The National Cancer Database Conforms to the Standardized Framework for Registry and Data Quality.

BACKGROUND: Standardization of procedures for data abstraction by cancer registries is fundamental for cancer surveillance, clinical and policy decision-making, hospital benchmarking, and research efforts. The objective of the current study was to evaluate adherence to the four components (completeness, comparability, timeliness, and validity) defined by Bray and Parkin that determine registries' ability to carry out these activities to the hospital-based National Cancer Database (NCDB). METHODS: Tbis study used data from U.S. Cancer Statistics, the official federal cancer statistics and joint effort between the Centers for Disease Control and Prevention (CDC) and the National Cancer Institute (NCI), which includes data from National Program of Cancer Registries (NPCR) and Surveillance, Epidemiology, and End Results (SEER) to evaluate NCDB completeness between 2016 and 2020. The study evaluated comparability of case identification and coding procedures. It used Commission on Cancer (CoC) standards from 2022 to assess timeliness and validity. RESULTS: Completeness was demonstrated with a total of 6,828,507 cases identified within the NCDB, representing 73.7% of all cancer cases nationwide. Comparability was followed using standardized and international guidelines on coding and classification procedures. For timeliness, hospital compliance with timely data submission was 92.7%. Validity criteria for re-abstracting, recording, and reliability procedures across hospitals demonstrated 94.2% compliance. Additionally, data validity was shown by a 99.1% compliance with histologic verification standards, a 93.6% assessment of pathologic synoptic reporting, and a 99.1% internal consistency of staff credentials. CONCLUSION: The NCDB is characterized by a high level of case completeness and comparability with uniform standards for data collection, and by hospitals with high compliance, timely data submission, and high rates of compliance with validity standards for registry and data quality evaluation.

Counts, incidence rates, and trends of pediatric cancer in the United States, 2003-2019.

BACKGROUND: Cancer is a leading cause of death by disease among children and adolescents in the United States. This study updates cancer incidence rates and trends using the most recent and comprehensive US cancer registry data available. METHODS: We used data from US Cancer Statistics to evaluate counts, age-adjusted incidence rates, and trends among children and adolescents younger than 20 years of age diagnosed with malignant tumors between 2003 and 2019. We calculated the average annual percent change (APC) and APC using joinpoint regression. Rates and trends were stratified by demographic and geographic characteristics and by cancer type. RESULTS: With 248 749 cases reported between 2003 and 2019, the overall cancer incidence rate was 178.3 per 1 million; incidence rates were highest for leukemia (46.6), central nervous system neoplasms (30.8), and lymphoma (27.3). Rates were highest for males, children 0 to 4 years of age, Non-Hispanic White children and adolescents, those in the Northeast census region, the top 25% of counties by economic status, and metropolitan counties with a population of 1 million people or more. Although the overall incidence rate of pediatric cancer increased 0.5% per year on average between 2003 and 2019, the rate increased between 2003 and 2016 (APC = 1.1%), and then decreased between 2016 and 2019 (APC = -2.1%). Between 2003 and 2019, rates of leukemia, lymphoma, hepatic tumors, bone tumors, and thyroid carcinomas increased, while melanoma rates decreased. Rates of central nervous system neoplasms increased until 2017, and then decreased. Rates of other cancer types remained stable. CONCLUSIONS: Incidence of pediatric cancer increased overall, although increases were limited to certain cancer types. These findings may guide future public health and research priorities.

Cancer survival in the United States 2007-2016: Results from the National Program of Cancer Registries.

