Cancer statistics for African American/Black People 2022.

African American/Black individuals have a disproportionate cancer burden, including the highest mortality and the lowest survival of any racial/ethnic group for most cancers. Every 3 years, the American Cancer Society estimates the number of new cancer cases and deaths for Black people in the United States and compiles the most recent data on cancer incidence (herein through 2018), mortality (through 2019), survival, screening, and risk factors using population-based data from the National Cancer Institute and the Centers for Disease Control and Prevention. In 2022, there will be approximately 224,080 new cancer cases and 73,680 cancer deaths among Black people in the United States. During the most recent 5-year period, Black men had a 6% higher incidence rate but 19% higher mortality than White men overall, including an approximately 2-fold higher risk of death from myeloma, stomach cancer, and prostate cancer. The overall cancer mortality disparity is narrowing between Black and White men because of a steeper drop in Black men for lung and prostate cancers. However, the decline in prostate cancer mortality in Black men slowed from 5% annually during 2010 through 2014 to 1.3% during 2015 through 2019, likely reflecting the 5% annual increase in advanced-stage diagnoses since 2012. Black women have an 8% lower incidence rate than White women but a 12% higher mortality; further, mortality rates are 2-fold higher for endometrial cancer and 41% higher for breast cancer despite similar or lower incidence rates. The wide breast cancer disparity reflects both later stage diagnosis (57% localized stage vs 67% in White women) and lower 5-year survival overall (82% vs 92%, respectively) and for every stage of disease (eg, 20% vs 30%, respectively, for distant stage). Breast cancer surpassed lung cancer as the leading cause of cancer death among Black women in 2019. Targeted interventions are needed to reduce stark cancer inequalities in the Black community.

American Cancer Society's report on the status of cancer disparities in the United States, 2021.

In this report, the authors provide comprehensive and up-to-date US data on disparities in cancer occurrence, major risk factors, and access to and utilization of preventive measures and screening by sociodemographic characteristics. They also review programs and resources that have reduced cancer disparities and provide policy recommendations to further mitigate these inequalities. The overall cancer death rate is 19% higher among Black males than among White males. Black females also have a 12% higher overall cancer death rate than their White counterparts despite having an 8% lower incidence rate. There are also substantial variations in death rates for specific cancer types and in stage at diagnosis, survival, exposure to risk factors, and receipt of preventive measures and screening by race/ethnicity, socioeconomic status, and geographic location. For example, kidney cancer death rates by sex among American Indian/Alaska Native people are ≥64% higher than the corresponding rates in each of the other racial/ethnic groups, and the 5-year relative survival for all cancers combined is 14% lower among residents of poorer counties than among residents of more affluent counties. Broad and equitable implementation of evidence-based interventions, such as increasing health insurance coverage through Medicaid expansion or other initiatives, could substantially reduce cancer disparities. However, progress will require not only equitable local, state, and federal policies but also broad interdisciplinary engagement to elevate and address fundamental social inequities and longstanding systemic racism.

Wnt7a deficit is associated with dysfunctional angiogenesis in pulmonary arterial hypertension.

