The transcriptional landscape of coding and non-coding RNAs in recurrent and non-recurrent colon cancer.

A considerable number of colon cancer patients with local or local advanced disease suffer from recurrence and there is an urgent need for better prognostic biomarkers in this setting. Here, the transcriptomic landscape of messenger RNAs (mRNAs), long non-coding RNAs (lncRNAs), small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs), small Cajal body-specific RNAs (scaRNAs), pseudogenes and circular RNAs (circRNAs), as well as RNAs denoted as miscellaneous RNAs, was profiled by total RNA sequencing. In addition to well-known coding and non-coding RNAs, differential expression analysis also uncovered transcripts, which have not previously been implicated in colon cancer, such as RNA5SP149, RNU4-2 and SNORD3A. Moreover, there was a profound global upregulation of snRNA pseudogenes, snoRNAs and rRNA pseudogenes in more advanced tumours. A global downregulation of circRNAs in tumours relative to normal tissues was observed, while only few were differentially expressed between tumour stages. Many previously undescribed transcripts, including RNU6-620P, RNU2-20P, VTRNA1-3 and RNA5SP60 indicated strong prognostic biomarker potential in ROC analyses. In summary, this study unveiled numerous differentially expressed RNAs across various classes between recurrent and non-recurrent colon cancer. Notably, there was a significant global upregulation of snRNA pseudogenes, snoRNAs and rRNA pseudogenes in advanced tumours. Many of these newly discovered candidates demonstrated a strong prognostic potential for stage II colon cancer.

Case-Cohort Study of the Association between PFAS and Selected Cancers among Participants in the American Cancer Society's Cancer Prevention Study II LifeLink Cohort.

BACKGROUND: Previous epidemiological studies found associations between exposure to per- and polyfluoroalkyl substances (PFAS) and some cancer types. Many studies considered highly exposed populations, so relevance to less-exposed populations can be uncertain. Additionally, many studies considered only cancer site, not histology. OBJECTIVES: We conducted a case-cohort study within the American Cancer Society's prospective Cancer Prevention Study II (CPS-II) LifeLink cohort to examine associations between PFAS exposure and risk of selected cancers, considering histologic subtypes. METHODS: Serum specimens were collected from cohort participants during the period 1998-2001. This study included a subcohort (500 men, 499 women) randomly selected from participants without prior cancer diagnoses at serum collection, and all participants with incident (after serum collection) first cancers of the breast (females only, n=786), bladder (n=401), kidney (n=158), pancreas (n=172), prostate (males only, n=1,610) or hematologic system (n=635). PFAS concentrations [perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA)] were measured in stored serum. We assessed associations between PFAS concentrations and incident cancers, by site and histologic subtype, using multivariable Cox proportional hazards models stratified by sex and controlling for age and year at blood draw, education, race/ethnicity, smoking, and alcohol use. RESULTS: Serum PFOA concentrations were positively associated with renal cell carcinoma of the kidney among women [hazard ratio (HR) and 95% confidence interval (CI) per PFOA doubling: 1.54 (95% CI: 1.05, 2.26)] but not men. Among men, we observed a positive association between PFHxS concentrations and chronic lymphocytic leukemia/small lymphocytic lymphoma [CLL/SLL, HR and 95% CI per PFHxS doubling: 1.34 (95% CI: 1.02, 1.75)]. We observed some heterogeneity of associations by histologic subtype within sites. DISCUSSION: This study supports the previously observed association between PFOA and renal cell carcinoma among women and suggests an association between PFHxS and CLL/SLL among men. Consideration of histologic subtypes might be important in future studies of PFAS-cancer associations. https://doi.org/10.1289/EHP13174.

Spatial Profiling of Circular RNAs in Cancer Reveals High Expression in Muscle and Stromal Cells.