BACKGROUND: Cancer survival has improved for the most common cancers. However, less improvement and lower survival has been observed in some groups perhaps due to differential access to cancer care including prevention, screening, diagnosis, and treatment. METHODS: To further understand contemporary relative cancer survival (one- and five- year), we used survival data from CDC's National Program of Cancer Registries (NPCR) for cancers diagnosed during 2007-2016. We examined overall relative cancer survival by sex, race and ethnicity, age, and county-level metropolitan and non-metropolitan status. Relative cancer survival by metropolitan and non-metropolitan status was further examined by sex, race and ethnicity, age, and cancer type. RESULTS: Among persons with cancer diagnosed during 2007-2016 the overall one-year and five-year relative survival was 80.6% and 67.4%, respectively. One-year relative survival for persons living in metropolitan counties was 81.1% and 77.8% among persons living in non-metropolitan counties. We found that persons who lived in non-metropolitan counties had lower survival than those who lived in metropolitan counties, and this difference persisted across sex, race and ethnicity, age, and most cancer types. CONCLUSION: Further examination of the differences in cancer survival by cancer type or other characteristics might be helpful for identifying potential interventions, such as programs that target screening and early detection or strategies to improve access to high quality cancer treatment and follow-up care, that could improve long-term outcomes. IMPACT: This analysis provided a high-level overview of contemporary cancer survival in the United States.

Trends in breast cancer mortality by race/ethnicity, age, and US census region, United States─1999-2020.

BACKGROUND: Breast cancer remains a leading cause of morbidity and mortality among women in the United States. Previous analyses show that breast cancer incidence increased from 1999 to 2018. The purpose of this article is to examine trends in breast cancer mortality. METHODS: Analysis of 1999 to 2020 mortality data from the Centers for Disease Control and Prevention, National Center for Health Statistics, among women by race/ethnicity, age, and US Census region. RESULTS: It was found that overall breast cancer mortality is decreasing but varies by race/ethnicity, age group, and US Census region. The largest decrease in mortality was observed among non-Hispanic White women, women aged 45 to 64 years of age, and women living in the Northeast; whereas the smallest decrease in mortality was observed among non-Hispanic Asian or Pacific Islander women, women aged 65 years or older, and women living in the South. CONCLUSION: This report provides national estimates of breast cancer mortality from 1999 to 2020 by race/ethnicity, age group, and US Census region. The decline in breast cancer mortality varies by demographic group. Disparities in breast cancer mortality have remained consistent over the past two decades. Using high-quality cancer surveillance data to estimate trends in breast cancer mortality may help health care professionals and public health prevention programs tailor screening and diagnostic interventions to address these disparities.

Cancer disparities among non-Hispanic urban American Indian and Alaska Native populations in the United States, 1999-2017.

BACKGROUND: Disparities in cancer incidence have not been described for urban American Indian/Alaska Native (AI/AN) populations. The purpose of the present study was to examine incidence rates (2008-2017) and trends (1999-2017) for leading cancers in urban non-Hispanic AI/AN (NH AI/AN) compared to non-Hispanic White (NHW) populations living in the same urban areas. METHODS: Incident cases from population-based cancer registries were linked with the Indian Health Service patient registration database for improved racial classification of NH AI/AN populations. This study was limited to counties in Urban Indian Health Organization service areas. Analyses were conducted by geographic region. Age-adjusted rates (per 100,000) and trends (joinpoint regression) were calculated for leading cancers. RESULTS: Rates of colorectal, liver, and kidney cancers were higher overall for urban NH AI/AN compared to urban NHW populations. By region, rates of these cancers were 10% to nearly 4 times higher in NH AI/AN compared to NHW populations. Rates for breast, prostate, and lung cancer were lower in urban NH AI/AN compared to urban NHW populations. Incidence rates for kidney, liver, pancreatic, and breast cancers increased from 2% to nearly 7% annually between 1999 to 2017 in urban NH AI/AN populations. CONCLUSIONS: This study presents cancer incidence rates and trends for the leading cancers among urban NH AI/AN compared to urban NHW populations for the first time, by region, in the United States. Elevated risk of certain cancers among urban NH AI/AN populations and widening cancer disparities highlight important health inequities and missed opportunities for cancer prevention in this population.

Trends in Breast Cancer Incidence, by Race, Ethnicity, and Age Among Women Aged ≥20 Years - United States, 1999-2018.