INTRODUCTION: Pulmonary arterial hypertension (PAH) is characterised by loss of microvessels. The Wnt pathways control pulmonary angiogenesis but their role in PAH is incompletely understood. We hypothesised that Wnt activation in pulmonary microvascular endothelial cells (PMVECs) is required for pulmonary angiogenesis, and its loss contributes to PAH. METHODS: Lung tissue and PMVECs from healthy and PAH patients were screened for Wnt production. Global and endothelial-specific Wnt7a -/- mice were generated and exposed to chronic hypoxia and Sugen-hypoxia (SuHx). RESULTS: Healthy PMVECs demonstrated >6-fold Wnt7a expression during angiogenesis that was absent in PAH PMVECs and lungs. Wnt7a expression correlated with the formation of tip cells, a migratory endothelial phenotype critical for angiogenesis. PAH PMVECs demonstrated reduced vascular endothelial growth factor (VEGF)-induced tip cell formation as evidenced by reduced filopodia formation and motility, which was partially rescued by recombinant Wnt7a. We discovered that Wnt7a promotes VEGF signalling by facilitating Y1175 tyrosine phosphorylation in vascular endothelial growth factor receptor 2 (VEGFR2) through receptor tyrosine kinase-like orphan receptor 2 (ROR2), a Wnt-specific receptor. We found that ROR2 knockdown mimics Wnt7a insufficiency and prevents recovery of tip cell formation with Wnt7a stimulation. While there was no difference between wild-type and endothelial-specific Wnt7a -/- mice under either chronic hypoxia or SuHx, global Wnt7a +/- mice in hypoxia demonstrated higher pulmonary pressures and severe right ventricular and lung vascular remodelling. Similar to PAH, Wnt7a +/- PMVECs exhibited an insufficient angiogenic response to VEGF-A that improved with Wnt7a. CONCLUSIONS: Wnt7a promotes VEGF signalling in lung PMVECs and its loss is associated with an insufficient VEGF-A angiogenic response. We propose that Wnt7a deficiency contributes to progressive small vessel loss in PAH.

Advancing More Equitable Care Through the Development of a Health Equity Report Card.

The root causes of racial disparities in access to optimal cancer care and related cancer outcomes are complex, multifactorial, and not rooted in biology. Contributing factors to racial disparities in care delivery include implicit and explicit bias, lack of representation of people of color in the oncology care and research workforce, and homogenous research participants that are not representative of the larger community. Systemic and structural barriers include policies leading to lack of insurance and underinsurance, costs of cancer treatment and associated ancillary costs of care, disparate access to clinical trials, and social determinants of health, including exposure to environmental hazards, access to housing, childcare, and economic injustices. To address these issues, ACS CAN, NCCN, and NMQF convened the Elevating Cancer Equity (ECE) initiative. The ECE Working Group developed the Health Equity Report Card (HERC). In this manuscript, we describe the process taken by the ECE Working Group to develop the HERC recommendations, the strategies employed by NCCN to develop an implementation plan and scoring methodology for the HERC, and next steps to pilot the HERC tool in practice settings.

Lysocardiolipin acyltransferase regulates NSCLC cell proliferation and migration by modulating mitochondrial dynamics.

Lysocardiolipin acyltransferase (LYCAT), a cardiolipin (CL)-remodeling enzyme, is crucial for maintaining normal mitochondrial function and vascular development. Despite the well-characterized role for LYCAT in the regulation of mitochondrial dynamics, its involvement in lung cancer, if any, remains incompletely understood. In this study, in silico analysis of TCGA lung cancer data sets revealed a significant increase in LYCAT expression, which was later corroborated in human lung cancer tissues and immortalized lung cancer cell lines via indirect immunofluorescence and immunoblotting, respectively. Stable knockdown of LYCAT in NSCLC cell lines not only reduced CL and increased monolyso-CL levels but also reduced in vivo tumor growth, as determined by xenograft studies in athymic nude mice. Furthermore, blocking LYCAT activity using a LYCAT mimetic peptide attenuated cell migration, suggesting a novel role for LYCAT activity in promoting NSCLC. Mechanistically, the pro-proliferative effects of LYCAT were mediated by an increase in mitochondrial fusion and a G1/S cell cycle transition, both of which are linked to increased cell proliferation. Taken together, these results demonstrate a novel role for LYCAT in promoting NSCLC and suggest that targeting LYCAT expression or activity in NSCLC may provide new avenues for the therapeutic treatment of lung cancer.

Addressing Disparities in Lung Cancer Screening Eligibility and Healthcare Access. An Official American Thoracic Society Statement.

