DNA Repair as an Emerging Target for COPD-Lung Cancer Overlap

Cigarette smoking is the leading cause of lung cancer and chronic obstructive pulmonary disease (COPD). Many of the detrimental effects of cigarette smoke have been attributed to the development of DNA damage, either directly from chemicals contained in cigarette smoke or as a product of cigarette smoke-induced inflammation and oxidative stress. In this review, we discuss the environmental, epidemiological, and physiological links between COPD and lung cancer and the likely role of DNA damage and repair in COPD and lung cancer development. We explore alterations in DNA damage repair by DNA repair proteins and pathways. We discuss emerging data supporting a key role for the DNA repair protein, xeroderma pigmentosum group C (XPC), in cigarette smoke-induced COPD and early lung cancer development. Understanding the interplay between cigarette smoke, DNA damage repair, COPD, and lung cancer may lead to prognostic tools and new, potentially targetable, pathways for lung cancer prevention and treatment

Recognition of DNA Termini by the C-Terminal Region of the Ku80 and the DNA-Dependent Protein Kinase Catalytic Subunit

DNA double strand breaks (DSBs) can be generated by endogenous cellular processes or exogenous agents in mammalian cells. These breaks are highly variable with respect to DNA sequence and structure and all are recognized in some context by the DNA-dependent protein kinase (DNA-PK). DNA-PK is a critical component necessary for the recognition and repair of DSBs via non-homologous end joining (NHEJ). Previously studies have shown that DNA-PK responds differentially to variations in DSB structure, but how DNA-PK senses differences in DNA substrate sequence and structure is unknown. Here we explore the enzymatic mechanisms by which DNA-PK is activated by various DNA substrates and provide evidence that the DNA-PK is differentially activated by DNA structural variations as a function of the C-terminal region of Ku80. Discrimination based on terminal DNA sequence variations, on the other hand, is independent of the Ku80 C-terminal interactions and likely results exclusively from DNA-dependent protein kinase catalytic subunit interactions with the DNA. We also show that sequence differences in DNA termini can drastically influence DNA repair through altered DNA-PK activation. These results indicate that even subtle differences in DNA substrates influence DNA-PK activation and ultimately the efficiency of DSB repair

Frequency and Circadian Timing of Eating May Influence Biomarkers of Inflammation and Insulin Resistance Associated with Breast Cancer Risk.

Emerging evidence suggests that there is interplay between the frequency and circadian timing of eating and metabolic health. We examined the associations of eating frequency and timing with metabolic and inflammatory biomarkers putatively associated with breast cancer risk in women participating in the National Health and Nutrition Examination 2009-2010 Survey. Eating frequency and timing variables were calculated from 24-hour food records and included (1) proportion of calories consumed in the evening (5 pm-midnight), (2) number of eating episodes per day, and (3) nighttime fasting duration. Linear regression models examined each eating frequency and timing exposure variable with C-reactive protein (CRP) concentrations and the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Each 10 percent increase in the proportion of calories consumed in the evening was associated with a 3 percent increase in CRP. Conversely, eating one additional meal or snack per day was associated with an 8 percent reduction in CRP. There was a significant interaction between proportion of calories consumed in the evening and fasting duration with CRP (p = 0.02). A longer nighttime fasting duration was associated with an 8 percent lower CRP only among women who ate less than 30% of their total daily calories in the evening (p = 0.01). None of the eating frequency and timing variables were significantly associated with HOMA-IR. These findings suggest that eating more frequently, reducing evening energy intake, and fasting for longer nightly intervals may lower systemic inflammation and subsequently reduce breast cancer risk. Randomized trials are needed to validate these associations

51 year-old male with dyspnea and hypoxia

AbstractWith continued advancements in medical practice, physicians are caring for more adult patients with congenital heart diseases and their sequelae. We report a 51 year-old with obstructive sleep apnea presenting with dyspnea, hypoxia and pulmonary hypertension, found to have a congenital atrial septal defect. The patient had symptomatic improvement following percutaneous closure of his ostium secundum atrial septal defect