Breast cancer is commonly diagnosed among women, accounting for approximately 30% of all cancer cases reported among women.* A slight annual increase in breast cancer incidence occurred in the United States during 2013-2017 (1). To examine trends in breast cancer incidence among women aged ≥20 years by race/ethnicity and age, CDC analyzed data from U.S. Cancer Statistics (USCS) during 1999-2018. Overall, breast cancer incidence rates among women decreased an average of 0.3% per year, decreasing 2.1% per year during 1999-2004 and increasing 0.3% per year during 2004-2018. Incidence increased among non-Hispanic Asian or Pacific Islander women and women aged 20-39 years and decreased among non-Hispanic White women and women aged 50-64 and ≥75 years. The U.S. Preventive Services Task Force currently recommends biennial screening mammography for women aged 50-74 years (2). These findings suggest that women aged 20-49 years might benefit from discussing potential breast cancer risk and ways to reduce risk with their health care providers. Further examination of breast cancer trends by demographic characteristics might help tailor breast cancer prevention and control programs to address state- or county-level incidence rates† and help prevent health disparities.

Multi-Instrument Characterization of Magnetospheric Cold Plasma Dynamics in the June 22, 2015 Geomagnetic Storm.

We present a comparison of magnetospheric plasma mass/electron density observations during an 11-day interval which includes the geomagnetic storm of June 22, 2015. For this study we used: Equatorial plasma mass density derived from geomagnetic field line resonances (FLRs) detected by Van Allen Probes and at the ground-based magnetometer networks EMMA and CARISMA; in situ electron density inferred by the Neural-network-based Upper hybrid Resonance Determination algorithm applied to plasma wave Van Allen Probes measurements. The combined observations at L ∼ 4, MLT ∼ 16 of the two longitudinally separated magnetometer networks show a temporal pattern very similar to that of the in situ observations: A density decrease by an order of magnitude about 1 day after the Dst minimum, a partial recovery a few hours later, and a new strong decrease soon after. The observations are consistent with the position of the measurement points with respect to the plasmasphere boundary as derived by a plasmapause test particle simulation. A comparison between plasma mass densities derived from ground and in situ FLR observations during favorable conjunctions shows a good agreement. We find however, for L < âˆ¼3, the spacecraft measurements to be higher than the corresponding ground observations with increasing deviation with decreasing L, which might be related to the rapid outbound spacecraft motion in that region. A statistical analysis of the average ion mass using simultaneous spacecraft measurements of mass and electron density indicates values close to 1 amu in plasmasphere and higher values (∼2-3 amu) in plasmatrough.

Incidence and Mortality of Cancers of the Biliary Tract, Gallbladder, and Liver by Sex, Age, Race/Ethnicity, and Stage at Diagnosis: United States, 2013 to 2017.

BACKGROUND: Few population-based studies have examined incidence and mortality of cancers of the biliary tract, including intrahepatic bile duct, extrahepatic bile duct, ampulla of Vater, and overlapping or other lesions of the biliary tract in one study. METHODS: To further the understanding of recent rates of biliary tract cancers, we used population-based data, to examine incidence and mortality during 2013 to 2017. We examined how rates varied by sex, age, race/ethnicity, U.S. census region, and stage at diagnosis. RESULTS: Intrahepatic bile duct was the most common biliary tract cancer, with an incidence rate of 1.49 per 100,000 persons. Cancer incidence rates per 100,000 persons were 0.96 for extrahepatic bile duct, 0.45 for ampulla of Vater, and 0.24 for overlapping or other lesions of the biliary tract. Cancer death rates per 100,000 persons were 1.66 for intrahepatic bile duct and 0.45 for other biliary tract. Intrahepatic bile duct incidence and death rates were higher among males than females, higher among Hispanic and Asian and Pacific Islander persons compared with non-Hispanic Whites, and higher in the Northeast and in urban counties. CONCLUSIONS: This report provides national estimates of these rare biliary tract cancers. IMPACT: Key interventions targeted to high-risk populations may help reduce incidence and mortality of cancers of the biliary tract by improving primary prevention through strategies to reduce tobacco and alcohol use, control overweight and obesity, and promote hepatitis B vaccination and use of syringe service programs meant to curb the transmission of infectious diseases such as viral hepatitis.

