Colorectal cancer detected by liquid biopsy 2 years prior to clinical diagnosis in the HUNT study.

BACKGROUND: Colorectal cancer (CRC) is often diagnosed in advanced stages. Circulating tumour DNA (ctDNA) has been proposed as an early diagnostic biomarker. However, as a screening tool, ctDNA has mainly been studied in selected populations at the time of clinical diagnosis. The aim of this study was to detect CRC by known ctDNA markers up to 2 years prior to clinical diagnosis. METHODS: In this case-control study, methylated ctDNA markers were detected in plasma samples from 106 healthy controls and 106 individuals diagnosed with CRC within 24 months following participation in The Trøndelag Health Study. RESULTS: The most specific single markers were BMP3, FLI1, IKZF1, SFRP1, SFRP2, NPTX2, SLC8A1 and VIM (specificity >70%). When combining these into a panel, the CRC sensitivity was 43% (95% CI 42.7-43.4) and the CRC specificity was 86% (95% CI 85.7-86.2). The findings were reproduced in an independent validation set of samples. CONCLUSIONS: Detection of known methylated ctDNA markers of CRC is possible up to 2 years prior to the clinical diagnosis in an unselected population resembling the screening setting. This study supports the hypothesis that some patients could be diagnosed earlier, if ctDNA detection was part of the CRC screening programme.

Promoter hypermethylation in plasma-derived cell-free DNA as a prognostic marker for pancreatic adenocarcinoma staging.

Correct staging of pancreatic cancer is paramount, as treatment is stage specific. However, minimally invasive tools to facilitate staging are lacking. DNA promoter hypermethylation is a hallmark of cancer. The aim of this study is to evaluate promoter hypermethylation in cell-free DNA as a prognostic marker for stage classification of pancreatic adenocarcinoma. Consecutive patients with pancreatic adenocarcinoma were prospectively included. Plasma samples were obtained before diagnostic work-up and treatment. Patients were staged according to the TNM classification. Methylation-specific PCR of 28 genes was performed. Prognostic prediction models for staging of pancreatic adenocarcinoma were developed by multivariable logistic regression analysis using stepwise backwards elimination. Ninety-five patients with pancreatic adenocarcinoma were included. The mean number of hypermethylated genes was identical for stage I, II and III disease (7.09 (95% CI; 5.51-8.66), 7.00 (95% CI; 5.93-8.07) and 6.77 (95% CI; 5.08-8.46)), respectively, and highly significantly different from stage IV disease (10.24 (95% CI; 8.88-11.60)). The prediction model (SEPT9v2, SST, ALX4, CDKN2B, HIC1, MLH1, NEUROG1, and BNC1) enabled the differentiation of stage IV from stage I-III disease (AUC of 0.87 (cut point 0.55; sensitivity 74%, specificity 87%)). Model (MLH1, SEPT9v2, BNC1, ALX4, CDKN2B, NEUROG1, WNT5A, and TFPI2) enabled the differentiation of stage I-II from stage III-IV disease (AUC of 0.82 (cut point 0.66; sensitivity 73%, specificity 80%)). Cell-free DNA promoter hypermethylation has the potential to be blood-based prognostic markers for pancreatic adenocarcinoma, as panels of hypermethylated genes enables the differentiation according to cancer stage. However, further validation is required.

Symptomatology, Clinical Presentation and Basic Work up in Patients with Suspected Pulmonary Embolism.

Basic knowledge of pulmonary embolism is relevant to most practicing physicians. Many medical specialties care for patients with increased risk of pulmonary embolism, why recognition of relevant symptoms, a thorough medical history, assessment of the clinical condition of the patient and possibly referral to a relevant facility should be a part of the skills of all clinicians. Sudden onset dyspnea, chest pain, syncope and hemoptysis are essential symptoms of pulmonary embolism, and in most of these patients basic investigations like arterial blood gas analysis, electrocardiogram, chest x-ray and biochemical analyses are appropriate. In addition, lung ultrasound and echocardiography are indicated in many of these patients. The information available from the medical history, clinical assessment and basic investigation form the basis on which the decision about further diagnostic imaging and intensity of treatment and monitoring can be made. These decisions can be guided by clinical scoring systems like the Wells score, revised Geneva score and the PESI.

Radionuclide Diagnosis of Pulmonary Embolism.