XPC protects against smoking- and carcinogen-induced lung adenocarcinoma

Cigarette smoke (CS) contains hundreds of carcinogens and is a potent inducer of oxidative and bulky DNA damage, which when insufficiently repaired leads to activation of DNA damage response and possibly mutations. The DNA repair protein xeroderma pigmentosum group C (XPC) is primed to play an important role in CS-induced DNA damage because of its function in initiating repair of both bulky oxidative DNA damage. We hypothesized that loss of XPC function will increase susceptibility to developing CS- and carcinogen-induced lung cancer through impaired repair of oxidative DNA damage. Mice deficient in XPC (XPC-/-) exposed to chronic CS developed lung tumors whereas their wild-type littermates (XPC+/+) did not. XPC-/- mice treated with the CS-carcinogen urethane developed lung adenocarcinomas representing progressive stages of tumor development, with lung tumor number increased 17-fold compared with XPC+/+ mice. Mice heterozygous for XPC (XPC+/-) demonstrated a gene-dose effect, developing an intermediate number of lung tumors with urethane treatment. Treatment of XPC-/- mice with the carcinogen 3-methylcholanthrene followed by the proliferative agent butylated hydroxytoluene resulted in a 2-fold increase in lung adenocarcinoma development. Finally, tumor number decreased 7-fold in the lungs of XPC-/- mice by concurrent treatment with the antioxidant, N-acetylcysteine. Altogether, this supports a mechanism by which decreased XPC expression promotes lung adenocarcinoma development in response to CS-carcinogen exposure, due in part to impaired oxidative DNA damage repair

Xeroderma Pigmentosum Group C Deficiency Alters Cigarette Smoke DNA Damage Cell Fate and Accelerates Emphysema Development

Cigarette smoke (CS) exposure is a major risk factor for the development of emphysema, a common disease characterized by loss of cells comprising the lung parenchyma. The mechanisms of cell injury leading to emphysema are not completely understood but are thought to involve persistent cytotoxic or mutagenic DNA damage induced by CS. Using complementary cell culture and mouse models of CS exposure, we investigated the role of the DNA repair protein, xeroderma pigmentosum group C (XPC), on CS-induced DNA damage repair and emphysema. Expression of XPC was decreased in mouse lungs after chronic CS exposure and XPC knockdown in cultured human lung epithelial cells decreased their survival after CS exposure due to activation of the intrinsic apoptosis pathway. Similarly, cell autophagy and apoptosis were increased in XPC-deficient mouse lungs and were further increased by CS exposure. XPC deficiency was associated with structural and functional changes characteristic of emphysema, which were worsened by age, similar to levels observed with chronic CS exposure. Taken together, these findings suggest that repair of DNA damage by XPC plays an important and previously unrecognized role in the maintenance of alveolar structures. These findings support that loss of XPC, possibly due to chronic CS exposure, promotes emphysema development and further supports a link between DNA damage, impaired DNA repair, and development of emphysema

DNA damage response (DDR) pathway engagement in cisplatin radiosensitization of non-small cell lung cancer

Non-small cell lung cancers (NSCLC) are commonly treated with a platinum-based chemotherapy such as cisplatin (CDDP) in combination with ionizing radiation (IR). Although clinical trials have demonstrated that the combination of CDDP and IR appear to be synergistic in terms of therapeutic efficacy, the mechanism of synergism remains largely uncharacterized. We investigated the role of the DNA damage response (DDR) in CDDP radiosensitization using two NSCLC cell lines. Using clonogenic survival assays, we determined that the cooperative cytotoxicity of CDDP and IR treatment is sequence dependent, requiring administration of CDDP prior to IR (CDDP-IR). We identified and interrogated the unique time and agent-dependent activation of the DDR in NSCLC cells treated with cisplatin-IR combination therapy. Compared to treatment with CDDP or IR alone, CDDP-IR combination treatment led to persistence of γH2Ax foci, a marker of DNA double-strand breaks (DSB), for up to 24h after treatment. Interestingly, pharmacologic inhibition of DDR sensor kinases revealed the persistence of γ-H2Ax foci in CDDP-IR treated cells is independent of kinase activation. Taken together, our data suggest that delayed repair of DSBs in NSCLC cells treated with CDDP-IR contributes to CDDP radiosensitization and that alterations of the DDR pathways by inhibition of specific DDR kinases can augment CDDP-IR cytotoxicity by a complementary mechanism

Hemophagocytic Lymphohistiocytosis in the Medical ICU: A Single-Institution Cohort Study on Acute Liver Failure and Mortality