Trends in solitary plasmacytoma, extramedullary plasmacytoma, and plasma cell myeloma incidence and myeloma mortality by racial-ethnic group, United States 2003-2016.

Plasma cell myeloma (also called multiple myeloma), solitary plasmacytoma, and extramedullary plasmacytoma are primarily diseases of the elderly. Evidence suggests an association between excess body weight and multiple myeloma. Few population-based studies have examined incidence and mortality of each site in one study. We analyzed incidence and death rates by site (solitary plasmacytoma, extramedullary plasmacytoma, and multiple myeloma) by gender, age, race/ethnicity, and rural-urban status among adult males and females (aged 20 years or older) in the United States during 2003-2016. Trends were characterized as average annual percentage change (AAPC) in rates. During 2003-2016, overall incidence rates among adults were 0.45 for solitary plasmacytoma, 0.09 for extramedullary plasmacytoma, and 8.47 for multiple myeloma per 100,000 persons. Incidence rates for multiple myeloma increased during 2003-2016 among non-Hispanic whites (AAPC = 1.78%) and non-Hispanic blacks (2.98%) 20-49 years of age; non-Hispanic whites (1.17%) and non-Hispanic blacks (1.24%) 50-59 years of age; and whites non-Hispanic (0.91%), and non-Hispanic blacks (0.96%). During 2003-2016 overall myeloma (extramedullary plasmacytoma and multiple myeloma) death rates among adults was 4.77 per 100,00 persons. Myeloma death rates decreased during 2003-2016 among non-Hispanic white (AAPC = -1.23%) and Hispanic (-1.34%) women; and non-Hispanic white (-0.74%), non-Hispanic American Indian/Alaska Native (-3.05%) men. The US population is projected to become older and will have a larger proportion of persons who have had an earlier and longer exposure to excess body weight. The potential impact of these population changes on myeloma incidence and mortality can be monitored with high-quality cancer surveillance data.

Breast Cancer Survival Among Males by Race, Ethnicity, Age, Geographic Region, and Stage - United States, 2007-2016.

Breast cancer among males in the United States is rare; approximately 2,300 new cases and 500 associated deaths were reported in 2017, accounting for approximately 1% of all breast cancers.* Risk for male breast cancer increases with increasing age (1), and compared with women, men receive diagnoses later in life and often at a later stage of disease (1). Gradual improvement in breast cancer survival from 1976-1985 to 1996-2005 has been more evident for women than for men (1). Studies examining survival differences among female breast cancer patients observed that non-Hispanic White (White) females had a higher survival than non-Hispanic Black (Black) females (2), but because of the rarity of breast cancer among males, few studies have examined survival differences by race or other factors such as age, stage, and geographic region. CDC's National Program of Cancer Registries (NPCR)† data were used to examine relative survival of males with breast cancer diagnosed during 2007-2016 by race/ethnicity, age group, stage at diagnosis, and U.S. Census region. Among males who received a diagnosis of breast cancer during 2007-2016, 1-year relative survival was 96.1%, and 5-year relative survival was 84.7%. Among characteristics examined, relative survival varied most by stage at diagnosis: the 5-year relative survival for males was higher for cancers diagnosed at localized stage (98.7%) than for those diagnosed at distant stage (25.9%). Evaluation of 1-year and 5-year relative survival among males with breast cancer might help guide health care decisions regarding early detection of male breast cancer and establishing programs to support men at high risk for breast cancer and male breast cancer survivors.

Pediatric cancer mortality and survival in the United States, 2001-2016.