Background: There are well-documented disparities in lung cancer outcomes across populations. Lung cancer screening (LCS) has the potential to reduce lung cancer mortality, but for this benefit to be realized by all high-risk groups, there must be careful attention to ensuring equitable access to this lifesaving preventive health measure.Objectives: To outline current knowledge on disparities in eligibility criteria for, access to, and implementation of LCS, and to develop an official American Thoracic Society statement to propose strategies to optimize current screening guidelines and resource allocation for equitable LCS implementation and dissemination.Methods: A multidisciplinary panel with expertise in LCS, implementation science, primary care, pulmonology, health behavior, smoking cessation, epidemiology, and disparities research was convened. Participants reviewed available literature on historical disparities in cancer screening and emerging evidence of disparities in LCS.Results: Existing LCS guidelines do not consider racial, ethnic, socioeconomic, and sex-based differences in smoking behaviors or lung cancer risk. Multiple barriers, including access to screening and cost, further contribute to the inequities in implementation and dissemination of LCS.Conclusions: This statement identifies the impact of LCS eligibility criteria on vulnerable populations who are at increased risk of lung cancer but do not meet eligibility criteria for screening, as well as multiple barriers that contribute to disparities in LCS implementation. Strategies to improve the selection and dissemination of LCS in vulnerable groups are described.

Orthogonal lipid sensors identify transbilayer asymmetry of plasma membrane cholesterol.

Controlled distribution of lipids across various cell membranes is crucial for cell homeostasis and regulation. We developed an imaging method that allows simultaneous in situ quantification of cholesterol in two leaflets of the plasma membrane (PM) using tunable orthogonal cholesterol sensors. Our imaging revealed marked transbilayer asymmetry of PM cholesterol (TAPMC) in various mammalian cells, with the concentration in the inner leaflet (IPM) being ∼12-fold lower than that in the outer leaflet (OPM). The asymmetry was maintained by active transport of cholesterol from IPM to OPM and its chemical retention at OPM. Furthermore, the increase in the IPM cholesterol level was triggered in a stimulus-specific manner, allowing cholesterol to serve as a signaling lipid. We found excellent correlation between the IPM cholesterol level and cellular Wnt signaling activity, suggesting that TAPMC and stimulus-induced PM cholesterol redistribution are crucial for tight regulation of cellular processes under physiological conditions.

K-homology splicing regulatory protein (KSRP) promotes post-transcriptional destabilization of Spry4 transcripts in non-small cell lung cancer.

AU-rich element-binding proteins (ARE-BPs) offer post-transcriptional regulation of gene expression via physical interaction and recruitment of RNA decay machinery to the AU-rich elements within the 3'-UTR of the target transcripts. However, the role of ARE-BPs in lung cancer remains poorly understood. In this study, we have identified that K-homology splicing regulatory protein (KSRP), an ARE-BP, is robustly up-regulated in human lung cancer. Importantly, Kaplan-Meier survival analysis indicated that elevated KSRP expression was correlated with poor overall survival of lung cancer patients. Furthermore, cigarette smoke, a leading risk factor for lung cancer, was also identified to be an important contributor to increased KSRP expression. Remarkably, silencing of KSRP decreased cell proliferation, reversed anchorage-independent growth, and reduced migration/invasion, suggesting an oncogenic role for KSRP in lung cancer. Finally, we provide mechanistic evidence that KSRP promotes the down-regulation of Spry4 by a previously unidentified mechanism, i.e. post-transcriptional mRNA regulation.

Wnt7a induces a unique phenotype of monocyte-derived macrophages with lower phagocytic capacity and differential expression of pro- and anti-inflammatory cytokines.

The variation of macrophage functions suggests the involvement of multiple signalling pathways in fine tuning their differentiation. Macrophages that originate from monocytes in the blood migrate to tissue in response to homeostatic or 'danger' signals and undergo substantial morphological and functional modifications to meet the needs of the dominant signals in the microenvironment. Wnts are secreted glycoproteins that play a significant role in organ and cell differentiation, yet their impact on monocyte differentiation is not clear. In this study, we assessed the role of Wnt1 and Wnt7a on the differentiation of monocytes and the subsequent phenotype and function of monocyte-derived macrophages (MDMs). We show that Wnt7a decreased the expression of CD14, CD11b, CD163 and CD206, whereas Wnt1 had no effect. The Wnt7a effect on CD11b was also observed in the brain and spleen of Wnt7a-/- adult brain mouse tissue and in embryonic Wnt7a-/- tissue. Wnt7a reduced the phagocytic capacity of M-MDMs, decreased interleukin-10 (IL-10) and IL-12 secretion and increased IL-6 secretion. Collectively, these findings demonstrate that Wnt7a generates an MDM phenotype with both pro-inflammatory and alternative MDM cytokine profiles and reduced phagocytic capacity. As such, Wnt7a can have a significant impact on macrophage responses in health and disease.