Circular RNAs (circRNA) are covalently closed molecules that can play important roles in cancer development and progression. Hundreds of differentially expressed circRNAs between tumors and adjacent normal tissues have been identified in studies using RNA sequencing or microarrays, emphasizing a strong translational potential. Most previous studies have been performed using RNA from bulk tissues and lack information on the spatial expression patterns of circRNAs. Here, we showed that the majority of differentially expressed circRNAs from bulk tissue analyses of colon tumors relative to adjacent normal tissues were surprisingly not differentially expressed when comparing cancer cells directly with normal epithelial cells. Manipulating the proliferation rates of cells grown in culture revealed that these discrepancies were explained by circRNAs accumulating to high levels in quiescent muscle cells due to their high stability; on the contrary, circRNAs were diluted to low levels in the fast-proliferating cancer cells due to their slow biogenesis rates. Thus, different subcompartments of colon tumors and adjacent normal tissues exhibited striking differences in circRNA expression patterns. Likewise, the high circRNA content in muscle cells was also a strong confounding factor in bulk analyses of circRNAs in bladder and prostate cancers. Together, these findings emphasize the limitations of using bulk tissues for studying differential circRNA expression in cancer and highlight a particular need for spatial analysis in this field of research. SIGNIFICANCE: The abundance of circRNAs varies systematically between subcompartments of solid tumors and adjacent tissues, implying that differentially expressed circRNAs discovered in bulk tissue analyses may reflect differences in cell type composition between samples.

Chemical genomics reveals targetable programs of human cancers rooted in pluripotency.

Overlapping principles of embryonic and tumor biology have been described, with recent multi-omics campaigns uncovering shared molecular profiles between human pluripotent stem cells (hPSCs) and adult tumors. Here, using a chemical genomic approach, we provide biological evidence that early germ layer fate decisions of hPSCs reveal targets of human cancers. Single-cell deconstruction of hPSCs-defined subsets that share transcriptional patterns with transformed adult tissues. Chemical screening using a unique germ layer specification assay for hPSCs identified drugs that enriched for compounds that selectively suppressed the growth of patient-derived tumors corresponding exclusively to their germ layer origin. Transcriptional response of hPSCs to germ layer inducing drugs could be used to identify targets capable of regulating hPSC specification as well as inhibiting adult tumors. Our study demonstrates properties of adult tumors converge with hPSCs drug induced differentiation in a germ layer specific manner, thereby expanding our understanding of cancer stemness and pluripotency.

Caries risk and social determinants of health: A big data report.

BACKGROUND: Oral health is influenced by social determinants of health (SDH), predisposing people and communities to greater risk of developing caries. This study evaluated the association between caries risk in adults and SDH such as ZIP Codes, systemic diseases, payment methods, and race or ethnicity. METHODS: The BigMouth Dental Data Repository (n = 57,211) was used to extract clinical and SDH data from patients' dental electronic health records for 2019. Caries risk categories were used as ZIP Code data was merged with the Social Deprivation Index, a composite measure of area-level deprivation based on 7 demographic characteristics collected in the American Community Survey. RESULTS: The results showed that the odds of being in the high caries risk group were higher for people in the 49- to 64-year age group (adjusted odds ratio [aOR], 2.24; 95% CI, 2.08 to 2.40; P ≤ .001), men (aOR, 1.19; 95% CI, 1.13 to 1.25; P ≤ .001), people who had comorbidities (diabetes: aOR, 1.16; 95% CI, 1.08 to 1.24; P ≤ .001; cardiovascular disease: aOR, 1.40; 95% CI, 1.32 to 1.50), and people with an Social Deprivation Index score above the 75th percentile (aOR, 2.39; 95% CI, 2.21 to 2.58; P ≤ .001). In addition, Hispanic and Black people had higher odds of being at high caries risk than other races or ethnicities (Hispanic: aOR, 3.05; 95% CI, 2.32 to 4.00; Black: aOR, 2.05; 95% CI, 1.02 to 4.01). CONCLUSIONS: This study shows the association of caries risk with higher social deprivation, reinforcing the role of structural and upstream factors in oral health. This study is unique in using recorded ZIP Code information and assessing caries risk levels for those regions. PRACTICAL IMPLICATIONS: The physical and structural environment should be considered contributors to caries risk in people.

circPVT1 and PVT1/AKT3 show a role in cell proliferation, apoptosis, and tumor subtype-definition in small cell lung cancer.

