Cancer-free Individuals Research Articles

A method for classifying colorectal cancer and gastric/esophageal cancer using blood-based testing.

52 Background: Identifying the cancer signal of origin is of great value in the clinical use of blood-based cancer testing, especially in those tests that have potential to assess for more than one cancer type. Thus, an approach that can accurately identify cancer signal of origin in order to guide subsequent diagnostic workup is impactful to the adoption of this new technology. Here, we report feasibility data using the DNA methylation signature of plasma cell-free DNA to differentiate between colorectal cancer (CRC) and gastric/esophageal cancer (GEC) types. Methods: We developed an algorithm to distinguish between CRC and GEC based on the DNA methylation signature of plasma cell-free DNA molecules from more than 3,000 differentially methylated regions. First, a regression model (a multi-cancer classifier) was trained to identify the samples with sufficient tumor derived methylation signal using 6,822 cancer samples of 24 cancer types and the samples from 4,423 cancer-free individuals. A second regression model (a CRC/GEC classifier) was trained to distinguish CRC from GEC cases on the samples with positive calls from the multi-cancer classifier. The second model was trained on methylation signals from advanced stage CRC samples, advanced stage GEC samples (including esophageal, gastroesophageal, and gastric cancers), and samples from cancer-free individuals. Results: The multi-cancer classifier identified 92% (2,954/3,204) of CRC and GEC samples as positive at 90% target specificity, including 93% (2,086/2,253) of CRC samples and 91% (868/951) of gastric/esophageal cancer samples. The performance of the CRC/GEC classifier is evaluated through 10-fold cross validation on these 3,204 cancer samples, where in each fold, an additional 6,298 samples from cancer-free individuals were also used in training. Among the 2,954 CRC and GEC samples detected by the multi-cancer classifier, 2,698 (91%) were accurately classified by the CRC/GEC classifier. Among the detected CRC samples, 91% (1,907/2,086) were correctly classified as CRC. Similarly, 91% (791/868) of the detected GEC samples were correctly classified. The precision of the CRC/GE prediction was also assessed and 91% (2,698/2,954) of the detected cancer samples were correctly classified. Of the 1,984 detected cancer samples predicted as CRC, 96% (1,907/1,984) were true CRC samples. Of the 970 detected cancer samples classified as GEC, 82% (791/970) were correct. Conclusions: This assay with high sensitivity and accurate CRC/GEC classification can effectively guide subsequent diagnostic workups following a positive result, maximizing potential clinical utility. Ongoing work will continue further refinements.

Effect of social support on memory ageing of middle-aged and older cancer survivors: a marginal structural modelling approach

BackgroundWhile social support is associated with better cognitive health among cancer-free individuals, this relationship is understudied among cancer survivors. We investigated whether overall social support before and after a cancer...

The Stockholm early detection of cancer study (STEADY-CAN): rationale, design, data collection, and baseline characteristics for 2.7 million participants.

The Stockholm Early Detection of Cancer Study (STEADY-CAN) cohort was established to investigate strategies for early cancer detection in a population-based context within Stockholm County, the capital region of Sweden. Utilising real-world data to explore cancer-related healthcare patterns and outcomes, the cohort links extensive clinical and laboratory data from both inpatient and outpatient care in the region. The dataset includes demographic information, detailed diagnostic codes, laboratory results, prescribed medications, and healthcare utilisation data. Since its inception, STEADY-CAN has collected longitudinal data on 2,732,005 individuals aged ≥ 18years old living in or having access to health care in Stockholm County during the years 2011-2021. Focusing on cancer, the cohort includes 140,042 (5.1%) individuals with incident cancer and a control group of 2,591,963 (94.9%) cancer-free individuals. The cohort's diverse adult population enables robust analyses of early symptom detection, incidental findings, and the impact of comorbidities on cancer diagnoses. Utilizing the wide range of available laboratory data and clinical variables allow for advanced statistical analyses and adjustments for important confounding factors. The cohort's primary focus is to improve understanding of the early diagnostic phase of cancer, offering a crucial resource for studying cancer detection in clinical practice. Its comprehensive data collection provides unique opportunities for research into comorbidities and cancer outcomes, making the cohort a useful resource for ongoing cancer surveillance and public health strategies. The present study gives a detailed description of the rationale for creating the STEADY-CAN cohort, its design, the data collection procedure, and baseline characteristics of collected data.