A geographic information system-based method for estimating cancer rates in non-census defined geographical areas.

PURPOSE: To address locally relevant cancer-related health issues, health departments frequently need data beyond that contained in standard census area-based statistics. We describe a geographic information system-based method for calculating age-standardized cancer incidence rates in non-census defined geographical areas using publically available data. METHODS: Aggregated records of cancer cases diagnosed from 2009 through 2013 in each of Chicago's 77 census-defined community areas were obtained from the Illinois State Cancer Registry. Areal interpolation through dasymetric mapping of census blocks was used to redistribute populations and case counts from community areas to Chicago's 50 politically defined aldermanic wards, and ward-level age-standardized 5-year cumulative incidence rates were calculated. RESULTS: Potential errors in redistributing populations between geographies were limited to <1.5% of the total population, and agreement between our ward population estimates and those from a frequently cited reference set of estimates was high (Pearson correlation r = 0.99, mean difference = -4 persons). A map overlay of safety-net primary care clinic locations and ward-level incidence rates for advanced-staged cancers revealed potential pathways for prevention. CONCLUSIONS: Areal interpolation through dasymetric mapping can estimate cancer rates in non-census defined geographies. This can address gaps in local cancer-related health data, inform health resource advocacy, and guide community-centered cancer prevention and control.

PRMT1 Is a Novel Regulator of Epithelial-Mesenchymal-Transition in Non-small Cell Lung Cancer.

Protein arginine methyl transferase 1 (PRMT1) was shown to be up-regulated in cancers and important for cancer cell proliferation. However, the role of PRMT1 in lung cancer progression and metastasis remains incompletely understood. In the present study, we show that PRMT1 is an important regulator of epithelial-mesenchymal transition (EMT), cancer cell migration, and invasion, which are essential processes during cancer progression, and metastasis. Additionally, we have identified Twist1, a basic helix-loop-helix transcription factor and a well-known E-cadherin repressor, as a novel PRMT1 substrate. Taken together, we show that PRMT1 is a novel regulator of EMT and arginine 34 (Arg-34) methylation of Twist1 as a unique "methyl arginine mark" for active E-cadherin repression. Therefore, targeting PRMT1-mediated Twist1 methylation might represent a novel strategy for developing new anti-invasive/anti-metastatic drugs. Moreover, methylated Twist1 (Arg-34), as such, could also emerge as a potential important biomarker for lung cancer.

Novel Role for γ-Catenin in the Regulation of Cancer Cell Migration via the Induction of Hepatocyte Growth Factor Activator Inhibitor Type 1 (HAI-1).

γ-Catenin (Plakoglobin), a well-described structural protein functioning at the adherens junctions and desmosomes, was shown to be either lost or weakly expressed in non-small cell lung cancer (NSCLC) cells and tumor tissues. However, the tumor suppressive affects of γ-catenin were not fully understood. In this study, we have identified a novel role for the affects of γ-catenin on non-small cell lung cancer (NSCLC) cell migration. Expression of γ-catenin in NSCLC cells resulted in reduced cell migration as determined by both scratch assays and trans-well cell migration assays. Moreover, the affects of γ-catenin on cell migration were observed to be p53-dependent. Mechanistically, the anti-migratory effects seen via γ-catenin were driven by the expression of hepatocyte growth factor activator inhibitor Type I (HAI-1 or SPINT-1), an upstream inhibitor of the c-MET signaling pathway. Furthermore, the re-expression of γ-catenin sensitized NSCLC cells to c-MET inhibitor-mediated growth inhibition. Taken together, we identify γ-catenin as a novel regulator of HAI-1, which is a critical regulator of HGF/c-MET signaling. Therefore, targeting γ-catenin-mediated HAI-1 expression might be a useful strategy to sensitize NSCLC to c-MET inhibitors.