Small cell lung cancer (SCLC) is treated as a homogeneous disease, although the expression of NEUROD1, ASCL1, POU2F3, and YAP1 identifies distinct molecular subtypes. The MYC oncogene, amplified in SCLC, was recently shown to act as a lineage-specific factor to associate subtypes with histological classes. Indeed, MYC-driven SCLCs show a distinct metabolic profile and drug sensitivity. To disentangle their molecular features, we focused on the co-amplified PVT1, frequently overexpressed and originating circular (circRNA) and chimeric RNAs. We analyzed hsa_circ_0001821 (circPVT1) and PVT1/AKT3 (chimPVT1) as examples of such transcripts, respectively, to unveil their tumorigenic contribution to SCLC. In detail, circPVT1 activated a pro-proliferative and anti-apoptotic program when over-expressed in lung cells, and knockdown of chimPVT1 induced a decrease in cell growth and an increase of apoptosis in SCLC in vitro. Moreover, the investigated PVT1 transcripts underlined a functional connection between MYC and YAP1/POU2F3, suggesting that they contribute to the transcriptional landscape associated with MYC amplification. In conclusion, we have uncovered a functional role of circular and chimeric PVT1 transcripts in SCLC; these entities may prove useful as novel biomarkers in MYC-amplified tumors.

Sindbis Virus Replication Reduces Dependence on Mitochondrial Metabolism During Infection.

Alphaviruses are single stranded, positive sense RNA viruses that are often transmitted through mosquito vectors. With the increasing spread of mosquito populations throughout the world, these arboviruses represent a significant global health concern. Viruses such as Sindbis Virus (SINV), Chikungunya Virus (CHIKV) and Equine Encephalitis Viruses (EEV) are all alphaviruses. As viruses, these pathogens are dependent on the host cell environment for successful viral replication. It has been observed that viruses manipulate cellular metabolism and mitochondrial shape, activity, and dynamics to favor viral infection. This report looked to understand the metabolic changes present during Sindbis virus infection of hamster and human kidney cells. Cells were infected with increasing levels of SINV and at 24 hours post infection the mitochondria morphology was assessed with staining and mitochondrial activity was measured with a real-time Seahorse Bioanalyzer. The relative amount of mitochondrial staining intensity decreased with Sindbis virus infected cells. Both oxygen consumption rate and ATP production were decreased during SINV infection while non-mitochondrial respiration and extracellular acidification rate increased during infection. Collectively, the data indicates that SINV primarily utilizes non-mitochondrial metabolism to support viral infection within the first 24 hours. This understanding of viral preference for host cell metabolism may provide critical targets for antiviral therapies and help further define the nature of alphavirus infection.

Prevalence of Americans reporting a family history of cancer indicative of increased cancer risk: Estimates from the 2015 National Health Interview Survey.

The collection and evaluation of family health history in a clinical setting presents an opportunity to discuss cancer risk, tailor cancer screening recommendations, and identify people with an increased risk of carrying a pathogenic variant who may benefit from referral to genetic counseling and testing. National recommendations for breast and colorectal cancer screening indicate that men and women who have a first-degree relative affected with these types of cancers may benefit from talking to a healthcare provider about starting screening at an earlier age and other options for cancer prevention. The prevalence of reporting a first-degree relative who had cancer was assessed among adult respondents of the 2015 National Health Interview Survey who had never had cancer themselves (n = 27,999). We found 35.6% of adults reported having at least one first-degree relative with cancer at any site. Significant differences in reporting a family history of cancer were observed by sex, age, race/ethnicity, educational attainment, and census region. Nearly 5% of women under age 50 and 2.5% of adults under age 50 had at least one first-degree relative with breast cancer or colorectal cancer, respectively. We estimated that 5.8% of women had a family history of breast or ovarian cancer that may indicate increased genetic risk. A third of U.S. adults who have never had cancer report a family history of cancer in a first-degree relative. This finding underscores the importance of using family history to inform discussions about cancer risk and screening options between healthcare providers and their patients.

Utility of linking survey and registry data to evaluate interventions and policies to address disparities in breast cancer survivorship among young women.