Diagnostic imaging plays an integral role in the diagnostic workup of suspected pulmonary embolism, and several modalities have been employed over the years. In recent years, the choice has been narrowed to either computer tomographic or radionuclide based methods, i.e. computer tomographic angiography (CTA) and ventilation-perfusion scintigraphy (V/Q-scan). Both methods display advantages and shortcomings, and while we provide some insights into CTA and alternative methods, the paper's main focus is a review of the V/Q-scan. We discuss basic considerations, interpretation criteria, clinical value, and controversies of conventional planar lung scintigraphy as well as the more contemporary 3-dimensional imaging technique of single photon emission tomography (SPECT) with or without CT.

State-of-the-Art Imaging in Pulmonary Embolism: Ventilation/Perfusion Single-Photon Emission Computed Tomography versus Computed Tomography Angiography - Controversies, Results, and Recommendations from a Systematic Review.

Pulmonary embolism (PE) is a common, ubiquitous, and potentially lethal disease. As symptoms and clinical findings are notoriously nonspecific, diagnostic imaging is essential to avoid undertreatment as well as overtreatment. Controversies remain regarding first-line imaging in suspected PE. The two main contemporary contenders are ventilation/perfusion scintigraphy with single-photon emission computed tomography (V/Q SPECT) with or without additional low-dose CT (SPECT/CT) and CT angiography (CTA). We present our results from a systematic review and meta-analysis of the diagnostic performances of these modalities: V/Q SPECT, V/Q SPECT/CT, and CTA are all viable options, but we consider V/Q SPECT/CT to be superior in most clinical settings with better overall diagnostic performance, that is, pooled sensitivities (97.6 vs. 82.0%), specificities (95.9 vs. 94.9%), positive predictive values (93.0 vs. 93.8%), negative predictive values (98.6 vs. 84.7%), and accuracies (96.5 vs. 88.6%). We further address some of the ongoing controversies regarding the various modalities, that is, radiation exposure, the issues of subsegmental PE, nondiagnostic studies, and various challenges in specific patient populations.

Clinical utility of F-18 FDG PET-CT in the initial evaluation of lung cancer.

PURPOSE: Positron emission tomography-computed tomography (PET-CT) is a resource-demanding imaging modality with increasing popularity in the workup of patients with suspected or proven lung cancer. METHODS: To review the clinical usefulness of this imaging modality in the diagnosis, staging, and pre-operative evaluation, we conducted a systematic literature search, review, and quality assessment using the rapid evidence assessment toolkit and the Oxford Centre for Evidence-Based Medicine methodology. The literature search resulted in 4,208 records including 918 reviews, of which 139 met the predefined criteria and were read in full to identify relevant original articles on F-18 FDG PET-CT (1) in the evaluation of solitary pulmonary nodules (n = 14), (2) in curative-intent treatment trials (n = 9), and (3) in planning of invasive procedures (n = 18). RESULTS: We found the following important results from the literature review: 1) PET-CT can rule out malignancy in most solitary pulmonary nodules due to high sensitivity (recommendation level A). 2) PET-CT reduces the number of futile treatment trials (recommendation level A). 3) The sensitivity of PET-CT in general is insufficient to rule out mediastinal lymph node metastasis (recommendation level A). CONCLUSIONS: ᅟ 1) With few exceptions, solitary pulmonary nodules can safely be considered benign if the PET-CT scan is negative. Exceptions consist of small (<1 cm) and non-solid, solitary pulmonary nodules. These abnormalities should be followed up by CT in a structured programme. 2) No curative-intent treatment should be commenced until a PET-CT scan has excluded occult distant metastases. 3) In general, lymph node metastasis in the mediastinum cannot be ruled out on the basis of a negative PET-CT, and confirmative invasive staging should be performed in most patients before mediastinal metastasis is confirmed or ruled out.

FDG PET/CT in cancer: comparison of actual use with literature-based recommendations.