Effectiveness of the Korean National Cancer Screening Program in Reducing Colorectal Cancer Mortality.

Whether colorectal cancer (CRC) screening with a fecal immunochemical test (FIT) reduces mortality remains unclear. In South Korea, CRC screening with a FIT for individuals aged ≥ 50 years has been part of the Korean National Cancer Screening Program (KNCSP) since 2004. The aim of this study was to evaluate the effectiveness of the KNCSP in reducing CRC-specific mortality. We conducted a nested case-control study using cohort-based data derived from the KNCSP database. The cohort included 5,944,540 colorectal cancer-free individuals aged ≥ 50 years as of 2004. Individuals who died after CRC diagnosis were defined as cases (n = 29,992) and their sociodemographic characteristics were matched to those of the selected controls. The effects of screening exposure, frequency, and time interval on CRC-specific mortality were analyzed according to age group. Conditional logistic regression analysis was performed. Compared with individuals who had never been screened, those who had ever been screened showed an OR of 0.74 (95% CI, 0.71-0.76) for CRC-specific mortality. CRC-specific mortality decreased as the number of screenings increased. Similar results were observed for those aged 50-79 years; however, the results for those aged 75-79 years were not statistically significant. Moreover, those aged ≥ 80 years had the opposite results. CRC mass screening using FIT is effective for individuals aged 50-74 years; therefore, this study suggests that countries considering introducing national CRC screening implement FIT for those within this age range.

Urinary DNA-methylation and protein biomarkers identify urothelial carcinoma among other genitourinary diseases and cancer-free individuals

BackgroundFor more than 80 years, cystoscopy has been the gold standard for identification of urothelial carcinoma (UCa). Because of many factors, such as pain of the patients during this procedure or the costs involved, non-invasive detection of UCa remains a challenge. Herein, we verify our previously identified urinary biomarkers C-X-C Motif Chemokine Ligand 16 (CXCL16) and transforming growth-factor beta induced protein (TGFBI) on the protein level as well as the CpG sites ALOX5, TRPS1 and an intergenic region on Chromosome 16 on DNA methylation level in an independent cross-sectional study.MethodsWe collected N = 1119 urines from individuals coming to urological and gynecological check-ups, follow-up care or patients suspicious for UCa or already diagnosed for different urologic or gynecologic cancer entities. We performed methylation analysis of various CpG sites with DNA isolated from urine sediment and quantified the concentration of the protein markers CXCL16 and TGFBI in the corresponding urine supernatant using ELISA. We tested for patient-group differences with two-sided Wilcoxon rank sum tests and examined the performance with receiver operating characteristic curves. For verification, we analyzed the marker performance with previously set cutoff-values and marker combinations with established and experimental algorithms (with logical OR-conjunction, iterative threshold-based biomarker and score combining algorithm “PanelomiX”).ResultsEvaluation confirmed that our previously identified protein and DNA methylation biomarkers can distinguish UCa from frequent urological and gynecological cancers. CXCL16 and TGFBI discriminated UCa cases with a sensitivity of 31% and 56% and a specificity of 94% and 85%, respectively. Combining methylation markers resulted in UCa detection in men with a sensitivity of 54% and a specificity of 94%. Extending analysis by combining all methylation and protein markers (up to five markers in total) yielded a convincingly high specificity of 97% at a sensitivity of 72% for the identification of UCa patients within a heterogeneous collective of cancer-free individuals and patients suffering from urological or gynecological cancers.ConclusionCombining various biomarkers at protein and DNA level demonstrates a new option of non-invasive UCa diagnosis in urine, and thus might help to reduce the number of unnecessary cystoscopies, especially in patients without a history of UCa.

Evaluation of A. actinomycetemcomitans and P. gingivalis from the mouth of patients irradiated in the head and neck region: a cross-sectional study.

