PETCH-DB: a Portal for Exploring Tissue-specific and Complex disease-associated 5-Hydroxymethylcytosines.

Epigenetic modifications play critical roles in gene regulation and disease pathobiology. Highly sensitive enabling technologies, including microarray- and sequencing-based approaches have allowed genome-wide profiling of cytosine modifications in DNAs in clinical samples to facilitate discovery of epigenetic biomarkers for disease diagnosis and prognosis. Historically, many previous studies, however, did not distinguish the most investigated 5-methylcytosines (5mC) from other modified cytosines, especially the biochemically stable 5-hydroxymethylcytosines (5hmC), which have been shown to have a distinct genomic distribution and regulatory role from 5mC. Notably, during the past several years, the 5hmC-Seal, a highly sensitive chemical labeling technique, has been demonstrated to be a powerful tool for genome-wide profiling of 5hmC in clinically feasible biospecimens (e.g. a few milliliter of plasma or serum). The 5hmC-Seal technique has been utilized by our team in biomarker discovery for human cancers and other complex diseases using circulating cell-free DNA (cfDNA), as well as the characterization of the first 5hmC Human Tissue Map. Convenient access to the accumulating 5hmC-Seal data will allow the research community to validate and re-use these results, potentially providing novel insights into epigenetic contribution to a range of human diseases. Here we introduce the PETCH-DB, an integrated database that was implemented to provide 5hmC-related results generated using the 5hmC-Seal technique. We aim the PETCH-DB to be a central portal, which will be available to the scientific community with regularly updated 5hmC data in clinical samples to reflect current advances in this field. Database URL http://petch-db.org/.

PETCH-DB: a Portal for Exploring Tissue-specific and Complex disease-associated 5-Hydroxymethylcytosines.

Epigenetic modifications play critical roles in gene regulation and disease pathobiology. Highly sensitive enabling technologies, including microarray- and sequencing-based approaches have allowed genome-wide profiling of cytosine modifications in DNAs in clinical samples to facilitate discovery of epigenetic biomarkers for disease diagnosis and prognosis. Historically, many previous studies, however, did not distinguish the most investigated 5-methylcytosines (5mC) from other modified cytosines, especially the biochemically stable 5-hydroxymethylcytosines (5hmC), which have been shown to have a distinct genomic distribution and regulatory role from 5mC. Notably, during the past several years, the 5hmC-Seal, a highly sensitive chemical labeling technique, has been demonstrated to be a powerful tool for genome-wide profiling of 5hmC in clinically feasible biospecimens (e.g. a few milliliter of plasma or serum). The 5hmC-Seal technique has been utilized by our team in biomarker discovery for human cancers and other complex diseases using circulating cell-free DNA (cfDNA), as well as the characterization of the first 5hmC Human Tissue Map. Convenient access to the accumulating 5hmC-Seal data will allow the research community to validate and re-use these results, potentially providing novel insights into epigenetic contribution to a range of human diseases. Here we introduce the PETCH-DB, an integrated database that was implemented to provide 5hmC-related results generated using the 5hmC-Seal technique. We aim the PETCH-DB to be a central portal, which will be available to the scientific community with regularly updated 5hmC data in clinical samples to reflect current advances in this field. Database URL http://petch-db.org/.

Geospatial analysis of population-based incidence of multiple myeloma in the United States.

BACKGROUND: We investigated the spatial patterns of multiple myeloma (MM) incidence in the United States (US) between 2013 and 2017 to improve understanding of potential environmental risk factors for MM. METHODS: We analyzed the average county-level age-adjusted incidence rates ("ASR") of MM between 2013 and 2017 in 50 states and the District of Columbia using the U.S. Cancer Statistics Public Use Databases. We firstly divided the ASR into quintiles and described spatial patterns using a choropleth map. To identify global and local clusters of the ASR, we performed the Spatial Autocorrelation (Global Moran's I) analysis and the Anselin's Local Indicator of Spatial Autocorrelation (LISA) analysis. We compared the means of selected demographic and socioeconomic factors between the clusters and counties of the whole US using Welch one-sided t-test. RESULTS: We identified distinct spatial dichotomy of the ASR across counties. High ASR were observed in counties in the Southeast of the US as well as the Capital District (metropolitan areas surrounding Albany) and New York City in the state of New York, while low ASR were observed in counties in the Southwest and West of the US. The ASR showed a significant positive spatial autocorrelation. We identified two major high-high local clusters of the ASR in Georgia and Southern Carolina and five major low-low local clusters of the ASR in Alabama, Arizona, New Hampshire, Ohio, Oregon, and Tennessee. The racial population distribution may partly explain the spatial distribution of MM incidence in the US. CONCLUSION: Findings from this study showed distinct spatial distribution of MM in the US and two high-high and five low-low local clusters. The non-random distribution of MM suggests that environmental exposures in certain regions may be important for the risk of MM.