PURPOSE: The Region of Southern Denmark (RSD), covering 1.2 of Denmark's 5.6 million inhabitants, established a task force to (1) retrieve literature evidence for the clinical use of positron emission tomography (PET)/CT and provide consequent recommendations and further to (2) compare the actual use of PET/CT in the RSD with these recommendations. This article summarizes the results. METHODS: A Work Group appointed a professional Subgroup which made Clinician Groups conduct literature reviews on six selected cancers responsible for 5,768 (62.6 %) of 9,213 PET/CT scans in the RSD in 2012. Rapid Evidence Assessment was applied, using the methodology of systematic reviews with predefined limitations to search PubMed, Embase and the Cochrane Library for articles published in English/Danish/Swedish/Norwegian since 2002. PICO questions were defined, data recorded and quality appraised and rated with regard to strength and evidence level. Consequent recommendations for applications of PET/CT were established. The actual use of PET/CT was compared with these, where grades A and B indicated "established" and "useful" and grades C and D "potentially useful" and "non-recommendable" indications, respectively. RESULTS: Of 11,729 citations, 1,729 were considered for review, and 204 were included. The evidence suggested usefulness of PET/CT in lung, lymphoma, melanoma, head and neck, and colorectal cancers, whereas evidence was sparse in gynaecological cancers. The agreement between actual use of PET/CT and literature-based recommendations was high in the first five mentioned cancers in that 96.2 % of scans were made for grade A or B indications versus only 22.2 % in gynaecological cancers. CONCLUSION: Evidence-based usefulness was reported in five of six selected cancers; evidence was sparse in the sixth, gynaecological cancers. Actual use of PET/CT agreed well with recommendations.

Positron emission tomography in chronic obstructive pulmonary disease.

The purpose of this paper was to systematically search the literature on (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET) in the management of chronic obstructive pulmonary disease (COPD) and to provide a concise review of the reported results. Papers were searched through PubMed, EMBASE and Cochrane Library using the MESH terms "pulmonary disease, chronic obstructive", "pulmonary emphysema", and "positron-emission tomography". Of the 38 citations from the search and from browsing the literature lists of selected articles, seven relevant reports were identified. The sparse and heterogeneous literature available provide some indication that (18)F-FDG-PET could prove useful in COPD by a) differentiating COPD from chronic asthma and alpha-1-antitrypsin deficiency, b) measuring pulmonary and systemic inflammation to guide treatment and estimate prognosis, c) quantifying respiratory muscle use, and d) diagnosing cor pulmonale. In conclusion, the role of (18)F-FDG-PET in diagnosing and managing COPD patients seems to be promising and deserves to be further studied.

Promoter hypermethylation of SFRP1 as a prognostic and potentially predictive blood-based biomarker in patients with localized pancreatic ductal adenocarcinoma.

Introduction: Current prognostic blood-based biomarkers for pancreatic adenocarcinoma (PDAC) are limited. Recently, promoter hypermethylation of SFRP1 (phSFRP1) has been linked to poor prognosis in patients with gemcitabine-treated stage IV PDAC. This study explores the effects of phSFRP1 in patients with lower stage PDAC. Methods: Based on a bisulfite treatment process, the promoter region of the SFRP1 gene was analyzed with methylation-specific PCR. Kaplan-Meier curves, log-rank tests, and generalized linear regression analysis were used to assess restricted mean survival time survival at 12 and 24 months. Results: The study included 211 patients with stage I-II PDAC. The median overall survival of patients with phSFRP1 was 13.1 months, compared to 19.6 months in patients with unmethylated SFRP1 (umSFRP1). In adjusted analysis, phSFRP1 was associated with a loss of 1.15 months (95%CI -2.11, -0.20) and 2.71 months (95%CI -2.71, -0.45) of life at 12 and 24 months, respectively. There was no significant effect of phSFRP1 on disease-free or progression-free survival. In stage I-II PDAC, patients with phSFRP1 have worse prognoses than patients with umSFRP1. Discussion: Results could indicate that the poor prognosis may be caused by reduced benefit from adjuvant chemotherapy. SFRP1 may help guide the clinician and be a possible target for epigenetically modifying drugs.

High recovery of cell-free methylated DNA based on a rapid bisulfite-treatment protocol.

BACKGROUND: Detection of cell-free methylated DNA in plasma is a promising tool for tumour diagnosis and monitoring. Due to the very low amounts of cell-free DNA in plasma, analytical sensitivity is of utmost importance. The vast majority of currently available methods for analysing DNA methylation are based on bisulfite-mediated deamination of cytosine. Cytosine is rapidly converted to uracil during bisulfite treatment, whereas 5-methylcytosine is only slowly converted. Hence, bisulfite treatment converts an epigenetic modification into a difference in sequence, amenable to analysis either by sequencing or PCR based methods. However, the recovery of bisulfite-converted DNA is very poor. RESULTS: Here we introduce an alternative method for the crucial steps of bisulfite treatment with high recovery. The method is based on an accelerated deamination step and alkaline desulfonation in combination with magnetic silica purification of DNA, allowing preparation of deaminated DNA from patient samples in less than 2 hours. CONCLUSIONS: The method presented here allows low levels of DNA to be easily and reliably analysed, a prerequisite for the clinical usefulness of cell-free methylated DNA detection in plasma.