This study aimed to quantify Aggregatibacter actinomycetemcomitans (A.a) and Porphyromonas gingivalis (P.g) from the mouth of head and neck irradiated and cancer-free patients. Information such as age, presence of tongue coating, salivary flow, and biofilm were collected from head and neck irradiated patients (Group 1) and compared the results with a group of cancer-free individuals (Group 2). The presence of tongue coating was clinically examined. Sialometry was performed through a stimulating technique by chewing paraffin. Microbiological samples were collected from buccal and labial mucosa and tongue dorsum. Subsequently, the samples were processed and analyzed by qPCR to detect the presence and quantify the bacteria. There was a statistical difference in the quantity of bacteria among the 24 individuals in Group 1 (A.a, 2817 ± 8718; P.g, 3145 ± 11297) and 26 individuals in Group 2 (A.a, 133996 ± 398545; P.g, 60 ± 195) regarding tongue coating (Group 1, A.a 2194.6 ± 4641.5; Group 2, A.a 92767.8 ± 333385.7) and salivary volume (Group 1, 0.69mL; Group 2, 3.09mL). The linear regression analysis found that the variable group was the main responsible for the difference in the quantity of periodontal pathogens (p-value < 0.001). There was no statistical difference in the amount of Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis between totally edentulous and partially edentulous (with 12 or fewer teeth) patients. Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis were present in significant amounts in patients of both groups, with a greater quantity in cancer-free individuals.

Multi-ethnic heterozygote frequencies of cancer susceptibility genes to inform counseling of reproductive risk.

Pathogenic germline variants (PGVs) in a subset of cancer predisposition genes (CPGs) are associated with adult-onset autosomal dominant (AD) cancer susceptibility and life-limiting autosomal recessive (AR) disease. Counseling in adult cancer genetics clinics regarding reproductive risk for PGV heterozygotes is limited. Estimated heterozygote frequencies across ancestries were calculated for AD CPGs with AR risk (ATM, BRCA1, BRCA2, BRIP1, FH, NBN, MLH1, MSH2, MSH6, PMS2, RAD51C, SDHA, SDHB, and SDHD) from gnomADv.3.0, the Penn Medicine Biobank, and FLOSSIES. Average frequencies of heterozygotes with PGVs across ancestries for BRCA1 and BRCA2 were 0.33% ± 0.41% and 0.43% ± 0.36%, with variability cross-ancestry from 0.06% to 1.32% and 0.17% to 1.29%, respectively. ATM had the next highest PGV heterozygote frequency (0.31% ± 0.12%) and SDHD the lowest (0.01% ± 0.01%) average PGV heterozygote frequency. Heterozygote PGV frequencies from gnomAD were similar as cancer-free individuals in Penn Medicine Biobank and higher than in the FLOSSIES data. Heterozygote frequency estimates for AD CPGs that cause AR disease provides information to facilitate discussions regarding reproductive risk. Future studies are needed to assess whether utilization of these data will influence couples' reproductive risk planning.

Altered immunophenotypic expression in the peripheral bladder cancer immune landscape.

Treatments targeting the immune system only benefit a subset of patients with bladder cancer (BC). Biomarkers predictive of BC progression and response to specific therapeutic interventions are required. We evaluated whether peripheral blood immune subsets and expression of clinically relevant immune checkpoint markers are associated with clinicopathologic features of BC. Peripheral blood mononuclear cells isolated from blood collected from 23 patients with BC and 9 age-matched unaffected-by-cancer control donors were assessed using a 21-parameter flow cytometry panel composed of markers of T, B, natural killer and myeloid populations and immune checkpoint markers. Patients with BC had significantly lower numbers of circulating CD19+ B cells and elevated circulating CD4+CD8+ Tcells compared with the control cohort. Immune checkpoint markers programmed cell death protein 1 (PD-1) and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) were elevated in the total peripheral immune cell population in patients with BC. Within the BC cohort, PD-1 expression in T and myeloid cells was elevated in muscle-invasive compared with non-muscle-invasive disease. In addition, elevated T, B and myeloid PD-1 cell surface expression was significantly associated with tumor stage, suggesting that measures of peripheral immune cell exhaustion may be a predictor of tumor progression in BC. Finally, positive correlations between expression levels of the various immune checkpoints both overall and within key peripheral blood immune subsets collected from patients with BC were observed, highlighting likely coregulation of peripheral immune checkpoint expression. The peripheral blood immunophenotype in patients with BC is altered compared with cancer-free individuals. Understanding this dysregulated immune profile will contribute to the identification of diagnostic and prognostic indicators to guide effective immune-targeted, personalized treatments.

