors than healthy cells [3,4]. Although challenges such as the acquisition of drug resistance need to be faced, the clinical success of inhibitory drugs targeting DNA repair enzymes is highly encouraging. In this context, the DNArepair enzyme polymerase θ (POLQ) has received increasing attention. POLQ is upregulated in numerous cancers and its overexpression is associated with poor prognosis [5][6][7][8][9]. Moreover, synthetic lethal interactions between POLQ and multiple DNA repair genes, including factors involv...