Negative HCV-RNA 2 weeks after initiation of treatment predicts sustained virological response to pegylated interferon alfa-2a and ribavirin in patients with chronic hepatitis C.

OBJECTIVE: The aim of this study was to examine the early viral kinetics as predictor for sustained virological response (SVR) during hepatitis C treatment. MATERIALS AND METHODS: We included patients with biopsy-proven chronic hepatitis C and ALT above the upper limit of normal, who received a standard treatment of pegylated interferon alfa-2a and ribavirin. The HCV-RNA concentration (limit of detection 20 IU/mL) was determined at days 0, 1, 2, 3, 4, 7, 14, 21 and monthly thereafter. RESULTS: Among 46 patients who completed the trial, 30 (65%) had SVR. Low baseline viral load, IL28B genotype CC and absence of cirrhosis were statistically associated with SVR. In multivariate analysis only absence of cirrhosis and HCV-RNA negativity at day 14 were independent predictors for SVR. Eight patients who became HCV-RNA negative on day 14 as well as 13 of 14 patients (93%) with HCV-RNA levels of <1000 IU/mL at day 7 obtained a SVR. Among 8 of 18 (44%) genotype 1 and 4 patients with more than a one log drop in HCV-RNA titer at day 7, 75% achieved SVR. CONCLUSIONS: We observed a correlation between low HCV-RNA titers in week 2 and SVR during pegylated interferon/ribavirin-based treatment. This may help identify a group of patients for whom SVR may be obtained without the addition of directly acting antivirals, and thereby save the patients for unnecessary side effects and the health care system for additional costs.

A case of unexplained hypoxemia.

We present a patient with acute-onset dyspnea and unexplained severe hypoxemia. No signs of severe cardiopulmonary disease, pulmonary arterial hypertension, or pulmonary embolism were present. The patient was diagnosed with hepatopulmonary syndrome, since liver disease of alcoholic origin was present, markedly increased alveolar-arterial oxygen difference existed, and intrapulmonary vascular dilations were demonstrated. The condition of the patient did not improve and he was referred for liver transplantation, which is the only treatment option with documented efficacy. The case highlights the importance of thinking outside the thorax when evaluating patients with dyspnea.

HBeAg and not genotypes predicts viral load in patients with hepatitis B in Denmark: a nationwide cohort study.

OBJECTIVE: To explore the influence of HBV genotype on viral load in patients with HBV infection, and to investigate the relation to gender, age and country of origin or antibodies against hepatitis Be antigen (anti-HBe). MATERIALS: We investigated 1025 patients with hepatitis B virus infection in a nationwide study in Denmark. RESULTS: Prevalence of genotypes were: 10.5% A, 17.3% B, 20.5% C, 45.7% D, 3.2% E, 0.6% F, 1.1% G and 1% had more than one genotype. Nearly 60% of patients with genotype A were from Africa, 82% and 93% with genotypes B or C were from East Asia, 62% with genotype D came from the Middle East and 91% with genotype E came from Africa. More women had genotypes B (p = 0.006) or C (p < 0.001) while more men had genotypes A (p = 0.015) or D (p < 0.001). Women with genotypes B and D were younger than men (p < 0.001, p = 0.026). Viral load differed in genotype A and D compared with B and C (p < 0.001), and between anti-HBe and hepatitis B e antigen (HBeAg) positive patients (median values 5.4 × 10(3) IU/ml and 7.4 × 10(7) IU/ml, respectively, p < 0.001). Viral load depended on the presence of HBeAg (p < 0.001; OR, 95% CI: 0.05, 0.03-0.07) in the adjusted analysis and was not affected by origin (p = 0.65), age (p = 0.12), gender (p = 0.06) or genotype (p = 0.10). CONCLUSION: HBeAg status and not HBV genotype influenced viral load in this nationwide study. HBeAg positive patients had median HBV-DNA levels 10,000 times higher than those anti-HBe positive across genotypes.