BACKGROUND: Although pediatric cancer mortality and survival have improved in the United States over the past 40 years, differences exist by age, race/ethnicity, cancer site, and economic status. To assess progress, this study examined recent mortality and survival data for individuals younger than 20 years. METHODS: Age-adjusted death rates were calculated with the National Vital Statistics System for 2002-2016. Annual percent changes (APCs) and average annual percent changes (AAPCs) were calculated with joinpoint regression. Five-year relative survival was calculated on the basis of National Program of Cancer Registries data for 2001-2015. Death rates and survival were estimated overall and by sex, 5-year age group, race/ethnicity, cancer type, and county-based economic markers. RESULTS: Death rates decreased during 2002-2016 (AAPC, -1.5), with steeper declines during 2002-2009 (APC, -2.6), and then plateaued (APC, -0.4). Leukemia and brain cancer were the most common causes of death from pediatric cancer, and brain cancer surpassed leukemia in 2011. Death rates decreased for leukemia and lymphoma but were unchanged for brain, bone, and soft-tissue cancers. From 2001-2007 to 2008-2015, survival improved from 82.0% to 85.1%. Survival was highest in both periods among females, those aged 15 to 19 years, non-Hispanic Whites, and those in counties in the top 25% by economic status. Survival improved for leukemias, lymphomas, and brain cancers but plateaued for bone and soft-tissue cancers. CONCLUSIONS: Although overall death rates have decreased and survival has increased, differences persist by sex, age, race/ethnicity, cancer type, and economic status. Improvements in pediatric cancer outcomes may depend on improving therapies, access to care, and supportive and long-term care.

Trends in Incidence of Cancers of the Oral Cavity and Pharynx - United States 2007-2016.

Cancers of the oral cavity and pharynx account for 3% of cancers diagnosed in the United States* each year. Cancers at these sites can differ anatomically and histologically and might have different causal factors, such as tobacco use, alcohol use, and infection with human papillomavirus (HPV) (1). Incidence of combined oral cavity and pharyngeal cancers declined during the 1980s but began to increase around 1999 (2,3). Because tobacco use has declined in the United States, accompanied by a decrease in incidence of many tobacco-related cancers, researchers have suggested that the increase in oral cavity and pharynx cancers might be attributed to anatomic sites with specific cell types in which HPV DNA is often found (4,5). U.S. Cancer Statistics† data were analyzed to examine trends in incidence of cancers of the oral cavity and pharynx by anatomic site, sex, race/ethnicity, and age group. During 2007-2016, incidence rates increased for cancers of the oral cavity and pharynx combined, base of tongue, anterior tongue, gum, tonsil, oropharynx, and other oral cavity and pharynx. Incidence rates declined for cancers of the lip, floor of mouth, soft palate and uvula, hard palate, hypopharynx, and nasopharynx, and were stable for cancers of the cheek and other mouth and salivary gland. Ongoing implementation of proven population-based strategies to prevent tobacco use initiation, promote smoking cessation, reduce excessive alcohol use, and increase HPV vaccination rates might help prevent cancers of the oral cavity and pharynx.

Trends in short-term survival from distant-stage cutaneous melanoma in the United States, 2001-2013 (CONCORD-3).