Physical activity and the risk of non-Hodgkin lymphoma subtypes: A pooled analysis.

Non-Hodgkin lymphoma (NHL) is composed of a heterogeneous collection of subtypes with considerable differences in genetics, biology and aetiology. Studies to date on physical activity and NHL risk have not had sufficient sample size to evaluate whether associations differ by subtype. We pooled data from nine case-control studies to examine the association between moderate-to-vigorous intensity physical activity (MVPA) and risk of NHL overall and by subtype (diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukaemia/small lymphocytic lymphoma, marginal zone lymphoma and mature T-cell lymphoma). A total of 5653 cases and 9115 controls were included in the pooled analysis. Physical activity was harmonised across nine studies and modelled as study-specific tertiles. Multinomial logistic regression was used to estimate the association between physical activity and NHL, adjusting for confounders. The overall odds of NHL was 13% lower among participants in the most active tertile of MVPA compared to the least active tertile (adjusted odds ratio = 0.87, 95% CI = 0.80, 0.95). Similar decreases were observed across NHL subtypes. In summary, in this pooled analysis of case-control studies, physical activity was associated with a modest risk reduction for each NHL subtype examined and with overall NHL.

Body Mass Index and Overall Survival of Patients with Newly Diagnosed Multiple Myeloma.

Obesity is associated with survival in several solid tumors and non-Hodgkin lymphoma, but its impact on multiple myeloma (MM) survival is unclear. We examined the associations between body mass index (BMI) at different periods of life up to the time of diagnosis and overall survival (OS) among 563 patients newly diagnosed with MM in 2010-2019. BMI at diagnosis was calculated using measured height and weight from electronic medical records (EMR). BMIs at age 20, maximum during adulthood, and 5 years before diagnosis were calculated using self-reported weights and measured height from EMR. Over a median follow-up of 49.3 months, 191 (33.93%) deaths were identified. We used multivariable Cox proportional-hazards models to examine the associations between BMIs and OS. Height as well as BMI before and at diagnosis was not associated with OS, but there is a U-shape association between weight and OS. Higher BMIs at diagnosis were associated with better OS among females (HR = 0.39 [0.22-0.71]), irrespective of race. In conclusion, our results suggest that BMI at different periods of life up to the time of diagnosis may not be associated with OS in MM, except that a higher BMI at diagnosis was associated with superior OS for females.

Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes.

Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P < 5 × 10-8) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P = 3.27 × 10-9). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P < 5 × 10-8), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture.

Genome-wide profiling of 5-hydroxymethylcytosines in circulating cell-free DNA reveals population-specific pathways in the development of multiple myeloma.

Multiple myeloma (MM) and its precursors monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) are 2-3 times more common in African Americans (AA) than European Americans (EA). Although epigenetic changes are well recognized in the context of myeloma cell biology, the contribution of 5-hydroxymethylcytosines (5hmC) to racial disparities in MM is unknown. Using the 5hmC-Seal and next-generation sequencing, we profiled genome-wide 5hmC in circulating cell-free DNA (cfDNA) from 342 newly diagnosed patients with MM (n = 294), SMM (n = 18), and MGUS (n = 30). We compared differential 5hmC modifications between MM and its precursors among 227 EA and 115 AA patients. The captured 5hmC modifications in cfDNA were found to be enriched in B-cell and T-cell-derived histone modifications marking enhancers. Of the top 500 gene bodies with differential 5hmC levels between MM and SMM/MGUS, the majority (94.8%) were distinct between EA and AA and enriched with population-specific pathways, including amino acid metabolism in AA and mainly cancer-related signaling pathways in EA. These findings improved our understanding of the epigenetic contribution to racial disparities in MM and suggest epigenetic pathways that could be exploited as novel preventive strategies in high-risk populations.

Physical functioning, frailty and risks of locally-advanced breast cancer among older women.

