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BACKGROUND No consensus germline testing guidelines currently exist for glioma patients. Hence such testing is not routinely performed. The prevalence and type of germline pathogenic variants in these brain tumors remains unknown. DESIGN/ METHODS A retrospective review of patients treated at Baylor College of Medicine with paired tumor/normal sequencing using the Tempus xT tumor/normal matched approach from August 2018- April 2022 was performed. Corresponding clinical data was collected for these patients. RESULTS We identified 152 glioma patients of which 15 (9.8%) had pathogenic germline variants. Pathogenic germline variants were seen in 11/84 (13.1%) of Glioblastoma, IDH wildtype, 3/42 (7.1%) of Astrocytoma, IDH mutant and 1/26 (3.8%) of Oligodendroglioma, IDH mutant and 1p/19q co-deleted patients. Pathogenic variants in BRCA2, MUTYH and CHEK2 were seen more commonly (3/15 or 20% each). BRCA1 variants were seen in 2/15 (13%) patients, with variants in NF1, ATM, MSH2, and MSH3 occurring in one patient (7%) each. Second hit somatic variants were seen in 3/15 patients (20%). A second somatic hit was seen in NF1, MUTYH and MSH2 in one patient (7%) each. Referral to genetics was performed in 6/15 (40%) patients with pathogenic germline variants. Median overall survival was 1.6 years for glioblastoma, IDH wildtype patients with a pathogenic germline variant compared to 1.79 years for glioblastoma, IDH wildtype patients without it (p = 0.67). CONCLUSIONS Although not routinely performed in glioma patients, pathogenic germline variants occurred in ~10% of our patients. Only 40% of these patients were referred to genetics. These findings suggest a possible overlooked opportunity for determination of hereditary cancer syndromes with impact on surveillance as well as potential broader treatment options. Further research to confirm the occurrence and types of pathogenic germline variants in patients with IDH wildtype compared to IDH mutant tumors is necessary.

Background: Following the declaration of the COVID-19 national emergency, screening mammograms (SM) abruptly dropped across the United States. Stay-at-home orders discourage cancer patients from seeking care, and cancer screenings and surgeries were postponed. Upon resumption of screening services, rates of screening were slow to recover. At Baylor St. Luke’s CHI (BSL), one of the largest tertiary care centers providing comprehensive cancer screening in Houston, we investigated patient level predictors, including comorbidities and area deprivation index (ADI), and the risk of skipping SM in the first year of the COVID-19 Pandemic. Methods: We used the local PENRAD database to retrieve the monthly gross number of SM performed at all BSL sites from 02/2018 to 01/2021. We obtained patient level data through EPIC, including address and demographics, comorbid conditions e.g., diabetes, hypertension, obesity (BMI30), chronic kidney disease and cardiovascular diseases (CVD). We identified ADI associated with patient addresses. We included patient who received at least one SM between 02/2018 to 01/2020. We compared patients did not get a mammogram in the first year of the pandemic; 02/2020 to 01/2021, to those who maintained screening during the pandemic. We performed a logistic regression analysis to assess the influence of age, 0 to +3 comorbid conditions, and ADI in quartiles on the odds ratio of skipping SM in the first year of the pandemic. Statistical significance was set at p< 0.05. The study was IRB approved. Results: Out of the 4591 women that screened in 2018 and/or 2019, only 1628 came back for SM in 2020 (35.5%). Women who obtained SM during the pandemic vs those who did not were slightly older, mean age 58 vs 56 (P< 0.001), were less likely to be living in the most deprived neighborhood, Q4 of ADI, 23.8% vs. 25.6%, more likely to be obese 39% vs. 35% (P< 0.001), more likely to have diabetes 48% vs. 41% (P< 0.001), more likely to have CVD, 16% vs. 13% (P< 0.001), and more likely to have hypertension 80% vs. 71% (P< 0.001). On multivariate logistic regression, living in Q4 ADI was associated with 22% higher risk of skipping SM in 2020 (95% CI 1.02-1.42), having one vs. two vs. three comorbid conditions increased the likelihood of obtaining SM in 2020 by 25% (95% CI 0.62-0.91) vs. 30% vs (95% CI 0.58-0.85), 42% (95% CI 0.48-0.7) compared to no comorbid conditions. Conclusion: Women living in Q4 of the ADI (most deprived neighborhood) were more likely to miss 2020 screening when compared with the Q1 women (least deprived neighborhood). The more chronic diseases women had, the less likely they were to skip 2020 screening when compared with those that had no chronic disease. This could because women with many health issues have to frequent health facilities at higher rates and thus less likely to miss mammograms. Citation Format: Maryam Nemati Shafaee, Omar Rosales, Randall Parker Kirby, Tamara Ortiz-Perez, Luke Gilman, Ashley Hardeman, Preeya Bhavsar Bhakta, Chris Amos, Abiodun Oluyomi. Patient-level predictors of skipping screening mammograms during the COVID-19 pandemic at a large tertiary care center in Texas [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-25.