PURPOSE: There is limited research linking data sources to evaluate the multifactorial impacts on the quality of treatment received and financial burden among young women with breast cancer. To address this gap and support future evaluation efforts, we examined the utility of combining patient survey and cancer registry data. PATIENT AND METHODS: We administered a survey to women, aged 18-39 years, with breast cancer from four U.S. states. We conducted a systematic response-rate analysis and evaluated differences between racial groups. Survey responses were linked with cancer registry data to assess whether surveys could reliably supplement registry data. RESULTS: A total of 830 women completed the survey for a response rate of 28.4 %. Blacks and Asian/Pacific Islanders were half as likely to respond as white women. Concordance between survey and registry data was high for demographic variables (Cohen's kappa [k]: 0.879 to 0.949), moderate to high for treatments received (k: 0.467 to 0.854), and low for hormone receptor status (k: 0.167 to 0.553). Survey items related to insurance status, employment, and symptoms revealed racial differences. CONCLUSION: Cancer registry data, supplemented by patient surveys, can provide a broader understanding of the quality of care and financial impacts of breast cancer among young women.

Involvement of the endocannabinoid system in the inhibition of Sindbis virus replication: a preliminary study.

BACKGROUND: Sindbis virus (Alphaviridae) is a plus-strand RNA virus that is dependent on the host cell for replication. Cannabinoid (CB) receptors are found on most human cells, including virally infected cells. Activation of cannabinoid receptors has been shown to alter normal cellular physiology. This study aimed to assess how agonist (ACEA) or antagonists/inverse agonist (AM251) of the cannabinoid receptors would alter the cellular environment and impact Sindbis virus replication. METHODS: Human hepatoma (Huh7) cells were used as our model for viral replication. Cells were infected with Sindbis virus (SINV) and then treated with CB agonist (ACEA) (10 µM) or antagonist/inverse agonist (AM-251) (10 µM) and virus replication was monitored. A double subgenomic Sindbis virus containing a green fluorescent protein (GFP) reporter gene inserted into a 3' subgenomic promoter was utilized for these assays to quickly measure viral replication. GFP fluorescent cells were analyzed using flow cytometry to measure the percentage of cells expressing the viral reporter and also quantify the levels of GFP fluorescence. RESULT: Treatment of SINV-infected Huh7 cells with CB1 receptor antagonist/inverse agonist (AM251, 10 µM) resulted in a significant decrease in viral replication, while infected cells treated with a CB1 receptor agonist (ACEA, 10 µM) resulted in a significant increase of viral infection. The data indicates that activation of CB1 receptor by cannabinoids significantly influences the ability of Sindbis virus to replicate in the host cell. CONCLUSION: Blocking CB1 receptor activity with 10 µM AM251 reduced viral replication, but activating the CB1 receptor with 10 µM ACEA resulted in an increase in viral infection. These results indicate cannabinoids may significantly impact a virus replicating in human liver cells. Future confirmation with other viruses and cell lines will be performed to better understand the impact of cannabinoids on viral infections.

Phosphorylation state of the histone variant H2A.X controls human stem and progenitor cell fate decisions.

Histone variants (HVs) are a subfamily of epigenetic regulators implicated in embryonic development, but their role in human stem cell fate remains unclear. Here, we reveal that the phosphorylation state of the HV H2A.X (γH2A.X) regulates self-renewal and differentiation of human pluripotent stem cells (hPSCs) and leukemic progenitors. As demonstrated by CRISPR-Cas deletion, H2A.X is essential in maintaining normal hPSC behavior. However, reduced levels of γH2A.X enhances hPSC differentiation toward the hematopoietic lineage with concomitant inhibition of neural development. In contrast, activation and sustained levels of phosphorylated H2A.X enhance hPSC neural fate while suppressing hematopoiesis. This controlled lineage bias correlates to occupancy of γH2A.X at genomic loci associated with ectoderm versus mesoderm specification. Finally, drug modulation of H2A.X phosphorylation overcomes differentiation block of patient-derived leukemic progenitors. Our study demonstrates HVs may serve to regulate pluripotent cell fate and that this biology could be extended to somatic cancer stem cell control.