Increased cancer incidence in patients with pre-existing heart failure: results from a French Nationwide Cohort study

Abstract Background It is unclear whether patients with a history of heart failure (HF) have an increased risk of developing cancer. Purpose To assess the incidence of cancer (all types) in patients with pre-existing HF compared with patients without known HF at a nationwide level. Secondary objectives include analysis by cancer site and impact on all-cause mortality. Methods We used the French National Administrative Health Data System (SNDS), a comprehensive database containing all health care information (outpatient and hospital) for 99% of the French population, to identify adult patients with a first diagnosis of HF (ICD-10 diagnosis code I50) between 2010 and 2019 and without a personal history of cancer before HF diagnosis. HF patients were matched for sex and age to HF-free and cancer-free individuals (3:1 ratio), randomly identified in the SNDS. Incident cancers were identified by corresponding ICD 10th codes. Results We found 330,867 adult patients with a first diagnosis of HF between 2010 and 2019, and 992,601 matched controls (54.7% women, mean age 77.7±13.5 years in both groups). There was an increased risk of a first cancer in HF patients as compared to controls: 28,151 (8.5%) in HF patients over a mean follow-up of 4.3±2.8 years vs. 77,325(7.8%) in controls over a mean follow-up of 4.9±2.8 years (unadjusted HR: 1.12 [1.11-1.13], P&amp;lt;0.001). The higher risk of new cancer in HF patients remained after adjustment for major comorbidities (i.e., ischemic heart disease, diabetes, arterial hypertension, renal dysfunction, morbid obesity), age, sex, year of diagnosis, region of residence, tobacco use and alcohol consumption (adjusted HR=1.06, [1.04-1.07]; P&amp;lt;0.0001). Overall, the estimated attributable risk of new cancer after HF was 16.53% (9.88-16.76%). This increased risk was observed for most solid malignancies (especially colorectal and lung cancer), and for multiple myeloma. We finally observed that the risk of all-cause mortality after cancer diagnosis was significantly higher in patients with pre-existing HF compared to controls (adjusted HR: 1.36 [1.33-1.39], P&amp;lt;0.001). Conclusions People with a history of HF have a higher risk of developing cancer than the general population. These findings suggest that cancer screening strategies should be encouraged in patients with HF.

Future sick leave, disability pension, and unemployment among patients with cancer after returning to work: Swedish register-based matched prospective cohort study.

Despite increasing numbers of working-age cancer survivors, evidence on their future work-related circumstances is limited. This study examined their future sick leave, disability pension, and unemployment benefits compared to matched cancer-free individuals. A matched cohort study was conducted using nationwide Swedish registers. In total, 94,411 individuals aged 25 to 59 years when diagnosed with incident cancer in 2001-2012 and who returned to work after cancer were compared with their matched cancer-free individuals (N = 354,814). Follow-up started from the year before cancer diagnosis and continued up to 14 years. Generalized estimating equations were used to calculate incidence rate ratios (IRR) and odds ratios for the difference between cancer survivors and matched cancer-free individuals. Compared with cancer-free individuals, cancer survivors had six times higher sick-leave days per year after cancer (IRR 6.25 [95% CI, 5.97-6.54] for men; IRR, 5.51 [5.39-5.64] for women). This higher number of sick-leave days declined over time but a two-fold difference persisted. An approximate 1.5 times higher risk of receiving disability pension remained during follow-up. The unemployment days tended to be lower for cancer survivors (IRR, 0.84 [0.75-0.94] for men; IRR, 0.91 [0.86-0.96] for women). Risk of sick leave and disability pension was higher among those with leukemia, colorectal, and breast cancer than skin and genitourinary cancers. Cancer survivors who returned to work experienced a high and persisting sick leave and disability pension for over a decade. Prolonged receipt of a high amount of benefits may have long-term adverse impacts on financial circumstances; more knowledge to promote the environment that encourages returning to and remaining in work is needed.

GastricAITool: A Clinical Decision Support Tool for the Diagnosis and Prognosis of Gastric Cancer.

Gastric cancer (GC) is a complex disease representing a significant global health concern. Advanced tools for the early diagnosis and prediction of adverse outcomes are crucial. In this context, artificial intelligence (AI) plays a fundamental role. The aim of this work was to develop a diagnostic and prognostic tool for GC, providing support to clinicians in critical decision-making and enabling personalised strategies. Different machine learning and deep learning techniques were explored to build diagnostic and prognostic models, ensuring model interpretability and transparency through explainable AI methods. These models were developed and cross-validated using data from 590 Spanish Caucasian patients with primary GC and 633 cancer-free individuals. Up to 261 variables were analysed, including demographic, environmental, clinical, tumoral, and genetic data. Variables such as Helicobacter pylori infection, tobacco use, family history of GC, TNM staging, metastasis, tumour location, treatment received, gender, age, and genetic factors (single nucleotide polymorphisms) were selected as inputs due to their association with the risk and progression of the disease. The XGBoost algorithm (version 1.7.4) achieved the best performance for diagnosis, with an AUC value of 0.68 using 5-fold cross-validation. As for prognosis, the Random Survival Forest algorithm achieved a C-index of 0.77. Of interest, the incorporation of genetic data into the clinical-demographics models significantly increased discriminatory ability in both diagnostic and prognostic models. This article presents GastricAITool, a simple and intuitive decision support tool for the diagnosis and prognosis of GC.