BACKGROUND: Survival from metastatic cutaneous melanoma is substantially lower than for localized disease. Treatments for metastatic melanoma have been limited, but remarkable clinical improvements have been reported in clinical trials in the last decade. We described the characteristics of US patients diagnosed with cutaneous melanoma during 2001-2013 and assessed trends in short-term survival for distant-stage disease. METHODS: Trends in 1-year net survival were estimated using the Pohar Perme estimator, controlling for background mortality with life tables of all-cause mortality rates by county of residence, single year of age, sex, and race for each year 2001-2013. We fitted a flexible parametric survival model on the log-hazard scale to estimate the effect of race on the hazard of death because of melanoma and estimated 1-year net survival by race. RESULTS: Only 4.4% of the 425 915 melanomas were diagnosed at a distant stage, cases diagnosed at a distant stage are more commonly men, older patients, and African Americans. Age-standardized, 1-year net survival for distant-stage disease was stable at approximately 43% during 2001-2010. From 2010 onward, survival improved rapidly, reaching 58.9% (95% confidence interval = 56.6% to 61.2%) for patients diagnosed in 2013. Younger patients experienced the largest improvement. Survival for distant-stage disease increased in both Blacks and Whites but was consistently lower in Blacks. CONCLUSIONS: One-year survival for distant-stage melanoma improved during 2001-2013, particularly in younger patients and those diagnosed since 2010. This improvement may be a consequence of the introduction of immune-checkpoint-inhibitors and other targeted treatments for metastatic and unresectable disease. Persistent survival inequalities exist between Blacks and Whites, suggesting differential access to treatment.

Cancer collection efforts in the United States provide clinically relevant data on all primary brain and other CNS tumors.

Cancer surveillance is critical for monitoring the burden of cancer and the progress in cancer control. The accuracy of these data is important for decision makers and others who determine resource allocation for cancer prevention and research. In the United States, cancer registration is conducted according to uniform data standards, which are updated and maintained by the North American Association of Central Cancer Registries. Underlying cancer registration efforts is a firm commitment to ensure that data are accurate, complete, and reflective of current clinical practices. Cancer registries ultimately depend on medical records that are generated for individual patients by clinicians to record newly diagnosed cases. For the cancer registration of brain and other CNS tumors, the Central Brain Tumor Registry of the United States is the self-appointed guardian of these data. In 2017, the Central Brain Tumor Registry of the United States took the initiative to promote the inclusion of molecular markers found in the 2016 WHO Classification of Tumours of the Central Nervous System into information collected by cancer registries. The complexities of executing this latest objective are presented according to the cancer registry standard-setting organizations whose collection practices for CNS tumors are directly affected.

Geographic Variation in Pediatric Cancer Incidence - United States, 2003-2014.

Approximately 15,000 persons aged <20 years receive a cancer diagnosis each year in the United States (1). National surveillance data could provide understanding of geographic variation in occurrence of new cases to guide public health planning and investigation (2,3). Past research on pediatric cancer incidence described differences by U.S. Census region but did not provide state-level estimates (4). To adequately describe geographic variation in cancer incidence among persons aged <20 years in the United States, CDC analyzed data from United States Cancer Statistics (USCS) during 2003-2014 and identified 171,432 cases of pediatric cancer during this period (incidence = 173.7 cases per 1 million persons). The cancer types with the highest incidence rates were leukemias (45.7), brain tumors (30.9), and lymphomas (26.2). By U.S. Census region, pediatric cancer incidence was highest in the Northeast (188.0) and lowest in the South (168.0), whereas by state (including the District of Columbia [DC]), rates were highest in New Hampshire, DC, and New Jersey. Among non-Hispanic whites (whites) and non-Hispanic blacks (blacks), pediatric cancer incidence was highest in the Northeast, and the highest rates among Hispanics were in the South. The highest rates of leukemia were in the West, and the highest rates of lymphoma and brain tumors were in the Northeast. State-based differences in pediatric cancer incidence could guide interventions related to accessing care (e.g., in states with large distances to pediatric oncology centers), clinical trial enrollment, and state or regional studies designed to further explore variations in cancer incidence.

Invasive Cancer Incidence and Survival - United States, 2013.