E2F1 and E2F2-Mediated Repression of CPT2 Establishes a Lipid-Rich Tumor-Promoting Environment.

Lipid metabolism rearrangements in nonalcoholic fatty liver disease (NAFLD) contribute to disease progression. NAFLD has emerged as a major risk for hepatocellular carcinoma (HCC), where metabolic reprogramming is a hallmark. Identification of metabolic drivers might reveal therapeutic targets to improve HCC treatment. Here, we investigated the contribution of transcription factors E2F1 and E2F2 to NAFLD-related HCC and their involvement in metabolic rewiring during disease progression. In mice receiving a high-fat diet (HFD) and diethylnitrosamine (DEN) administration, E2f1 and E2f2 expressions were increased in NAFLD-related HCC. In human NAFLD, E2F1 and E2F2 levels were also increased and positively correlated. E2f1 -/- and E2f2 -/- mice were resistant to DEN-HFD-induced hepatocarcinogenesis and associated lipid accumulation. Administration of DEN-HFD in E2f1 -/- and E2f2 -/- mice enhanced fatty acid oxidation (FAO) and increased expression of Cpt2, an enzyme essential for FAO, whose downregulation is linked to NAFLD-related hepatocarcinogenesis. These results were recapitulated following E2f2 knockdown in liver, and overexpression of E2f2 elicited opposing effects. E2F2 binding to the Cpt2 promoter was enhanced in DEN-HFD-administered mouse livers compared with controls, implying a direct role for E2F2 in transcriptional repression. In human HCC, E2F1 and E2F2 expressions inversely correlated with CPT2 expression. Collectively, these results indicate that activation of the E2F1-E2F2-CPT2 axis provides a lipid-rich environment required for hepatocarcinogenesis. SIGNIFICANCE: These findings identify E2F1 and E2F2 transcription factors as metabolic drivers of hepatocellular carcinoma, where deletion of just one is sufficient to prevent disease. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/11/2874/F1.large.jpg.

Employment After Breast Cancer Diagnosis and Treatment Among Women in the Sister and the Two Sister Studies.

Purpose Women undergoing diagnosis and treatment for breast cancer may face challenges in employment. We investigated the impact of demographic, clinical, workplace, and psychosocial characteristics on loss of employment after a breast cancer diagnosis and treatment. We further describe changes in work status and work environment for cancer survivors who sustain employment. Methods We analyzed responses from a survey of breast cancer survivors from the Sister Study and the Two Sister Study cohorts who reported being employed at the time of their breast cancer diagnosis and who reported employment status (lost vs. sustained employment) at the time of survey administration. Multivariate logistic regression was used to identify the effects of lymphedema, neuropathy, problems with memory or attention, social support, health insurance, and sick leave on lost employment, adjusting for demographic characteristics, cancer stage, treatment, and general health. Results Of the 1675 respondents who reported being employed at the time of diagnosis, 83.5% reported being 'currently' employed at the time of the survey. Older age, peripheral neuropathy, lack of sick leave, late stage at diagnosis, a recurrence or a new cancer, problems with memory or attention, and poor general health were significantly associated with lost employment. Conclusions The long-term effects of breast cancer treatment and workplace provisions for leave and accommodation may have a substantial effect on women's ability to sustain employment. The findings from this study highlight challenges reported by cancer survivors that may inform clinical and occupational interventions to support survivors' return to work.

Health-related quality of life outcomes among breast cancer survivors.

