Interspersed repeat sequences comprise much of our DNA, although their functional effects are poorly understood. The most commonly occurring repeat is the Alu short interspersed element. New Alu insertions occur in human populations, and have been responsible for several instances of genetic disease. In this study, we sought to determine if there are instances of polymorphic Alu insertion variants that function in a common variant, common disease paradigm. We cataloged 809 polymorphic Alu elements mapping to 1,159 loci implicated in disease risk by genome-wide association study (GWAS) (P < 10−8). We found that Alu insertion variants occur disproportionately at GWAS loci (P = 0.013). Moreover, we identified 44 of these Alu elements in linkage disequilibrium (r2 > 0.7) with the trait-associated SNP. This figure represents a >20-fold increase in the number of polymorphic Alu elements associated with human phenotypes. This work provides a broader perspective on how structural variants in repetitive DNAs may contribute to human disease.

Alu are high copy number interspersed repeats that have accumulated near genes during primate and human evolution. They are a pervasive source of structural variation in modern humans. Impacts that Alu insertions may have on gene expression are not well understood, although some have been associated with expression quantitative trait loci (eQTLs). Here, we directly test regulatory effects of polymorphic Alu insertions in isolation of other variants on the same haplotype. To screen insertion variants for those with such effects, we used ectopic luciferase reporter assays and evaluated 110 Alu insertion variants, including more than 40 with a potential role in disease risk. We observed a continuum of effects with significant outliers that up- or down-regulate luciferase activity. Using a series of reporter constructs, which included genomic context surrounding the Alu, we can distinguish between instances in which the Alu disrupts another regulator and those in which the Alu introduces new regulatory sequence. We next focused on three polymorphic Alu loci associated with breast cancer that display significant effects in the reporter assay. We used CRISPR to modify the endogenous sequences, establishing cell lines varying in the Alu genotype. Our findings indicate that Alu genotype can alter expression of genes implicated in cancer risk, including PTHLH, RANBP9, and MYC. These data show that commonly occurring polymorphic Alu elements can alter transcript levels and potentially contribute to disease risk.

Introduction: Pulmonary adenocarcinoma is a major cause of mortality worldwide. The majority of patients present with advanced stage disease, and minimally invasive procedures are desirable for diagnosis and treatment plans. Herein, we report our experience with percutaneous/transthoracic needle aspiration (TT-NA) in the cytologic diagnosis of pulmonary adenocarcinoma. Material and Methods: After institutional review board approval, the cytopathology electronic data system was searched for all consecutive TT-NA of the lung masses from January 2011 to November 2015. Patients' medical records were reviewed and cytologic materials were evaluated. Results: A total of 151 specimens were identified, with a mean age of 62.8 years; 62.9% of the patients had a prior history of malignancy. Carcinoma/adenocarcinoma was the most common (80%) diagnosis. The targeted lesions were predominantly located in the lung (56.3%, 81/151) and pleural based (27.8%, 42/151). The mean size of the lesions was 3.6 cm. Cytology specimens were adequate in 70.9% of the cases, while 72.8% (110/151) of the cases also had concurrent core biopsy. A ma-lignant diagnosis was rendered in the majority of the cases (64.9%). In 71% of the cases, immunohistochemistry/histochemistry studies were successfully performed. Molecular/genetic studies were requested in 80% of the cases and had adequate material. Complications of the procedure were seen in 9.9% of the patients including pneumothorax (7.9%) and hemoptysis (1.9%). Conclusion: TT-NA is a relatively safe and reliable technique in the assessment of pulmonary lesions.