Acyl-coenzyme a binding protein (ACBP) - a risk factor for cancer diagnosis and an inhibitor of immunosurveillance

BackgroundThe plasma concentrations of acyl coenzyme A binding protein (ACBP, also known as diazepam-binding inhibitor, DBI, or ‘endozepine’) increase with age and obesity, two parameters that are also amongst the most important risk factors for cancer.MethodsWe measured ACBP/DBI in the plasma from cancer-free individuals, high-risk patients like the carriers of TP53 or BRCA1/2 mutations, and non-syndromic healthy subjects who later developed cancer. In mice, the neutralization of ACBP/DBI was used in models of non-small cell lung cancer (NSCLC) and breast cancer development and as a combination treatment with chemoimmunotherapy (chemotherapy + PD-1 blockade) in the context of NSCLC and sarcomas. The anticancer T cell response upon ACBP/DBI neutralization was characterized by flow cytometry and single-cell RNA sequencing.ResultsCirculating levels of ACBP/DBI were higher in patients with genetic cancer predisposition (BRCA1/2 or TP53 germline mutations) than in matched controls. In non-syndromic cases, high ACBP/DBI levels were predictive of future cancer development, and especially elevated in patients who later developed lung cancer. In preclinical models, ACBP/DBI neutralization slowed down breast cancer and NSCLC development and enhanced the efficacy of chemoimmunotherapy in NSCLC and sarcoma models. When combined with chemoimmunotherapy, the neutralizing monoclonal antibody against ACBP/DBI reduced the frequency of regulatory T cells in the tumor bed, modulated the immune checkpoint profile, and increased activation markers.ConclusionThese findings suggest that ACBP/DBI acts as an endogenous immune suppressor. We conclude that elevation of ACBP/DBI constitutes a risk factor for the development of cancer and that ACBP/DBI is an actionable target for improving cancer immunosurveillance.

Does Neighborhood Socioeconomic Status Alter Memory Change Associated with a Cancer Diagnosis? Preliminary Evidence from the US Health and Retirement Study.

Neighborhood disadvantage has been linked to cognitive impairment, but little is known about the effect of neighborhood disadvantage on long-term cancer-related memory decline. Incident cancer diagnosis and memory (immediate and delayed recall, combined with proxy-reported memory) were assessed at biennial interviews in the US Health and Retirement Study (N = 13,293, 1998-2016). Neighborhood disadvantage was measured using the National Neighborhood Data Archive disadvantage index, categorized into tertiles (T1: least disadvantaged-T3: most disadvantaged). Linear mixed-effects models estimated the standardized memory trajectories in participants with or without cancer, by neighborhood disadvantage. Living in more disadvantaged neighborhoods was associated with worse mean memory function and steeper memory declines, regardless of cancer status. An incident cancer diagnosis was associated with an acute memory drop for those living in least disadvantaged neighborhoods but not more disadvantaged neighborhoods [T1: -0.05, 95% confidence interval (CI): -0.08, -0.01; T3: -0.13, 95% CI: -0.06, 0.03]. Cancer survivors in the least disadvantaged neighborhoods had a slight memory advantage in the years prior to diagnosis (T1: 0.09, 95% CI: 0.04, 0.13) and after diagnosis (T1: 0.07, 95% CI: 0.01, 0.13). An incident cancer diagnosis among those living in the least disadvantaged neighborhoods was associated with an acute memory drop at the time of diagnosis and a long-term memory advantage before and after diagnosis compared with cancer-free individuals in similar neighborhoods. These findings could inform interventions to promote cancer survivor's long-term aging. Future studies should investigate the social and biological pathways through which neighborhood socioeconomic status could influence cancer-related memory changes.

