ABSTRACT
To address the current and long-term unmet health needs of the growing population of non-Hodgkin lymphoma (NHL) patients, we established the Lymphoma Epidemiology of Outcomes (LEO) cohort study (NCT02736357; https://leocohort.org/). A total of 7735 newly diagnosed patients aged 18 years and older with NHL were prospectively enrolled from 7/1/2015 to 5/31/2020 at 8 academic centers in the United States. The median age at diagnosis was 62 years (range, 18-99). Participants came from 49 US states and included 538 Black/African-Americans (AA), 822 Hispanics (regardless of race), 3386 women, 716 age <40 years, and 1513 rural residents. At study baseline, we abstracted clinical, pathology, and treatment data; banked serum/plasma (N = 5883, 76.0%) and germline DNA (N = 5465, 70.7%); constructed tissue microarrays for four major NHL subtypes (N = 1189); and collected quality of life (N = 5281, 68.3%) and epidemiologic risk factor (N = 4489, 58.0%) data. Through August 2022, there were 1492 deaths. Compared to population-based SEER data (2015-2019), LEO participants had a similar distribution of gender, AA race, Hispanic ethnicity, and NHL subtype, while LEO was underrepresented for patients who were Asian and aged 80 years and above. Observed overall survival rates for LEO at 1 and 2 years were similar to population-based SEER rates for indolent B-cell (follicular and marginal zone) and T-cell lymphomas, but were 10%-15% higher than SEER rates for aggressive B-cell subtypes (diffuse large B-cell and mantle cell). The LEO cohort is a robust and comprehensive national resource to address the role of clinical, tumor, host genetic, epidemiologic, and other biologic factors in NHL prognosis and survivorship.
Subject(s)
Lymphoma, Non-Hodgkin , Quality of Life , Humans , Female , United States/epidemiology , Adolescent , Young Adult , Adult , Middle Aged , Aged , Aged, 80 and over , Cohort Studies , Lymphoma, Non-Hodgkin/diagnosis , B-Lymphocytes/pathology , PrognosisABSTRACT
High-risk individuals (HRIs) with familial and genetic predisposition to pancreatic ductal adenocarcinoma (PDAC) are eligible for screening. There is no accurate biomarker for detecting early-stage PDAC. We previously demonstrated that a panel of methylated DNA markers (MDMs) accurately detect sporadic PDAC. In this study we compared the distribution of MDMs in DNA extracted from tissue of PDAC cases who carry germline mutations and non-carriers with family history, with control tissue and demonstrate high discrimination like that seen in sporadic PDAC. These results provide scientific rationale for examining plasma MDMs in HRIs with the goal of developing a minimally-invasive early detection test.
Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Carcinoma, Pancreatic Ductal/diagnosis , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Genetic Markers , Genetic Predisposition to Disease , Humans , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Pancreatic NeoplasmsABSTRACT
Lynch syndrome (LS) markedly increases risks of colorectal and endometrial cancers. Early detection biomarkers for LS cancers could reduce the needs for invasive screening and surgical prophylaxis.To validate a panel of methylated DNA markers (MDM) previously identified in sporadic colorectal cancer and endometrial cancer for discrimination of these cancers in LS.In a case-control design, previously identified MDMs for the detection of colorectal cancer and endometrial cancer were assayed by qMSP on tissue-extracted DNA. Results were normalized to ACTB values within each sample. Least absolute shrinkage and selection operator models to classify colorectal cancer and endometrial cancer were trained on sporadic cases and controls and then applied to classify colorectal cancer and endometrial cancer, in those with LS, and cross-validated.We identified colorectal cancer cases (23 with LS, 48 sporadic), colorectal controls (32 LS, 48 sporadic), endometrial cancer cases (30 LS, 48 sporadic), and endometrial controls (29 LS, 37 sporadic). A 3-MDM panel (LASS4, LRRC4, and PPP2R5C) classified LS-CRC from LS controls with an AUC of 0.92 (0.84-0.99); results were similar for sporadic colorectal cancer. A 6-MDM panel (SFMBT2, MPZ, CYTH2, DIDO1, chr10.4479, and EMX2OS) discriminated LS-EC from LS controls with an AUC of 0.92 (0.83-1.0); the AUC for sporadic endometrial cancer versus sporadic controls was nominally higher, 0.99 (0.96-1.0).MDMs previously identified in sporadic endometrial cancer and colorectal cancer discriminate between endometrial cancer and benign endometrium and colorectal cancer and benign colorectum in LS. This supports the inclusion of patients with LS within future prospective clinical trials evaluating endometrial cancer and colorectal cancer MDMs and may provide a new avenue for cancer screening or surveillance in this high-risk population. PREVENTION RELEVANCE: Lynch syndrome (LS) markedly increases risks of colorectal and endometrial cancers. Early detection biomarkers for LS cancers could reduce the needs for invasive screening and surgery. Methylated DNA markers previously identified in sporadic endometrial cancer and colorectal cancer discriminate between benign and cancer tissue in LS.
Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis , Endometrial Neoplasms , Female , Humans , Colorectal Neoplasms, Hereditary Nonpolyposis/complications , Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Genetic Markers , Endometrial Neoplasms/diagnosis , Endometrial Neoplasms/genetics , Risk Factors , Endometrium , Microsatellite InstabilityABSTRACT
PURPOSE: Surveillance after primary melanoma treatment aims to detect early signs of low-volume systemic disease. The current standard of care, surveillance imaging, is costly and difficult to access. We therefore sought to develop methylated DNA markers (MDMs) as promising alternatives for disease surveillance. METHODS: We used reduced representation bisulfite sequencing (RRBS) to identify MDMs in DNA samples obtained from metastatic melanoma, benign nevi, and normal skin tissues. The identified MDMs underwent validation in an independent cohort of tissue and buffy coat DNA samples. Subsequently, we tested the validated MDMs in the plasma DNA of patients with metastatic melanoma undergoing surveillance with total body imaging and compared them with cancer-free controls. To estimate the overall predictive accuracy of the MDMs, we used random forest modeling with bootstrap cross-validation. RESULTS: Forty MDMs demonstrated discrimination between melanoma cases and controls consisting of benign nevi and normal skin. Nine MDMs passing biological validation in tissue were run on 77 plasma samples from individuals with a history of metastatic melanoma, 49 of whom had evidence of disease detected by imaging at the time of blood draw, and 100 cancer-free controls. The cross-validated sensitivity of the panel for imaging-positive disease was 80% with a specificity of 100% in cancer-free controls, resulting in an overall AUC of 0.88 (95% CI, 0.81 to 0.96). The survival estimates for patients with melanoma who tested positive for the panel at 6 months and 1 year were 67% and 56%, respectively, while those who tested negative had survival rates of 100% and 92%. CONCLUSION: MDMs identified by RRBS demonstrate a high degree of concordance with imaging results in the plasma of patients with metastatic melanoma. Further prospective studies in larger intended use cohorts are needed to confirm these findings.
Subject(s)
Melanoma , Nevus , Humans , Genetic Markers , Prospective Studies , Melanoma/diagnosis , Melanoma/genetics , DNAABSTRACT
COVID-19 adversely affects individuals with cancer. Several studies have found that seroconversion rates among patients with hematologic malignancies are suboptimal when compared to patients without cancer. Patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) are immunocompromised due to impaired humoral and cellular immunity in addition to prescribed immunosuppressive therapy. Chimeric antigen receptor T-cell (CAR T) therapy is now widely used for NHL and MM, but little is known about seroconversion rates after COVID-19 vaccination among these populations. We evaluated SARS-CoV-2 spike-binding IgG antibody levels following COVID-19 vaccination among NHL and MM CAR T therapy recipients. Out of 104 CAR T infusions, 19 patients developed known COVID-19 infection post-CAR T. We tested 17 patients that received CAR T for antibody spike titers post COVID-19 vaccination, only 29 % (n = 5) were able to mount a clinically relevant antibody response (>250 IU/mL).
Subject(s)
COVID-19 , Lymphoma, Non-Hodgkin , Multiple Myeloma , Receptors, Chimeric Antigen , Humans , Multiple Myeloma/drug therapy , COVID-19 Vaccines/therapeutic use , COVID-19/prevention & control , SARS-CoV-2 , Antibodies, Viral , Immunoglobulin GABSTRACT
Background and Aims: Methylated DNA markers (MDMs) accurately identify several different cancer types, but there are limited data for pancreatic neuroendocrine tumors (pNETs). We aimed to identify MDM candidates in tissue that differentiate pNETs from normal pancreas. Methods: wUsing DNA from frozen normal pancreas (13) and pNET (51) tissues, we performed reduced representation bisulfite sequencing for MDM discovery. Validation in independent formalin fixed paraffin embedded tissues used pNET cases (67; solid = 50, cystic = 17), normal pancreas (24), and buffy coat (36) controls. Primary pNET MDM distributions were compared with lung (36), small bowel (36) NETs, and metastatic pNET (25) tissues. The discrimination accuracy was summarized as the area under the receiver operator characteristic curve (AUC) with corresponding 95% confidence intervals (CIs). Fisher's linear discriminant analysis was performed to estimate a linear discriminate score (LDS) differentiating normal from pNET tissue and applied to all patient groups; discrimination accuracy of the LDS was summarized as the bootstrap cross-validated AUC. Results: Median AUC for distinguishing normal pancreas from pNET tissue was 0.91 (interquartile range: 0.80-0.93). The cross-validated AUC for the LDS discriminating normal pancreatic tissue from primary and metastatic pNETs was 0.957 (95% CI 0.858-1.0, P < .0001) and 0.963 (95% CI 0.865-1.0, P < .0001), respectively. The LDS for the MDM panel was significantly higher for primary pNET, metastatic pNET, lung NET, and small bowel NET, each compared with normal pancreas tissue (P < .0001). There was no statistical difference between primary pNET and metastatic pNET (P = .1947). Conclusion: In independent tissue validation, MDMs accurately discriminate pNETs from normal pancreas. These results provide scientific rationale for exploration of these tissue MDMs in a plasma-based assay for clinical application.