Although cancer represents many heterogeneous diseases, some cancer types share common risk factors. For example, conclusive evidence links cancer at multiple sites with tobacco use, alcohol use, human papillomavirus (HPV) infection, excess body weight, and physical inactivity (1,2). To monitor changes in cancer incidence and assess progress toward achieving Healthy People 2020 objectives,* CDC analyzed data from the U.S. Cancer Statistics (USCS) data set for 2013, the most recent year for which incidence and survival data are available. In 2013, a total of 1,559,130 invasive cancers were reported to cancer registries in the United States (excluding Nevada), for an annual age-adjusted incidence rate of 439 cases per 100,000 persons. Cancer incidence rates were higher among males (479) than females (413), highest among blacks (444), and ranged by state from 364 (New Mexico) to 512 (Kentucky) per 100,000 persons (359 in Puerto Rico). The proportion of persons with cancer who survived ≥5 years after diagnosis was 67%. This proportion was the same for males and females (67%), but lower among blacks (62%) than among whites (67%). Cancer surveillance data are key to cancer epidemiologic and clinical outcomes research, program planning and monitoring, resource allocation, and state and federal appropriations accountability.

Cancer Incidence in Appalachia, 2004-2011.

BACKGROUND: Limited literature is available about cancer in the Appalachian Region. This is the only known analysis of all cancers for Appalachia and non-Appalachia covering 100% of the US population. Appalachian cancer incidence and trends were evaluated by state, sex, and race and compared with those found in non-Appalachian regions. METHODS: US counties were identified as Appalachian or non-Appalachian. Age-adjusted cancer incidence rates, standard errors, and confidence intervals were calculated using the most recent data from the United States Cancer Statistics for 2004 to 2011. RESULTS: Generally, Appalachia carries a higher cancer burden compared with non-Appalachia, particularly for tobacco-related cancers. For all cancer sites combined, Appalachia has higher rates regardless of sex, race, or region. The Appalachia and non-Appalachia cancer incidence gap has narrowed, with the exception of oral cavity and pharynx, larynx, lung and bronchus, and thyroid cancers. CONCLUSIONS: Higher cancer incidence continues in Appalachia and appears at least in part to reflect high tobacco use and potential differences in socioeconomic status, other risk factors, patient health care utilization, or provider practices. It is important to continue to evaluate this population to monitor results from screening and early detection programs, understand behavioral risk factors related to cancer incidence, increase efforts to reduce tobacco use and increase cancer screening, and identify other areas where effective interventions may mediate disparities. IMPACT: Surveillance and evaluation of special populations provide means to monitor screening and early detection programs, understand behavioral risk factors, and increase efforts to reduce tobacco use to mediate disparities.

Survivin, a novel target of the Hedgehog/GLI signaling pathway in human tumor cells.

Survivin, an important antiapoptotic protein, is expressed in tumors, whereas in normal tissues the expression of this protein is extremely low, defining a role for survivin as a cancer gene. Survivin exhibits multifunctional activity in tumor cells. However, why survivin expression is sharply and invariably restricted to tumor tissue remains unclear. Here, we identified 11 putative consensus binding sites for GLI transcription factors in the survivin promoter and characterized the promoter activity. Inhibitors of the Hedgehog/GLI pathway, cyclopamine and GANT61, decreased the promoter activity in reporter assays. ΔNGLI2 (which lacks the repressor domain) was the most potent vector in activating the survivin promoter-reporter. Moreover, GANT61, a GLI1/2 inhibitor, repressed endogenous survivin protein and mRNA expression in most cells across a large panel of tumor cell lines. Chromatin immunoprecipitation showed GLI2 binding to the survivin promoter. The ectopic GLI2-evoked expression of endogenous survivin was observed in normal human fibroblasts. GANT61 decreased survivin level in nude mice tumors, mimicking the activity of GANT61 in cultured cells. The immunohistochemistry and double immunofluorescence of human tumors revealed a correlation between the tissue regions showing high GLI2 and survivin positivity. Thus, these results demonstrated that survivin is a classical transcriptional target of GLI2, a Hedgehog pathway signaling effector. This potentially reflects the high expression of survivin in human tumor cells. As the Hedgehog pathway is upregulated in virtually all types of cancer cells, these findings substantially contribute to the explanation of uniform survivin expression in tumors as a potential target for the development of a more effective treatment of cancers through the inhibition of GLI2 to restrain survivin activity.