Factor modification in the association between high-density lipoprotein cholesterol and liver cancer risk in a nationwide cohort.

The effect modification by smoking and menopausal status in the association between high-density lipoprotein cholesterol (HDL-C) and liver cancer risk has not been reported. This population-based cohort study included 4.486 million cancer-free individuals among those who underwent national cancer screening in 2010 and were followed up until December 2017. We conducted analyses in populations that excluded people with chronic hepatitis B, chronic hepatitis C and liver cirrhosis (Model I) and that included those diseases (Model III). HDL-C level was classified into eight groups at 10-mg/dL intervals. Liver cancer risk by HDL-C was measured using adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). During follow-up, 18 795 liver cancers in Model I and 20 610 liver cancers in Model III developed. In Model I, low HDL-C levels (aHR 1.83; 95% CI 1.65-2.04) and extremely high HDL-C levels (aHR 1.24; 95% CI 1.10-1.40) were associated with an increased liver cancer risk compared with a moderate HDL-C level of 50-59mg/dL. This association was similar in both men and women with larger effect size in men (aHR, 1.91; 95% CI, 1.70-2.15). The hazardous association between low HDL-C and liver cancer risk was remarkable in current smokers (aHR, 2.19; 95% CI, 1.84-2.60) and in pre-menopausal women (aHR, 2.91; 95% CI, 1.29-6.58) compared with post-menopausal women (aHR, 1.45; 95% CI, 1.10-1.93). This association was similarly observed in Model III. Low and extremely high HDL-C levels were associated with an increased liver cancer risk. The unfavourable association between low HDL-C and liver cancer was remarkable in smokers and pre-menopausal women.

Polygenic risk score for ulcerative colitis predicts immune checkpoint inhibitor-mediated colitis

Immune checkpoint inhibitor-mediated colitis (IMC) is a common adverse event of treatment with immune checkpoint inhibitors (ICI). We hypothesize that genetic susceptibility to Crohn’s disease (CD) and ulcerative colitis (UC) predisposes to IMC. In this study, we first develop a polygenic risk scores for CD (PRSCD) and UC (PRSUC) in cancer-free individuals and then test these PRSs on IMC in a cohort of 1316 patients with ICI-treated non-small cell lung cancer and perform a replication in 873 ICI-treated pan-cancer patients. In a meta-analysis, the PRSUC predicts all-grade IMC (ORmeta=1.35 per standard deviation [SD], 95% CI = 1.12–1.64, P = 2×10−03) and severe IMC (ORmeta=1.49 per SD, 95% CI = 1.18–1.88, P = 9×10−04). PRSCD is not associated with IMC. Furthermore, PRSUC predicts severe IMC among patients treated with combination ICIs (ORmeta=2.20 per SD, 95% CI = 1.07–4.53, P = 0.03). Overall, PRSUC can identify patients receiving ICI at risk of developing IMC and may be useful to monitor patients and improve patient outcomes.

Abstract 5021: Circulating mutated and methylated tumor DNA detection for colorectal cancer diagnosis

Abstract Introduction: Detection of mutation and methylation patterns in liquid biopsies has emerged as a promising approach for screening early-stage cancers. We have developed a targeted next-generation sequencing (NGS)-based assay “OptiSeqTM Colorectal Cancer Detection Panel”, a combined platform for assessing mutation and methylation in both low-quantity (plasma cfDNA) and low-quality formalin-fixed paraffin-embedded (FFPE) tissue for colorectal cancer (CRC) detection. Methods: The OptiSeqTM Colorectal Cancer Detection Panel targets 442 SNVs and 434 CpG sites to detect circulating tumor DNA (ctDNA) in early-stage patients. With this panel, we profiled 6 early-stage and 6 metastatic CRC samples (matching cfDNA and FFPE) along with 2 primary colon specimens with adjacent normal tissue DNA. We also profiled 2 matching cfDNA and FFPE samples from precancerous adenomas (advanced adenomas (AA)) and 6 AA FFPE tissue DNA. In addition, we characterized the mutation and methylation pattern in 10 CRC fresh-frozen tissue DNA samples. For healthy individuals, we profiled 12 normal colon FFPE samples and 10 plasma cfDNA. The clinical performance for the CRC detection panel was calculated using AA, CRC, and cancer-free individuals. Results: For CRC early and metastatic matching cfDNA and FFPE samples, clinical samples testing showed that the CRC detection panel had a sensitivity of 100% (95% CI: 69.8-100.0) and specificity of 100% (95% CI: 81.5-100). For precancerous AA FFPE tissues, combined DNA mutation and methylation increased the CRC detection sensitivity to 100% (95% CI: 51.6-100.0) and specificity to 100% (95% CI: 61.8-100). More clinical samples testing is underway. Conclusion: We have developed the targeted NGS-based panel to detect clinically relevant mutation and methylation patterns and demonstrate its potential using the combined genetic and epigenetic markers making it a highly sensitive assay for early CRC diagnosis. Citation Format: Pushpinder Kaur Bains, Mikhail Kulak, Zhen Cui, Alisha Babu, Stella Tran, Aiguo Zhang, Michael Sha. Circulating mutated and methylated tumor DNA detection for colorectal cancer diagnosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5021.