Validation of SFRP1 Promoter Hypermethylation in Plasma as a Prognostic Marker for Survival and Gemcitabine Effectiveness in Patients with Stage IV Pancreatic Adenocarcinoma.

No reliable predictive blood-based biomarkers are available for determining survival from pancreatic adenocarcinoma (PDAC). This combined discovery and validation study examines promoter hypermethylation (ph) of secreted frizzled-related protein 1 (SFRP1) in plasma-derived cell-free DNA as an independent prognostic marker for survival and Gemcitabine effectiveness in patients with stage IV PDAC. We conducted methylation-specific polymerase chain reaction analysis of the promoter region of the SFRP1 gene, based on bisulfite treatment. Survival was analyzed with Kaplan-Meier curves, log-rank test, and Cox regression. The discovery cohort included 40 patients, 25 receiving Gem. Gem-treated patients with phSFRP1 had a shorter median overall survival (mOS) (4.4 months) than unmethylated patients (11.6 months). Adjusted Cox-regression yielded a hazard rate (HR) of 3.48 (1.39-8.70). The validation cohort included 58 Gem-treated patients. Patients with phSFRP1 had a shorter mOS (3.2 months) than unmethylated patients (6.3 months). Adjusted Cox regression yielded an HR of 3.53 (1.85-6.74). In both cohorts, phSFRP1 was associated with poorer survival in Gem-treated patients. This may indicate that tumors with phSFRP1 are more aggressive and less sensitive to Gem treatment. This knowledge may facilitate tailored treatment of patients with stage IV PDAC. Further studies are planned to examine phSFRP1 in more intensive chemotherapy regimens.

A prospective cohort study of shared decision making in lung cancer diagnostics: Impact of using a patient decision aid.

OBJECTIVE: The objective of this study was to describe the impact on patient-reported outcomes of introducing Shared Decision Making (SDM) and a Patient Decision Aid (PtDA) in the initial process of lung cancer diagnostics. METHODS: We conducted a prospective cohort study, where a control cohort was consulted according to usual clinical practice. After introducing SDM through a PtDA and training of the staff, the SDM cohort was enrolled in the study. All patients completed four questionnaires: the Decisional Conflict Scale (DCS) before and after the consultation, the CollaboRATE scale after the consultation, and the Decision Regret Scale (DRS). RESULTS: Patients exposed to SDM and a PtDA had significantly improved DCS scores after the consultation compared to the control group (a difference of 10.26, p = 0.0128) and significantly lower DRS scores (a difference of 8.98, p = 0.0197). Of the 82 control patients and 52 SDM patients 29% and 54%, respectively, gave the maximum score on the CollaboRATE scale (Pearson's chi2 8.0946, p = 0.004). CONCLUSION: The use of SDM and a PtDA had significant positive impact on patient-reported outcomes. PRACTICE IMPLICATIONS: Our results may encourage the increased uptake of SDM in the initial process of lung cancer diagnostics.

Birt-Hogg-Dubé syndrome: spontaneous pneumothorax as a first symptom.

Birt-Hogg-Dubé syndrome (BHDS) is a rare hereditary autosomal dominant condition characterised by benign cutaneous lesions, lung cysts, increased risk of spontaneous pneumothorax and renal cancer. It shows great heterogenous presentation within and between affected families. We report a case of a Danish female patient with recurrent pneumothoraces as the first symptom of BHDS. Over the years, she developed skin changes, and a family history of skin changes, pneumothoraces and renal cancer was discovered. BHDS was suspected, a genetic analysis was performed and a pathogenic variation c.1285delC in FLCN gene was detected in the patient. As we stated the diagnosis BHDS, we discovered several undiagnosed family members all of them now entering a lifelong follow-up programme with abdominal imaging because of the increased risk of developing renal cancer. BHDS should be known to oncologists, dermatologists and pulmonologists as the patients most often present to these medical disciplines.

The prognostic efficacy of cell-free DNA hypermethylation in colorectal cancer.