OBJECTIVE: Women with multiple comorbidities have competing health needs that may delay screening for early detection of breast cancer. Our objective was to determine associations between physical functioning and frailty with risk of locally-advanced breast cancer (BC). METHODS: We conducted a retrospective cohort study of women 65 years and older diagnosed with first primary stage I-III BC using the Surveillance, Epidemiology and End Results Medicare Health Outcome Survey Data Resource. Physical health-related quality of life was measured using Veterans RAND 12 Item Health Survey scales within two years before diagnosis; frailty was determined by calculating deficit-accumulation frailty index (DAFI) scores. Multivariable modified Poisson regression models were used to estimate rate ratios (RR) and 95% confidence intervals (CI) for risk of locally-advanced (stage III) versus early-stage (I-II) BC. RESULTS: Among 2411 women with a median age of 75 years at BC diagnosis, 2189 (91%) were diagnosed with incident stage I-II BC and 222 (9%) were diagnosed at stage III. Compared to women with early-stage disease, women with locally-advanced BC had lower physical component scores (37.8 vs. 41.4) and more classified as pre-frail or frail (55% vs. 50%). In multivariable models, frailty was not associated with increased risk of locally-advanced disease. However, worse physical function subscale scores (lowest vs. upper quartile; RR = 1.56, 95% CI 1.04-2.34) were associated with risk of locally-advanced BC. CONCLUSIONS: Breast cancer screening among non-frail older women should be personalized to include women with limited physical functioning if the benefits of screening and early detection outweigh the potential harms.

The association between physical health-related quality of life, physical functioning, and risk of contralateral breast cancer among older women.

BACKGROUND: Physical limitations prior to cancer diagnosis may lead to suboptimal health outcomes. Our objective was to evaluate the impacts of poor physical health-related quality of life (HRQOL) and physical functioning (PF) on the risk of contralateral breast cancer (CBC). METHODS: We performed a nested case-control study of women with invasive unilateral breast cancer (UBC) who did not receive prophylactic contralateral mastectomy using the Surveillance, Epidemiology and End Results Medicare Health Outcomes Survey data resource. Among 2938 women aged ≥ 65 years diagnosed with first stage I-III UBC between 1997 and 2011, we identified 100 subsequent CBC cases and 915 matched controls without CBC using incidence density sampling without replacement. Pre-diagnosis physical HRQOL and PF were determined using Medical Outcomes Trust Short Form-36 (SF-36)/Veterans Rand 12-Item Health Survey (VR-12) responses within 2 years prior to first UBC diagnosis. We estimated adjusted odds ratios (OR) and 95% confidence intervals (CI) using conditional logistic regression models. RESULTS: Cases and controls were similar with respect to comorbidities, stage, surgery, and radiation treatments, but differed by hormone receptor status (ER/PR-negative, 23% and 11%, respectively) of first UBC. Cases had modestly lower mean pre-diagnosis physical HRQOL (- 1.8) and PF (- 2.2) scores. In multivariable models, we observed an increased CBC risk associated with low physical HRQOL (lowest vs. highest quartile, OR = 1.8; 95% CI 0.8-4.3), but CIs included 1.0. Low PF was associated with a 2.7-fold (95% CI 1.1-6.7) increased CBC risk. CONCLUSIONS: Findings indicate that low physical HRQOL, specifically poor PF, is associated with CBC risk. Efforts to understand and minimize declines in PF post-breast cancer are well motivated.

Characterization of the humoral immune response to the EBV proteome in extranodal NK/T-cell lymphoma.

Extranodal natural killer/T-cell lymphoma (NKTCL) is an aggressive malignancy that has been etiologically linked to Epstein-Barr virus (EBV) infection, with EBV gene transcripts identified in almost all cases. However, the humoral immune response to EBV in NKTCL patients has not been well characterized. We examined the antibody response to EBV in plasma samples from 51 NKTCL cases and 154 controls from Hong Kong and Taiwan who were part of the multi-center, hospital-based AsiaLymph case-control study. The EBV-directed serological response was characterized using a protein microarray that measured IgG and IgA antibodies against 202 protein sequences representing the entire EBV proteome. We analyzed 157 IgG antibodies and 127 IgA antibodies that fulfilled quality control requirements. Associations between EBV serology and NKTCL status were disproportionately observed for IgG rather than IgA antibodies. Nine anti-EBV IgG responses were significantly elevated in NKTCL cases compared with controls and had ORshighest vs. lowest tertile > 6.0 (Bonferroni-corrected P-values < 0.05). Among these nine elevated IgG responses in NKTCL patients, three IgG antibodies (all targeting EBNA3A) are novel and have not been observed for other EBV-associated tumors of B-cell or epithelial origin. IgG antibodies against EBNA1, which have consistently been elevated in other EBV-associated tumors, were not elevated in NKTCL cases. We characterize the antibody response against EBV for patients with NKTCL and identify IgG antibody responses against six distinct EBV proteins. Our findings suggest distinct serologic patterns of this NK/T-cell lymphoma compared with other EBV-associated tumors of B-cell or epithelial origin.