Abstract 6148: Multiple new Ewing sarcoma susceptibility loci expand knowledge of germline genetic etiology and nominate mechanisms of risk

Abstract Ewing sarcoma (EwS) is a rare and aggressive pediatric cancer with peak incidence in the second decade of life. EwS occurs primarily in children of European ancestry suggesting a genetic component to susceptibility. Prior investigations identified six susceptibility loci associated with EwS, with evidence for additional signals not reaching the commonly accepted threshold for genome-wide significance (i.e., p&amp;lt;5×10−8). At least two of these loci demonstrate evidence of tagging variation in length of nearby GGAA microsatellites, which alter binding of the pathognomonic EWSR1::FLI1 fusion resulting in downstream dysregulation of target genes promoting sarcomagenesis. To identify additional susceptibility loci, we performed the largest genome-wide association study (GWAS) to date consisting of 1,640 EwS cases and 8,457 cancer-free individuals of European ancestry from 8 studies and matched by principal components. Genotype imputation was carried out by study/array using TOPMed data as the reference and each set was analyzed using PLINK 1.9 adjusting for significant principal components. Variants were included in each study if minor allele count was greater than five in each set of cases. Individual study results were combined using fixed effects meta-analysis in Metasoft with variants demonstrating evidence for heterogeneity excluded.For previously reported EwS loci (i.e., 1p36.22, 6p25.1, 10q21.3, 15q15.1, 20p11.22 and 20p11.23), odds ratios (OR) remained high for GWAS (OR=1.5-2.4) and the -log10 p-values grew by several orders of magnitude, providing strong evidence for replication in the additional 907 EwS cases and 7,111 cancer-free controls. Our analysis identified five novel loci reaching genome-wide significance (P-valuemeta&amp;lt; 5×10−8) at 5q32, 7q32.3, 8q24.2, 13q32.3, and 17q23.2. Risk allele frequency of newly identified loci ranged from 0.001 to 0.75with estimated ORs ranging from 1.31-4.30. eQTL analyses nominated nearby biologically plausible candidate genes for future functional investigation including LARS1, a gene implicated in osteosarcoma and skeletal muscle dysgenesis, at the 5q32 locus and COX5BP6, a gene implicated in age at menarche and testosterone levels, at 13q32.3.Our results add to evidence supporting a strong inherited genetic component to EwS risk and particularly a genetic architecture harboring a substantial number of common variants with moderate effect. Ongoing work is focusing on enrichment analyses of GGAA microsatellite repeat sequences in identified risk loci to search for evidence for germline-somatic interactions with EWSR1::FLI1. Citation Format: Aubrey K. Hubbard, Weiyin Zhou, Carrie Boyce, Javed Khan, Melissa M. Hudson, Kirsten K. Ness, Zhaoming Wang, Katherine A. Janeway, Philip J. Lupo, Lindsay M. Morton, Stephen J. Chanock, Thomas G. Grünewald, Olivier Delattre, Mitchell J. Machiela, Ewing Sarcoma Germline Genetics Group. Multiple new Ewing sarcoma susceptibility loci expand knowledge of germline genetic etiology and nominate mechanisms of risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6148.

Adipose Stromal Cell-Derived Cancer-Associated Fibroblasts Suppress FGFR Inhibitor Efficacy.