Epigenetic alterations in colorectal cancer (CRC) cause important differences in the underlying tumor biology and aggressiveness. DNA hypermethylation is central for the development of CRC but the prognostic impact remains elusive. We aimed to assess the association between cell-free hypermethylated DNA and stage and survival in colorectal cancer (CRC). We analyzed pre-treatment plasma samples from 193 patients with CRC. Thirty gene-promoter regions were analyzed using methylation specific PCR. We compared the median number (range) of hypermethylated promoter regions with CRC stage, and constructed a multivariable Cox-regression model adjusted for stage, to evaluate the added prognostic information. The median number of hypermethylated promoter regions was nine (0-28) in patients with distant metastasis compared to five (0-19) in patients without metastatic disease (p < 0.0001). The majority of the hypermethylated promoter regions inferred a poor prognosis. Cox-regression analysis adjusted for patient age, sex, pre-treatment CEA-levels, and disease stage, showed that RARB (HR = 1.99, 95% CI [1.07, 3.72]) and RASSF1A (HR = 3.35, 95% CI [1.76, 6.38]) hypermethylation inferred a significant effect on survival. The risk of metastasis increase with the number of cell-free hypermethylated promoter regions. The presence of RARB and RASSF1A hypermethylation indicated aggressive disease, regardless of stage at the time of diagnosis.

Cell-free DNA promoter hypermethylation in plasma as a predictive marker for survival of patients with pancreatic adenocarcinoma.

INTRODUCTION: Few prognostic biomarkers are available for pancreatic cancer. The aim of this study is to examine the correlation between the survival of pancreatic adenocarcinoma patients and hypermethylated genes in plasma-derived cell-free DNA. METHODS: Consecutive patients with pancreatic adenocarcinoma were prospectively included and staged according to the TNM classification. Methylation-specific PCR of 28 genes was conducted. A survival prediction model independent of cancer stage and stage-specific survival prediction models were developed by multivariable Cox regression analysis using backward stepwise selection. RESULTS: Ninety-five patients with pancreatic adenocarcinoma were included. Patients with more than 10 hypermethylated genes had a HR of 2.03 (95% CI; 1.15-3.57) compared to patients with fewer hypermethylated genes. Three survival prediction models were developed: Total group; (American Society of Anesthesiologists score (ASA)=3, GSTP1, SFRP2, BNC1, SFRP1, TFPI2, and WNT5A) Risk groups 2, 3 and 4 had a HR of 2.65 (95% CI; 1.24-5.66), 4.34 (95% CI; 1.98-9.51) and 21.19 (95% CI; 8.61-52.15), respectively, compared to risk group 1. Stage I-II; (ASA=3, SFRP2, and MESTv2) Risk groups 2, 3 and 4 had a HR of 4.83 (95% CI; 2.01-11.57), 9.12 (95% CI; 2.18-38.25) and 70.90 (95% CI; 12.63-397.96), respectively, compared to risk group 1. Stage IV; (BMP3, NPTX2, SFRP1, and MGMT) Risk group 2 had a HR of 5.23 (95% CI; 2.13-12.82) compared to risk group 1. CONCLUSION: Prediction models based on cell-free DNA hypermethylation stratified pancreatic adenocarcinoma patients into risk groups according to survival. The models have the potential to work as prognostic biomarkers. However, further validation of the results is required to substantiate the findings.

Hypermethylated DNA, a circulating biomarker for colorectal cancer detection.

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers in the western world. Screening is an efficient method of reducing cancer-related mortality. Molecular biomarkers for cancer in general and CRC in particular have been proposed, and hypermethylated DNA from stool or blood samples are already implemented as biomarkers for CRC screening. We aimed to evaluate the performance of proven hypermethylated DNA promoter regions as plasma based biomarkers for CRC detection. METHODS: We conducted a cross-sectional case-control study of 193 CRC patients and 102 colonoscopy-verified healthy controls. Using methylation specific polymerase chain reaction, we evaluated 30 DNA promoter regions previously found to be CRC specific. We used multivariable logistic regression with stepwise backwards selection, and subsequent leave-pair-out cross validation, to calculate the optimism corrected area under the receiver operating characteristics curve (AUC) for all stage as well as early stage CRC. RESULTS: None of the individual DNA promoter regions provided an overall sensitivity above 30% at a reasonable specificity. However, seven hypermethylated promoter regions (ALX4, BMP3, NPTX2, RARB, SDC2, SEPT9, and VIM) along with the covariates sex and age yielded an optimism corrected AUC of 0.86 for all stage CRC and 0.85 for early stage CRC. Overall sensitivity for CRC detection was 90.7% at 72.5% specificity using a cut point value of 0.5. CONCLUSIONS: Individual hypermethylated DNA promoter regions have limited value as CRC screening markers. However, a panel of seven hypermethylated promoter regions show great promise as a model for CRC detection.