Lung cancer is a multifactorial disease caused by both environmental exposures and genetic factors. Genome and transcriptome-wide association studies (GWAS and TWAS) successfully identified many genetic variants and candidate causal genes associated with lung cancer. However, the lack of functional studies of these genes remains a major bottleneck to clinical translation. Recently, we discovered that large networks of evolutionarily conserved DNA damageome proteins (DDPs) promote DNA damage and genome instability. Here, we discovered a lung cancer-associated DNA damageome network. We further discovered that one of the lung cancer DDPs, Aquaporin 3 (AQP3), can promote ROS dependent DNA damage upon overproduction. Furthermore, it potentiates DNA damage by a low dose of arsenic exposure, creating unique double strand break hotspots which help predict mutational signatures. We screened for high endogenous DNA damage levels for more than 40 TWAS and GWAS-nominated candidates using high-throughput single cell-based flow cytometric assays. We optimized and performed Mre11-Cut&Tag (Cleavage Under Targets and Tagmentation) to map double strand breaks, which are the most deleterious form of DNA damage. In addition, we used END-Seq to provide a much higher resolution of the DSB map and uncovered hotspots in arsenic-detoxifying genes. We are implementing duplex sequencing to map the mutational signatures caused by arsenic and the arsenic-Aquaporin 3 interaction. Our study brings function to endogenous DNA damage and DNA damageome proteins that interact with environmental toxicants. Mechanistic insights into how low-dose arsenic interacts with risk genes yield critical knowledge for the prevention, diagnosis, and treatment of arsenic-associated diseases. We also uncovered several early biomarkers to potentially predict the long-term health impacts of arsenic. Citation Format: Jun Xia, Mu Lin, Zhuoyi Song, Gail Fernandes, Susan Rosenberg, Chris Amos. Lung cancer associated DNA Damageome reveals a genome destabilizing role of Aquaporin 3 [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A018.

Globally, about 2 million people are diagnosed with lung cancer annually, making it the most common type of cancer in the world. In addition, lung cancer is the leading cause of cancer death among both men and women, accounting for ~25% of all cancer deaths in the United States and ~19% of cancer deaths worldwide. Although tobacco smoking is the most common cause of lung cancer, it is estimated that 10-25% of all patients diagnosed with lung cancer worldwide are never smokers, with higher proportions in Asians and women. Compared to former and current smokers with lung cancer, lung cancers in never smokers tend to present at an earlier age and more frequently have adenocarcinoma histology. Although a few risk factors are known to contribute to the etiology of lung cancer in never smokers, a large fraction of cancer cases cannot be explained by established environmental and genetic risk factors, highlighting the need for research in this area. One promising approach to identify the etiological factors involved in lung tumorigenesis in never smokers is based on the study of the “mutational signatures” that the exogenous and endogenous processes leave on the tumor tissue and surrounding areas. Somatic mutations accumulate throughout individuals’ lifetime, as a result of the balance between DNA damage and DNA repair. Mutational sources can change over time and mutational signatures can provide information on the tumor evolutionary trajectory, tracking activities of mutational processes. We designed “Sherlock-Lung” to identify mutational signatures in lung cancers from never smokers and order them based on their clonal and subclonal localization to have an insight on the factors involved in the initiation of the tumors. Prevention and treatment strategies are likely to be more effective when targeting the tumor initiating factors rather than those responsible for the tumor progression. Here, we present the Sherlock-Lung study design, which includes a combination of lung cancer cases from populations highly exposed to lung cancer risk factors and populations with unknown exposures. We also present preliminary data from this study and what we have learned from whole genome sequencing analysis of the mutational landscape of lung cancers from smokers and nonsmokers and from different histological subtypes. For example, although the mutational signature associated with tobacco smoking is largely clonal in all lung cancers from smokers, consistent with an initiating role of tobacco smoking in lung tumorigenesis, the mutational signatures distribution varies across histological subtypes. Moreover, the frequency of mutations in major cancer driver genes varies dramatically between smokers and never smokers, and mutational signatures distribution appears to differ between tumors with and without specific driver genes. In never smokers, without the dominant mutational source of tobacco smoking, other signatures emerged, e.g., that associated with reactive oxygen species. Although this approach has already revealed important information on the etiological processes involved in tumorigenesis of lung cancer and other cancer types, there is a growing list of open questions and challenges that need to be addressed. In population studies, careful exposure assessment to identify and validate new mutational signatures and the inclusion of study subjects from different geographical locations and ethnicities are critical. Citation Format: Maria Teresa Landi, Tongwu Zhang, Montserrat Garcia-Closas, Yohan Bossé, Jianxin Shi, Bin Zhu, Qing Lan, Nathaniel Rothman, Jiyeon Choi, Neil E. Caporaso, Wei Zhao, Chongyi Chen, Eytan Ruppin, Jennifer Rosenbaum, Dmitry Gordenin, Sai Yendamuri, Chris Amos, Paul Brennan, David C. Christiani, Geoff Liu, Bonnie Gould Rothberg, Matthew Schabath, Han Liang, Ludmil Alexandrov, David Wedge, Stephen Chanock. Sherlock-Lung: Tracing lung cancer mutational processes in never smokers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY26-02.