Associations between frailty and cancer-specific mortality among older women with breast cancer.

PURPOSE: Frailty is assessed when making treatment decisions among older women with breast cancer (BC), which in turn impacts survival. We evaluated associations between pre-diagnosis frailty and risks of BC-specific and all-cause mortality in older women. METHODS: We conducted a retrospective cohort study of Medicare beneficiaries ages ≥ 65 years with stage I-III BC using the Surveillance, Epidemiology and End Results-Medicare Health Outcome Survey Data Resource. Frailty was measured using the deficit-accumulation frailty index, categorized as robust, pre-frail, or frail, at baseline and during follow-up. Fine and Gray competing risk and Cox proportional hazards models were used to estimate subdistribution hazard ratios (SHR) and hazard ratios (HR) with 95% confidence intervals (CI) for BC-specific and all-cause mortality, respectively. RESULTS: Among 2411 women with a median age of 75 years at BC diagnosis, 49.5% were categorized as robust, 29.4% were pre-frail and 21.1% were frail. Fewer frail women compared to robust women received breast-conserving surgery (52.8% vs. 61.5%, frail vs. robust, respectively) and radiation (43.5% vs. 51.8%). In multivariable analyses, degree of frailty was not associated with BC-specific mortality (frail vs robust SHR 1.47, 95% CI 0.97-2.24). However, frail women with BC had higher risks of all-cause mortality compared to robust women with BC (HR 2.32, 95% CI 1.84-2.92). CONCLUSION: Among a cohort of older women with BC, higher degrees of frailty were associated with higher risk of all-cause mortality, but not BC-specific mortality. Future study should examine if preventing progression of frailty may improve all-cause mortality.

Disparities in diagnosis, treatment and survival between Black and White Parkinson patients.

INTRODUCTION: Racial disparities in diagnosis, treatment and survival in Black patients with Parkinson's disease (PD) compared to White patients have not been well studied, largely due to limited number of studies and information on Black patients in healthcare systems. Studying racial disparities and identifying underlying factors in large populations are important to understand PD and improve care. METHODS: We retrospectively identified PD patients on both races from 1/1/2006 to 10/31/2017 and compared demographics, socioeconomic status (educations, incomes and insurances), comorbidities (all categories, including mood, cognition and psychosis), treatment (medications for parkinsonism and major non-motor symptoms, and frequency and locations of healthcare) and survival, and identified factors associated with medication usage and survival. RESULTS: We retrospectively studied 2033 PD patients, of whom 725 were Black. Black patients lacked male predominance, were 4 years older at first diagnosis here, more likely to smoke and live in a low education and income community, and possessed limited insurances compared to White patients. Black patients also had more comorbidities and were more likely to receive care through emergency or inpatient service, but less likely to be on medications for parkinsonism and mood disorders. Race, age, smoking status, insurance type, frequency and locations of healthcare and comorbidities were associated with medication usage. Black race, older age, inpatient admission and malignancy were associated with increased risk of death. CONCLUSION: We revealed racial disparities in diagnosis, treatment and survival, and factors associated with medication usage and survival in the largest reported Black PD cohort from a single center.

Alterations of 5-hydroxymethylation in circulating cell-free DNA reflect molecular distinctions of subtypes of non-Hodgkin lymphoma.

The 5-methylcytosines (5mC) have been implicated in the pathogenesis of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). However, the role of 5-hydroxymethylcytosines (5hmC) that are generated from 5mC through active demethylation, in lymphomagenesis is unknown. We profiled genome-wide 5hmC in circulating cell-free DNA (cfDNA) from 73 newly diagnosed patients with DLBCL and FL. We identified 294 differentially modified genes between DLBCL and FL. The differential 5hmC in the DLBCL/FL-differentiating genes co-localized with enhancer marks H3K4me1 and H3K27ac. A four-gene panel (CNN2, HMG20B, ACRBP, IZUMO1) robustly represented the overall 5hmC modification pattern that distinguished FL from DLBCL with an area under curve of 88.5% in the testing set. The median 5hmC modification levels in signature genes showed potential for separating patients for risk of all-cause mortality. This study provides evidence that genome-wide 5hmC profiles in cfDNA differ between DLBCL and FL and could be exploited as a non-invasive approach.

