Citations

Abstract Synthetic lethal interactions enable a novel approach for discovering specific genetic vulnerabilities in cancer cells that can be exploited for the development of therapeutics. Despite successes in model organisms such as yeast, discovering synthetic lethal interactions on a large scale in human cells remains a significant challenge. We describe a comparative genomic strategy for identifying cancer-relevant synthetic lethal interactions whereby candidate interactions are prioritized on the basis of genetic interaction data available in yeast, followed by targeted testing of candidate interactions in human cell lines. As a proof of principle, we describe two novel synthetic lethal interactions in human cells discovered by this approach, one between the tumor suppressor gene SMARCB1 and PSMA4, and another between alveolar soft-part sarcoma-associated ASPSCR1 and PSMC2. These results suggest therapeutic targets for cancers harboring mutations in SMARCB1 or ASPSCR1 and highlight the potential of a targeted, cross-species strategy for identifying synthetic lethal interactions relevant to human cancer. Cancer Res; 73(20); 6128–36. ©2013 AACR.

Background— Despite complete interruption of antegrade coronary artery flow in the setting of a chronic total occlusion (CTO), clinical recognition of myocardial infarction is often challenging. Using cardiac MRI, we investigated the frequency and extent of myocardial infarction in patients with CTO, and assessed their relationship with regional systolic function and the extent of angiographic collateral flow. Methods and Results— We included 170 consecutive patients (median age, 62 years) with angiographically documented CTO. Regional late gadolinium enhancement and wall motion score index were assessed by cardiac MRI with the use of a 17-segment model. Angiographic collateral flow was assessed by the collateral connection grade and the Rentrop score. Evidence of previous myocardial infarction was found in 25% of patients by ECG Q waves, in 69% by regional wall motion abnormality, and in 86% of patients by late gadolinium enhancement. Increased angiographic collateral flow was associated with a lower frequency of Q waves on ECG, and a lower regional wall motion score index, late gadolinium enhancement volume (%), and degree of late gadolinium enhancement transmurality (all P <0.001), as well. Conclusions— The frequency of myocardial infarction in territories subtended by CTO is significantly higher than previously recognized. The degree of myocardial injury downstream epicardial CTO is inversely correlated with the degree of angiographic collaterals.

Abstract Short constitutional telomere length has been associated with aging and cancer, but how telomere length is affected by other epidemiologic or environmental variables in health has not been thoroughly studied. Understanding these associations with telomere length in health is important for studies to evaluate the relationship of telomere length and diseases such as cancer. We measured peripheral blood leukocyte DNA telomere length with quantitative PCR in 1977 non-related healthy controls collected through the Colon Cancer Family Registry (an NCI cooperative group) and through the Mayo Biobank and Biobank for Gastrointestinal Health Research, two IRB approved prospective biospecimen collections based at Mayo Clinic, Rochester, MN. The controls were a median age of 50.6 years old, and 49.6% of the controls were male. Ninety-six percent of the controls were white; 1.8% were Asian, and &lt;1% were either black, Pacific Islander, or Native American. Less than 1% of controls were Hispanic. On univariate analysis, as age increased, telomere length decreased (Pearson correlation coefficient = −0.07, 95% CI: −0.11, −0.03). Telomeres were longer in people who consumed more fruits (p&lt;0.01) and vegetables (p&lt;0.01); took aspirin on a regular basis (p&lt;0.01); or had a family history of cancers of any type (p=0.05). Women had longer telomeres than men (p=0.03). Telomeres were shorter in people who consumed alcohol (p&lt;0.01), took folate on a regular basis (p=0.01), or who consumed red meat (p&lt;0.01). Statistical significance was not found in the following variables: tobacco use, diagnosis of diabetes, intake of calcium, use of hormone replacement therapy in women, or body mass index. On multivariate analysis, age, vegetable consumption, family history of colorectal cancer or any type of cancer, and folate intake were identified as being significantly associated with telomere length. Telomere length may be associated with multiple environmental and demographic variables in healthy individuals, and adjusting for these may be important for studies that test for an association between telomere length and diseases such as cancer. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A82.