Cancer aggressiveness has been linked with obesity, and studies have shown that adipose tissue can enhance cancer progression. In this issue of Cancer Research, Hosni and colleagues discover a paracrine mechanism mediated by adipocyte precursor cells through which urothelial carcinomas become resistant to erdafitinib, a recently approved therapy inhibiting fibroblast growth factor receptors (FGFR). They identified neuregulin 1 (NRG1) secreted by adipocyte precursor cells as an activator of HER3 signaling that enables resistance. The NRG1-mediated FGFR inhibitor resistance was amenable to intervention with pertuzumab, an antibody blocking the NRG1/HER3 axis. To investigate the nature of the resistance-associated NRG1-expressing cells in human patients, the authors analyzed published single-cell RNA sequencing data and observed that such cells appear in a cluster assigned as inflammatory cancer-associated fibroblasts (iCAF). Notably, the gene signature corresponding to these CAFs is highly similar to that shared by adipose stromal cells (ASC) in fat tissue and fibro-adipogenic progenitors (FAP) in skeletal muscle of cancer-free individuals. Because fibroblasts with the ASC/FAP signature are enriched in various carcinomas, it is possible that the paracrine signaling conferred by NRG1 is a pan-cancer mechanism of FGFR inhibitor resistance and tumor aggressiveness. See related article by Hosni et al., p. 725.

Discrepant effect of high-density lipoprotein cholesterol on esophageal and gastric cancer risk in a nationwide cohort.

The relationship between high-density lipoprotein cholesterol (HDL-C) and gastroesophageal cancer is not constant. In this population-based cohort study, 4.518 million cancer-free individuals among those who underwent national cancer screening in 2010 were enrolled and followed up until December 2017. HDL-C level was classified into eight groups at 10mg/dL intervals. The risk of gastroesophageal cancers by HDL-C was measured using adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). During 8years of follow-up, 38,362 gastric and 3022 esophageal cancers developed. Low HDL-C level was associated with an increased risk of gastric cancer; aHR was 1.19 (95% CI 1.09-1.30) for HDL-C < 30mg/dL, 1.07 (95% CI 1.03-1.12) for HDL-C of 30-39mg/dL, and 1.07 (95% CI 1.03-1.12) for HDL-C of 40-49mg/dL comparing to HDL-C of 60-69mg/dL. HDL-C was positively associated with esophageal cancer risk; aHR was 1.30 (1.12-1.51) for HDL-C of 70-79mg/dL, 1.84 (1.53-2.22) for HDL-C of 80-89mg/dL, 2.10 (1.67-2.61) for HDL-C ≥ 90mg/dL. These site-specific effects of HDL-C were robust in sensitivity analyses. The range of HDL-C for the lowest cancer risk was different by sex and site. The hazardous effect of low HDL-C on gastric cancer was prominent in never and past smokers, and extremely high HDL-C increased gastric cancer risk (aHR 1.19; 95% CI 1.04-1.36) only in current smokers. Unfavorable effect of high HDL-C on gastroesophageal cancer risk was remarkable in smokers. Low HDL-C increased the risk of gastric cancer, wherein high HDL-C was associated with esophageal cancer risk with discrepancies by sex and smoking status.

Lynch Syndrome: From Multidisciplinary Management to Precision Prevention.

Lynch syndrome (LS) is currently one of the most prevalent hereditary cancer conditions, accounting for 3% of all colorectal cancers and for up to 15% of those with DNA mismatch repair (MMR) deficiency, and it was one of the first historically identified. The understanding of the molecular carcinogenesis of LS tumors has progressed significantly in recent years. We aim to review the most recent advances in LS research and explore genotype-based approaches in surveillance, personalized cancer prevention, and treatment strategies. PubMed was searched to identify relevant studies, conducted up to December 2023, investigating molecular carcinogenesis in LS, surveillance strategies, cancer prevention, and treatment in LS tumors. Multigene panel sequencing is becoming the benchmark in the diagnosis of LS, allowing for the detection of a pathogenic constitutional variant in one of the MMR genes. Emerging data from randomized controlled trials suggest possible preventive roles of resistant starch and/or aspirin in LS. Vaccination with immunogenic frameshift peptides appears to be a promising approach for both the treatment and prevention of LS-associated cancers, as evidenced by pre-clinical and preliminary phase 1/2a studies. Although robust diagnostic algorithms, including prompt testing of tumor tissue for MMR defects and referral for genetic counselling, currently exist for suspected LS in CRC patients, the indications for LS screening in cancer-free individuals still need to be refined and standardized. Investigation into additional genetic and non-genetic factors that may explain residual rates of interval cancers, even in properly screened populations, would allow for more tailored preventive strategies.