Racial Disparities in Intravenous Bisphosphonate Use Among Older Patients With Multiple Myeloma Enrolled in Medicare.

PURPOSE: Intravenous (IV) bisphosphonates reduce the risk of skeletal-related events in patients with multiple myeloma (MM). However, data describing racial differences in IV bisphosphonate utilization outside of clinical trial settings are limited. We evaluated population-level IV bisphosphonate initiation and discontinuation among patients of age ≥ 65 years with MM. METHODS: We conducted a retrospective cohort study of patients of age ≥ 65 years diagnosed with first primary MM between 2001 and 2011. Patients were identified using the SEER-Medicare linked database and followed through December 2013. Cumulative incidences of IV bisphosphonate initiation and time to discontinuation among users were compared between racial and ethnic groups. In Fine and Gray competing risk models, we estimated subdistribution hazard ratios (SHRs) and 95% CIs for initiation and discontinuation. RESULTS: We included 14,231 eligible patients with MM (median age, 76 years; 52% male). Over a median follow-up of 23.1 months, 54% of patients received at least one IV bisphosphonate dose. Our final analytical sample included 10,456 non-Hispanic (NH) Whites, 2,267 NH Blacks, 548 Asian and Pacific islanders, and 815 Hispanic and Latino patients. A higher proportion of White patients (56.1%) newly received IV bisphosphonates after MM diagnosis compared with NH Blacks (45.4%). Compared with White patients, NH Black patients were less likely to initiate IV bisphosphonates (SHR, 0.74; 95% CI, 0.70 to 0.79) and slightly more likely to discontinue treatment (SHR, 1.10; 95% CI, 1.01 to 1.19). CONCLUSION: Approximately half of the patients with MM of age ≥ 65 years did not receive IV bisphosphonates, with significant delay among racial minority groups. These findings highlight the need for improvement of IV bisphosphonate uptake in patients with MM of age ≥ 65 years.

Racial differences in treatment and outcomes in multiple myeloma: a multiple myeloma research foundation analysis.

Findings on racial differences in survival in multiple myeloma (MM) have been inconclusive. We assessed differences in outcomes between White and Black individuals among 639 newly diagnosed MM patients in the MM Research Foundation CoMMpass registry with baseline cytogenetic data. Survival curves were constructed using the Kaplan-Meier method. Hazard ratios and 95% confidence intervals were derived from Cox proportional hazard regression models. Age, gender, and stage were similar between Whites (n = 526) and Blacks (n = 113). Blacks had inferior overall survival (OS) compared with Whites and were less likely to receive triplet therapies or frontline autologous stem cell transplant (ASCT). The following factors were significantly associated with inferior OS in multivariate analysis: higher international staging system (ISS) score, ≥1 or ≥2 high-risk cytogenetic abnormalities (HRCA), high-risk gene expression profile (GEP), and lack of ASCT. Multivariate analysis in the Black subset found that only lack of ASCT was significantly associated with inferior OS. The receipt of both triplet induction and ASCT only partly abrogated the effect of race on survival. HRCA did not track with survival in Blacks, emphasizing the need for race-specific risk prognostication schema to guide optimal MM therapy.

Self-reported health and survival in older patients diagnosed with multiple myeloma.

PURPOSE: Patient-reported outcomes such as self-reported health (SRH) are important in understanding quality cancer care, yet little is known about links between SRH and outcomes in older patients with multiple myeloma (MM). We evaluated associations between SRH and mortality among older patients with MM. METHODS: We analyzed a retrospective cohort of patients ages ≥ 65 years diagnosed with first primary MM using the Surveillance, Epidemiology, and End Results (SEER)-Medicare Health Outcomes Survey (MHOS) data resource. Pre-diagnosis SRH was grouped as high (excellent/very good/good) or low (fair/poor). We used Cox proportional hazards models to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for associations between SRH and all-cause and MM-specific mortality. RESULTS: Of 521 MM patients with mean (SD) age at diagnosis of 76.8 (6.1) years, 32% reported low SRH. In multivariable analyses, low SRH was suggestive of modest increased risks of all-cause mortality (HR 1.32, 95% CI 1.02-1.71) and MM-specific mortality (HR 1.22, 95% CI 0.87-1.70) compared to high SRH. CONCLUSION: Findings suggest that low pre-diagnosis SRH is highly prevalent among older patients with MM and is associated with modestly increased all-cause mortality. Additional research is needed to address quality of life and modifiable factors that may accompany poor SRH in older patients with MM.