BACKGROUND: Data from a nationwide sample of US breast cancer survivors were used to examine associations between patient characteristics (breast cancer clinical features, prognostic factors, and treatments) and health-related quality of life (HRQOL). Associations between postdiagnosis HRQOL and mortality were then evaluated. METHODS: The authors identified female breast cancer survivors (n = 2453) from the Sister Study or Two Sister Study who were at least 1 year from breast cancer diagnosis and who had responded to a survivorship survey in 2012. HRQOL was assessed with the Patient-Reported Outcomes Measurement Information System (PROMIS) Global 10 measures. Multivariable linear regression was used to assess predictors associated with HRQOL. Cox regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between HRQOL and all-cause mortality. RESULTS: HRQOL, assessed an average of 4.9 years after the cancer diagnosis (standard deviation of 1.9 years), was negatively associated with a higher cancer stage at diagnosis; a higher comorbidity score at the survey; experience of surgical complications; dissatisfaction with breast surgery; and experience of any recent recurrence, metastasis, or secondary malignancy. Since the completion of the survey, there were 85 deaths (3.5%) during a mean follow-up of 4 years (standard deviation of 0.5 years). In multivariate models, decreases in PROMIS physical T scores and mental T scores were associated with increased mortality (HR for physical T scores, 1.08; 95% CI, 1.05-1.11; HR for mental T scores, 1.03; 95% CI, 1.01-1.06). CONCLUSIONS: Prognostic and cancer treatment-related factors affect HRQOL in breast cancer survivors and may inform targeted survivorship care. PROMIS global health measures may offer additional insights into patients' well-being and mortality risk. LAY SUMMARY: Findings from a study suggest that prognostic and cancer treatment-related factors affect health-related quality of life (HRQOL) in breast cancer survivors and that poor HRQOL may increase the mortality risk. The evaluation of HRQOL is important because it may hold potential as a tool for optimizing survivorship care.

Implementing Cancer Genomics in State Health Agencies: Mapping Activities to an Implementation Science Outcome Framework.

OBJECTIVE: To show how state health agencies can plan and evaluate activities to strengthen the evidence base for public health genomics, we mapped state cancer genomics activities to the Doyle et al. [Genet Med. 2018;20(9):995-1003] implementation science outcome framework. METHODS: We identified state health agency activities addressing hereditary breast and ovarian cancer and Lynch syndrome by reviewing project narratives from Centers for Disease Control and Prevention Cancer Genomics Program funding recipients, leading discussions with state health agencies, and conducting an environmental scan. RESULTS: State health agencies' cancer genomics activities included developing or adding to state surveillance systems, developing educational materials, bidirectional reporting, promoting health plan policy change, training providers, and promoting recommendations and standards. To address health disparities, programs have tracked group differences, developed culturally appropriate educational materials, and promoted access to services for underserved populations. CONCLUSION: State health agencies can use the Doyle et al. [Genet Med. 2018;20(9):995-1003] performance objectives and outcome measures to evaluate proposed and ongoing activities. By demonstrating whether activities result in improved outcomes, state health agencies can build the evidence for the implementation of cancer genomics activities.

Treatment cost and access to care: experiences of young women diagnosed with breast cancer.

PURPOSE: Breast cancer is the leading cause of cancer-related deaths in women younger than 40 years. We aim to evaluate cost as a barrier to care among female breast cancer patients diagnosed between 18 to 39 years. METHODS: In early 2017, we distributed a survey to women diagnosed with breast cancer between the ages of 18 and 39 years, as identified by the central cancer registries of California, Georgia, North Carolina, and Florida. We used multivariable statistics to explore cost-related barriers to receiving breast cancer care for the 830 women that completed the survey. RESULTS: About half of the women (47.4%) reported spending more on breast cancer care than expected, and almost two-thirds (65.3%) had not discussed costs with their care team. A third of the patients (31.8%) indicated forgoing care due to cost. Factors associated with not receiving anticipated care due to cost included age less than35 years at diagnosis, self-insurance, comorbid conditions, and late-stage diagnosis. CONCLUSION: Previous studies using breast cancer registry data have not included detailed insurance information and care received by young women. Young women with breast cancer frequently forgo breast cancer care due to cost. Our results highlight the potential for policies that facilitate optimal care for young breast cancer patients which could include the provision of comprehensive insurance coverage.

Fertility-related experiences after breast cancer diagnosis in the Sister and Two Sister Studies.