Background: Genome-wide association study (GWAS) have identified over 45 susceptibility loci for lung cancer; many studies including our own group, have focused on low-frequency and rare coding variants using fine mapping and exome sequencing. This strategy, however, has met with limited success as about 90% of GWAS hits are noncoding and act primarily through altering transcriptional regulation in an allele-specific manner. The RNA-Seq based allele-specific expression (ASE) analysis affords an innovative approach to study preferential expression of an allele in direct relationship to its genotype, providing information on cis-regulatory effects for the expression of putative genes. However currently, there are no lung cancer studies that have rigorously evaluated the ASE variation in lung tumor and adjacent tissues. Methods: Leveraging The Cancer Genome Atlas (TCGA) resource, we performed transcriptomic-wide ASE analysis using existing RNA-Seq datasets of paired tumor and adjacent tissues from 54 lung adenocarcinoma patients. We first quantified the RNA read counts of Referent and Alternate alleles of heterozygous variants, then evaluated the allelic imbalance on a per-sample basis using Beta-binomial test, and explored the differential ASE between tumor and adjacent tissues using paired Wilcoxon test. Functional regulatory consequences were generated from Ensembl Variant Effect Predictor. Results: We identified total 208 significant ASEs, including 35 tissue-specific (only in tumor or only in adjacent), 28 sharing, and 145 differential variants. Of the 208 candidates, 41 were from the human leukocyte antigen (HLA) locus (primary DQA2, DQB1, DRB1, H and J), 26 were from the immunoglobulin (IG) superfamily (primary IGH, IGL, IGK and F11R). About 80% candidates were noncoding (mostly in 5’ and 3’ untranslated regions) and with regulatory features (21 promoter, seven enhancer, seven open chromatin region, two induce nonsense-mediated mRNA decay, one CTCF-binding site, and one transcription factor binding site). Other top genes included MDM2, APOL1, and CTSB. Pathway analyses revealed 27 genes involved in immune response pathway, and 12 genes involved in HLA antigen processing and presentation pathway. Conclusion: This study is the first transcriptomics ASE analysis in lung adenocarcinoma. The key somatic cis-regulatory ASE variants identified from this study, especially immunogenic allelic variations from HLA and IG genes, could be used for identifying high-risk individuals for targeted lung cancer checkpoint blockade and related immunotherapies. Citation Format: Yanhong Liu, Spiridon Tsavachidis, Farrah Kheradmand, Margaret R. Spitz, Chris Amos. Transcriptome analysis links immune genes allelic expression imbalances to lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1584.

We examined the effects of fishing with crustacean traps on benthic species in Great Britain by means of qualitative and quantitative experiments. Experimental sites were selected where fishing using pots or creels was practised regularly and where species perceived to be potentially sensitive to damage were present. The effect of Nephrops creels on different sea pen species was studied in Scottish sea lochs. Sea pens were observed to bend in response to the pressure wave before the creel made contact. After smothering and even uprooting, they re-established themselves when in contact with muddy substrate. Observations of lobster and crab pots being hauled from rocky substrates in southern England, revealed that the habitats and their communities appeared relatively unaffected by potting. The slow-growing, long-lived, pink sea fan Eunicella verrucosa were observed to flex under the weight of pots as they passed and then returned back to an upright position. Quantitative studies, undertaken in south England and west Wales, were based on surveys carried out along transect lines before and after a month of pot fishing for crabs and lobsters. The results suggest that four weeks of fairly intense fishing did not have immediate detrimental effects on the abundance of the species selected for study, although some individual ross coral colonies (Pentapora foliacea) were damaged.

In recent years, demand growth on Australian networks has been high, requiring additional capital expenditure to maintain acceptable standards of supply. In EnergyAustralia’s case, capital expenditure over the 2004-2009 period of the current regulatory Determination is expected to increase three-fold over the previous Determination, with the major factor driving this increase being demand growth. There is thus increased emphasis by Networks on managing demand, and increasing encouragement by Australian Regulators for them to do so. Efficient infrastructure pricing serves to directly influence customer behaviour and forms a foundation for other demand management options.