Biosocial determinants inform on enduring cancer disparities.

Social, environmental, and biological risk factors influence exposures to newly termed 'biosocial determinants of health'. As molecular factors that lie at the intersection between lived experiences and individual biology, biosocial determinants may inform on the enduring complexity of cancer disparity across transdisciplinary studies.

Reflections on the state of telehealth and cancer care research and future directions.

Telemedicine has routinely been used in cancer care delivery for the past 3 years. The current state of digital health provides convenience and efficiency for both health-care professional and patient, but challenges exist in equitable access to virtual services. As increasingly newer technologies are added to telehealth platforms, it is essential to eliminate barriers to access through technical, procedural, and legislative improvements. Moving forward, implementation of new strategies can help eliminate disparities in virtual cancer care, facilitate delivery of treatment in the home, and improve real-time data collection for patient safety and clinical trial participation. The ultimate goal will be to extend high-quality survival for all patients with cancer through improved digital delivery of cancer care.

The Effect of Exposure to Neighborhood Violence on Glucocorticoid Receptor Signaling in Lung Tumors.

Despite lower rates and intensity of smoking, Black men experience a higher incidence of lung cancer compared to white men. The racial disparity in lung cancer is particularly pronounced in Chicago, a highly segregated urban city. Neighborhood conditions, particularly social stress, may play a role in lung tumorigenesis. Preliminary studies indicate that Black men residing in neighborhoods with higher rates of violent crime have significantly higher levels of hair cortisol, an indicator of stress response. To examine the relationship between social stress exposure and gene expression in lung tumors, we investigated glucocorticoid receptor (GR) binding in 15 lung tumor samples in relation to GR target gene expression levels and zip code level residential violent crime rates. Spatial transcriptomics and a version of ChIP sequencing known as CUT&RUN were used. Heatmap of genes, pathway analysis, and motif analysis were conducted at the statistical significance of P < 0.05. GR recruitment to chromatin was correlated with zip code level residential violent crime rate and overall GR binding increased with higher violent crime rates. Our findings suggest that exposure to residential violent crime may influence tumor biology via reprogramming GR recruitment. Prioritizing lung cancer screening in neighborhoods with increased social stress, such as high levels of violent crime, may reduce racial disparities in lung cancer. SIGNIFICANCE: Exposure to neighborhood violent crime is correlated with glucocorticoid signaling and lung tumor gene expression changes associated with increased tumor aggressiveness, suggesting social conditions have downstream biophysical consequences that contribute to lung cancer disparities.

Re-Envisioning Electronic Health Records to Optimize Patient-Centered Cancer Care, Quality, Surveillance, and Research.

Electronic health records (EHRs) are a significant advancement over paper records. However, the full potential of EHRs for improving care quality, patient outcomes, surveillance, and research in cancer care is yet to be realized. The organic evolution of EHRs has resulted in a number of unanticipated consequences including increased time spent by clinicians interfacing with the EHR for daily workflows. Patient access to clinicians and their records has been an important advancement in patient-centered care; however, this has brought to light additional gaps and challenges in EHRs meeting these needs. A significant challenge for EHR design and physician workflows is how best to meet the complex goals and priorities of various stakeholders including providers, researchers, patients, health systems, payors, and regulatory agencies. The National Cancer Policy Forum convened a 2022 workshop, "Innovations in Electronic Health Records for Oncology Care, Research and Surveillance," to address these challenges and to facilitate collaboration across all user groups with the goal of re-envisioning EHRs that will better support shared goals of improving patient outcomes and advancing cancer care and research without overburdening clinicians with administrative tasks. Here, we summarize the current EHR ecosystem as discussed at the workshop and highlight opportunities to improve EHR contributions to oncology evidence and care.

Prostate Cancer Foundation Screening Guidelines for Black Men in the United States.