BACKGROUND: Commonly used chemotherapies can be toxic to the ovaries. To the authors' knowledge, the majority of studies evaluating receipt of fertility counseling for women in their reproductive years have been performed in specific settings, thereby limiting generalizability. METHODS: A nationwide sample of US women diagnosed with breast cancer before age 45 years completed a survey assessing the prevalence of fertility counseling. Age-adjusted log-binomial regression was used to estimate prevalence ratios (PRs) and 95% CIs for fertility counseling. RESULTS: Among 432 survivors diagnosed between 2004 and 2011, 288 (67%) had not discussed the effects of treatment on fertility with a health care provider before or during treatment. Fertility discussion was associated with younger age (PR, 3.49 [95% CI, 2.66-4.58] for aged <35 years vs ≥40 years) and lower parity (PR, 1.81 [95% CI, 1.29-2.53] for parity 1 vs 2). Approximately 20% of respondents reported that they were interested in future fertility (87 of 432 respondents) at the time of their diagnosis, but not all of these individuals (66 of 87 respondents) received counseling regarding the impact of treatment on their fertility, and few (8 of 87 respondents) used fertility preservation strategies. Among 68 women with a fertility interest who provided reasons for not taking steps to preserve fertility, reasons cited included concern for an adverse impact on cancer treatment (56%), lack of knowledge (26%), decision to not have a child (24%), and cost (18%). CONCLUSIONS: Across multiple treatment settings, the majority of women of reproductive age who are diagnosed with breast cancer did not discuss fertility with a health care provider or use fertility preservation strategies. Discussing the potential impact of cancer treatment on future fertility is an important aspect of patient education.

Evaluating the role of public health in implementation of genomics-related recommendations: a case study of hereditary cancers using the CDC Science Impact Framework.

Public health plays an important role in ensuring access to interventions that can prevent disease, including the implementation of evidence-based genomic recommendations. We used the Centers for Disease Control and Prevention (CDC) Science Impact Framework to trace the impact of public health activities and partnerships on the implementation of the 2009 Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Lynch Syndrome screening recommendation and the 2005 and 2013 United States Preventive Services Task Force (USPSTF) BRCA1 and BRCA2 testing recommendations.The EGAPP and USPSTF recommendations have each been cited by >300 peer-reviewed publications. CDC funds selected states to build capacity to integrate these recommendations into public health programs, through education, policy, surveillance, and partnerships. Most state cancer control plans include genomics-related goals, objectives, or strategies. Since the EGAPP recommendation, major public and private payers now provide coverage for Lynch Syndrome screening for all newly diagnosed colorectal cancers. National guidelines and initiatives, including Healthy People 2020, included similar recommendations and cited the EGAPP and USPSTF recommendations. However, disparities in implementation based on race, ethnicity, and rural residence remain challenges. Public health achievements in promoting the evidence-based use of genomics for the prevention of hereditary cancers can inform future applications of genomics in public health.

SUMOylation regulates LKB1 localization and its oncogenic activity in liver cancer.