Hemophagocytic lymphohistiocytosis is a life-threatening hyperinflammatory disorder that is associated with high morbidity and mortality in the ICU. It has also been associated with acute liver failure. Design: Retrospective observational study. Setting: Tertiary-care medical ICU. Patients: Thirty-one patients critically ill with hemophagocytic lymphohistiocytosis. Interventions: None. Measurements and main results: We performed a comprehensive review of critically ill hemophagocytic lymphohistiocytosis patients admitted to a tertiary-care medical ICU from January 2012 to December 2018. Most patients presented with constitutional symptoms and elevated liver enzymes and thrombocytopenia were common upon hospital admission. ICU admission laboratory and clinical variables were used to calculate Acute Physiology and Chronic Health Evaluation II, hemophagocytic syndrome diagnostic score, and model for end-stage liver disease. Mean age of the cohort was 48.1 years, and 45% were male. The mortality rate was 65% at 28 days and 77% at 1 year. About 28-day survivors were younger, had lower mean Acute Physiology and Chronic Health Evaluation II score (16.5 vs 23.0; p = 0.004), and higher mean hemophagocytic syndrome diagnostic score (249.1 vs 226.0; p = 0.032) compared with nonsurvivors. Survivors were less likely to receive mechanical ventilation, renal replacement therapy, or vasopressor support and were more likely to receive chemotherapy for hemophagocytic lymphohistiocytosis. In this ICU cohort, 29% were diagnosed with acute liver failure, of whom only 22% developed acute liver failure early during their hospital stay. Acute liver failure was associated with a higher model for end-stage liver disease score upon hospital admission. Available histology in those that developed acute liver failure showed massive hepatic necrosis, or histiocytic or lymphocytic infiltrates. Conclusions: Patients admitted to the ICU with hemophagocytic lymphohistiocytosis have a high mortality. Those who survived had lower Acute Physiology and Chronic Health Evaluation scores, had higher hemophagocytic syndrome diagnostic scores, are more likely to receive hemophagocytic lymphohistiocytosis specific chemotherapy, and are less likely to have organ failure. Hemophagocytic lymphohistiocytosis can be associated with acute liver failure especially when model for end-stage liver disease score is elevated upon admission.Supported, in part, through T32HL091816 to Indiana University (Dr. Al Nasrallah). Dr. Sears receives research support to the institution through the American Cancer Society (128511-MRSG-15-163-01-DMC), National Institutes of Health, and Veterans Affairs Health Services, and is on the Scientific and Medical Advisory Boards for Biodesix and bioAffinity Technologies. The remaining authors have disclosed that they do not have any potential conflicts of interest

DNA repair targeted therapy: The past or future of cancer treatment?

The repair of DNA damage is a complex process that relies on particular pathways to remedy specific types of damage to DNA. The range of insults to DNA includes small, modest changes in structure including mismatched bases and simple methylation events to oxidized bases, intra- and interstrand DNA crosslinks, DNA double strand breaks and protein-DNA adducts. Pathways required for the repair of these lesions include mismatch repair, base excision repair, nucleotide excision repair, and the homology directed repair/Fanconi anemia pathway. Each of these pathways contributes to genetic stability, and mutations in genes encoding proteins involved in these pathways have been demonstrated to promote genetic instability and cancer. In fact, it has been suggested that all cancers display defects in DNA repair. It has also been demonstrated that the ability of cancer cells to repair therapeutically induced DNA damage impacts therapeutic efficacy. This has led to targeting DNA repair pathways and proteins to develop anti-cancer agents that will increase sensitivity to traditional chemotherapeutics. While initial studies languished and were plagued by a lack of specificity and a defined mechanism of action, more recent approaches to exploit synthetic lethal interaction and develop high affinity chemical inhibitors have proven considerably more effective. In this review we will highlight recent advances and discuss previous failures in targeting DNA repair to pave the way for future DNA repair targeted agents and their use in cancer therapy

Real-World Evaluation of Universal Germline Screening for Cancer Treatment-Relevant Pharmacogenes

The purpose of this study was to determine the frequency of clinically actionable treatment-relevant germline pharmacogenomic variants in patients with cancer and assess the real-world clinical utility of universal screening using whole-exome sequencing in this population. Cancer patients underwent research-grade germline whole-exome sequencing as a component of sequencing for somatic variants. Analysis in a clinical bioinformatics pipeline identified clinically actionable pharmacogenomic variants. Clinical Pharmacogenetics Implementation Consortium guidelines defined clinical actionability. We assessed clinical utility by reviewing electronic health records to determine the frequency of patients receiving pharmacogenomically actionable anti-cancer agents and associated outcomes. This observational study evaluated 291 patients with cancer. More than 90% carried any clinically relevant pharmacogenetic variant. At least one disease-relevant variant impacting anti-cancer agents was identified in 26.5% (77/291). Nine patients with toxicity-associated pharmacogenomic variants were treated with a relevant medication: seven UGT1A1 intermediate metabolizers were treated with irinotecan, one intermediate DPYD metabolizer was treated with 5-fluorouracil, and one TPMT poor metabolizer was treated with mercaptopurine. These individuals were more likely to experience treatment-associated toxicities than their wild-type counterparts (p = 0.0567). One UGT1A1 heterozygote died after a single dose of irinotecan due to irinotecan-related adverse effects. Identifying germline pharmacogenomic variants was feasible using whole-exome sequencing. Actionable pharmacogenetic variants are common and relevant to patients undergoing cancer treatment. Universal pharmacogenomic screening can be performed using whole-exome sequencing data originally obtained for quality control purposes and could be considered for patients who are candidates for irinotecan, 5-fluorouracil, capecitabine, and mercaptopurine