BACKGROUND: In the United States, Black men are at highest risk for being diagnosed with and dying from prostate cancer. Given this disparity, we examined relevant data to establish clinical prostate-specific antigen (PSA) screening guidelines for Black men in the United States. METHODS: A comprehensive literature search identified 1848 unique publications for screening. Of those screened, 287 studies were selected for full-text review, and 264 were considered relevant and form the basis for these guidelines. The numbers were reported according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. RESULTS: Three randomized controlled trials provided Level 1 evidence that regular PSA screening of men 50 to 74 years of age of average risk reduced metastasis and prostate cancer death at 16 to 22 years of follow-up. The best available evidence specifically for Black men comes from observational and modeling studies that consider age to obtain a baseline PSA, frequency of testing, and age when screening should end. Cohort studies suggest that discussions about baseline PSA testing between Black men and their clinicians should begin in the early 40s, and data from modeling studies indicate prostate cancer develops 3 to 9 years earlier in Black men compared with non-Black men. Lowering the age for baseline PSA testing to 40 to 45 years of age from 50 to 55 years of age, followed by regular screening until 70 years of age (informed by PSA values and health factors), could reduce prostate cancer mortality in Black men (approximately 30% relative risk reduction) without substantially increasing overdiagnosis. CONCLUSIONS: These guidelines recommend that Black men should obtain information about PSA screening for prostate cancer. Among Black men who elect screening, baseline PSA testing should occur between ages 40 and 45. Depending on PSA value and health status, annual screening should be strongly considered. (Supported by the Prostate Cancer Foundation.).

Cooperation between PRMT1 and PRMT6 drives lung cancer health disparities among Black/African American men.

Lung cancer is the third most common cancer with Black/AA men showing higher risk and poorer outcomes than NHW men. Lung cancer disparities are multifactorial, driven by tobacco exposure, inequities in care access, upstream health determinants, and molecular determinants including biological and genetic factors. Elevated expressions of protein arginine methyltransferases (PRMTs) correlating with poorer prognosis have been observed in many cancers. Most importantly, our study shows that PRMT6 displays higher expression in lung cancer tissues of Black/AA men compared to NHW men. In this study, we investigated the underlying mechanism of PRMT6 and its cooperation with PRMT1 to form a heteromer as a driver of lung cancer. Disrupting PRMT1/PRMT6 heteromer by a competitive peptide reduced proliferation in non-small cell lung cancer cell lines and patient-derived organoids, therefore, giving rise to a more strategic approach in the treatment of Black/AA men with lung cancer and to eliminate cancer health disparities.

Insulin Resistance in Women Correlates with Chromatin Histone Lysine Acetylation, Inflammatory Signaling, and Accelerated Aging.

BACKGROUND: Epigenetic changes link medical, social, and environmental factors with cardiovascular and kidney disease and, more recently, with cancer. The mechanistic link between metabolic health and epigenetic changes is only starting to be investigated. In our in vitro and in vivo studies, we performed a broad analysis of the link between hyperinsulinemia and chromatin acetylation; our top "hit" was chromatin opening at H3K9ac. METHODS: Building on our published preclinical studies, here, we performed a detailed analysis of the link between insulin resistance, chromatin acetylation, and inflammation using an initial test set of 28 women and validation sets of 245, 22, and 53 women. RESULTS: ChIP-seq identified chromatin acetylation and opening at the genes coding for TNFα and IL6 in insulin-resistant women. Pathway analysis identified inflammatory response genes, NFκB/TNFα-signaling, reactome cytokine signaling, innate immunity, and senescence. Consistent with this finding, flow cytometry identified increased senescent circulating peripheral T-cells. DNA methylation analysis identified evidence of accelerated aging in insulin-resistant vs. metabolically healthy women. CONCLUSIONS: This study shows that insulin-resistant women have increased chromatin acetylation/opening, inflammation, and, perhaps, accelerated aging. Given the role that inflammation plays in cancer initiation and progression, these studies provide a potential mechanistic link between insulin resistance and cancer.