BACKGROUND: Even though liver kinase B1 (LKB1) is usually described as a tumor suppressor in a wide variety of tissues, it has been shown that LKB1 aberrant expression is associated with bad prognosis in Hepatocellular Carcinoma (HCC). METHODS: Herein we have overexpressed LKB1 in human hepatoma cells and by using histidine pull-down assay we have investigated the role of the hypoxia-related post-translational modification of Small Ubiquitin-related Modifier (SUMO)ylation in the regulation of LKB1 oncogenic role. Molecular modelling between LKB1 and its interactors, involved in regulation of LKB1 nucleocytoplasmic shuttling and LKB1 activity, was performed. Finally, high affinity SUMO binding entities-based technology were used to validate our findings in a pre-clinical mouse model and in clinical HCC. FINDINGS: We found that in human hepatoma cells under hypoxic stress, LKB1 overexpression increases cell viability and aggressiveness in association with changes in LKB1 cellular localization. Moreover, by using site-directed mutagenesis, we have shown that LKB1 is SUMOylated by SUMO-2 at Lys178 hampering LKB1 nucleocytoplasmic shuttling and fueling hepatoma cell growth. Molecular modelling of SUMO modified LKB1 further confirmed steric impedance between SUMOylated LKB1 and the STe20-Related ADaptor cofactor (STRADα), involved in LKB1 export from the nucleus. Finally, we provide evidence that endogenous LKB1 is modified by SUMO in pre-clinical mouse models of HCC and clinical HCC, where LKB1 SUMOylation is higher in fast growing tumors. INTERPRETATION: Overall, SUMO-2 modification of LKB1 at Lys178 mediates LKB1 cellular localization and its oncogenic role in liver cancer. FUND: This work was supported by grants from NIH (US Department of Health and Human services)-R01AR001576-11A1 (J.M.M and M.L.M-C.), Gobierno Vasco-Departamento de Salud 2013111114 (to M.L.M.-C), ELKARTEK 2016, Departamento de Industria del Gobierno Vasco (to M.L.M.-C), MINECO: SAF2017-87301-R and SAF2014-52097-R integrado en el Plan Estatal de Investigación Cientifica y Técnica y Innovación 2013-2016 cofinanciado con Fondos FEDER (to M.L.M.-C and J.M.M., respectively), BFU2015-71017/BMC MINECO/FEDER, EU (to A.D.Q. and I.D.M.), BIOEF (Basque Foundation for Innovation and Health Research): EITB Maratoia BIO15/CA/014; Instituto de Salud Carlos III:PIE14/00031, integrado en el Plan Estatal de Investigación Cientifica y Técnica y Innovacion 2013-2016 cofinanciado con Fondos FEDER (to M.L.M.-C and J.M.M), Asociación Española contra el Cáncer (T.C.D, P·F-T and M.L.M-C), Daniel Alagille award from EASL (to T.C.D), Fundación Científica de la Asociación Española Contra el Cancer (AECC Scientific Foundation) Rare Tumor Calls 2017 (to M.L.M and M.A), La Caixa Foundation Program (to M.L.M), Programma di Ricerca Regione-Università 2007-2009 and 2011-2012, Regione Emilia-Romagna (to E.V.), Ramón Areces Foundation and the Andalusian Government (BIO-198) (A.D.Q. and I.D.M.), ayudas para apoyar grupos de investigación del sistema Universitario Vasco IT971-16 (P.A.), MINECO:SAF2015-64352-R (P.A.), Institut National du Cancer, FRANCE, INCa grant PLBIO16-251 (M.S.R.), MINECO - BFU2016-76872-R to (E.B.). Work produced with the support of a 2017 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation (M.V-R). Finally, Ciberehd_ISCIII_MINECO is funded by the Instituto de Salud Carlos III. We thank MINECO for the Severo Ochoa Excellence Accreditation to CIC bioGUNE (SEV-2016-0644). Funding sources had no involvement in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Sociodemographic disparities in access to ovarian cancer treatment.

BACKGROUND: Ovarian cancer is the fifth most common cause of cancer death among women in the United States. Failure to receive optimal treatment and poorer survival rates have been reported for older women, African-American women, women with low income, and women with public health insurance coverage or no coverage. Additionally, regional differences in geographic access influence the type of treatment women may seek. This paper explores geographic accessibility and sociodemographic vulnerability in Georgia, which influence receipt of optimal ovarian cancer treatment. METHODS: An enhanced two-step floating catchment area (E2SFCA), defining physical access, was created for each census tract and gynecologic oncologist clinic. Secondly, sociodemographic variables reflecting potential social vulnerability were selected from U.S. Census and American Community Survey data at the tract level. These two measures were combined to create a measure of Geosocial Vulnerability. This framework was tested using Georgia ovarian cancer mortality records. RESULTS: Geospatial access was higher in urban areas with less accessibility in suburban and rural areas. Sociodemographic vulnerability varied geospatially, with higher vulnerability in urban citers and rural areas. Sociodemographic measures were combined with geospatial access to create a Geosocial Vulnerability Indicator, which showed a significant positive association with ovarian cancer mortality. CONCLUSIONS: Spatial and sociodemographic measures pinpointed areas of healthcare access vulnerability not revealed by either spatial analysis or sociodemographic assessment alone. Whereas lower healthcare accessibility in rural areas has been well described, our analysis shows considerable heterogeneity in access to care in urban areas where the disadvantaged census tracts can be easily identified.