Circulating tumor DNA in patients with colorectal adenomas: assessment of detectability and genetic heterogeneity (original) (raw)
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Circulating Tumor DNA in Precision Oncology and Its Applications in Colorectal Cancer
International Journal of Molecular Sciences
Circulating tumor DNA (ctDNA) is a component of cell-free DNA (cfDNA) that is shed by malignant tumors into the bloodstream and other bodily fluids. ctDNA can comprise up to 10% of a patient’s cfDNA depending on their tumor type and burden. The short half-life of ctDNA ensures that its detection captures tumor burden in real-time and offers a non-invasive method of repeatedly evaluating the genomic profile of a patient’s tumor. A challenge in ctDNA detection includes clonal hematopoiesis of indeterminate potential (CHIP), which can be distinguished from tumor variants using a paired whole-blood control. Most assays for ctDNA quantification rely on measurements of somatic variant allele frequency (VAF), which is a mutation-dependent method. Patients with certain types of solid tumors, including colorectal cancer (CRC), can have levels of cfDNA 50 times higher than healthy patients. ctDNA undergoes a precipitous drop shortly after tumor resection and therapy, and rising levels can for...
Circulating Tumor DNA in Colorectal Cancer—From Concept to Clinic
Oncology & Hematology Review (US)
A dvances in the ability to detect molecular alterations in cancer have led to the development of personalized oncology treatments in colorectal cancer. Tumor biopsies are currently the standard of care for both diagnosis and molecular testing, but have limitations in frequency of sampling, turnaround time and underrepresentation of tumor molecular heterogeneity. The advent of liquid biopsies, in the form of circulating tumor DNA (ctDNA), has many potential clinical applications including non-invasive methods of tumor genotyping, prognostication, monitoring treatment response and resistance, and detection of minimal residual disease. Prospective ctDNA-guided randomized adjuvant clinical trials are currently underway, taking us one step closer towards clinical implementation of ctDNA-guided personalized oncology in colorectal cancer.
Free circulating DNA as a biomarker of colorectal cancer
j o u r n a l h o m e p a g e : w w w. j o u r n a l-s u r g e r y. n e t A B S T R A C T Objectives: The purpose of this study is to evaluate the sensitivity and specificity of free circulating DNA (FCDNA) as a biomarker in patients suffering from colorectal cancer (CRC), investigating both its prognostic value correlated with stage of disease and its potential role in early recurrence diagnosis. Methods: The quantification of plasma DNA was achieved through the use of real time quantitative polymerase chain reaction (PCR) amplification of the RNAse P gene. The study enrolled patients undergoing surgery for primary CRC, at different stages of disease; samples were collected before surgery and during follow-up examinations every 3 months after surgery. Data were statistically analyzed using Software Packages SPSS ® for Windows. Results: FCDNA was detectable in all pre-operative samples and the mean value was 47.8 ng/mL. FCDNA values increased progressively related to UICC stage of disease, although statistical significance was demonstrated only when comparing patients by pT stage. The analysis of postoperative samples showed a significant decrease of FCDNA quantity after radical surgery and in specific cases a rise preceding disease recurrence. Conclusions: This study shows that absolute quantification of FCDNA in CRC patients could have a prognostic value, being related to stage of disease, and could be used as potential tool for early detection of recurrences.
Clinical implications of monitoring circulating tumor DNA in patients with colorectal cancer
Clinical cancer research : an official journal of the American Association for Cancer Research, 2017
We investigated if detection of circulating tumor DNA (ctDNA) after resection of colorectal cancer (CRC) identifies the patients with the highest risk of relapse, and furthermore, whether longitudinal ctDNA analysis allows early detection of relapse and informs about response to intervention.<br /><br />Experimental Design: In this longitudinal cohort study we used massively parallel sequencing to identify somatic mutations and used these as ctDNA markers to detect minimal residual disease and to monitor changes in tumor burden during a three year follow-up period.<br /><br />Results: A total of 45 patients and 371 plasma samples were included. Longitudinal samples from 27 patients revealed ctDNA post-operatively in all relapsing patients (n=14), but not in any of the non-relapsing patients. ctDNA detected relapse with an average lead-time of 9.4 months compared to CT imaging. Of 21 patients treated for localized disease, six had ctDNA detected within 3 month...
Clinical utility of circulating cell-free DNA in advanced colorectal cancer
PLOS ONE, 2017
Background Circulating cell-free DNA (cfDNA) isolated from the plasma of cancer patients (pts) has been shown to reflect the genomic mutation profile of the tumor. However, physician and patient assessment of clinical utility of these assays in patients with metastatic colorectal cancer (mCRC) has not been previously described.
Diagnostic and prognostic role of cell-free DNA testing for colorectal cancer patients
International journal of cancer, 2016
Circulating cell-free DNA (cfDNA) was found in increased amounts in cancer patients and tumor-associated molecular alteration can be detected in cancer patient's samples. For this reason, the cfDNA analysis is actually considered as a new concept of liquid biopsy. We evaluated the presence and integrity of plasma cfDNA by ALU-based qPCR and the methylation profile of OSMR and SFRP1 genes promoter in a large cohort of colorectal cancer (CRC) patients (n = 114) in comparison to healthy subjects (n = 56) and patients with adenomatous lesions (n = 22). Moreover, we studied the prognosis value focusing on histopathological staging and survival. The cfDNA concentration and the integrity index were increased in CRC patients. The ALU83 and ALU244 fragment dosage showed a moderate discriminant capacity between CRC patients and controls and CRC and adenoma patients. Especially, cfDNA was significantly higher in CRC patients at advanced histopathological stage. In addition, the increased c...
A feasibility study of colorectal cancer diagnosis via circulating tumor DNA derived CNV detection
PLOS ONE, 2018
Circulating tumor DNA (ctDNA) has shown great promise as a biomarker for early detection of cancer. However, due to the low abundance of ctDNA, especially at early stages, it is hard to detect at high accuracies while keeping sequencing costs low. Here we present a pilot stage study to detect large scale somatic copy numbers variations (CNVs), which contribute more molecules to ctDNA signal compared to point mutations, via cell free DNA sequencing. We show that it is possible to detect somatic CNVs in early stage colorectal cancer (CRC) patients and subsequently discriminate them from normal patients. With 25 normal and 24 CRC samples, we achieve 100% specificity (lower bound confidence interval: 86%) and~79% sensitivity (95% confidence interval: 63%-95%,), though the performance should be considered with caution given the limited sample size. We report a lack of concordance between the CNVs detected via cfDNA sequencing and CNVs identified in parent tissue samples. However, recent findings suggest that a lack of concordance is expected for CNVs in CRC because of their sub-clonal nature. Finally, the CNVs we detect very likely contribute to cancer progression as they lie in functionally important regions, and have been shown to be associated with CRC specifically. This study paves the path for a larger scale exploration of the potential of CNV detection for both diagnoses and prognoses of cancer.
The Oncologist
The use of genomic testing is rapidly emerging as an important clinical tool both for cancer diagnosis and for guiding treatment decisions in a wide range of malignancies, including gastrointestinal (GI) cancers such as colorectal cancer (CRC). Advances in technologies such as polymerase chain reaction and next-generation sequencing methods have made it possible to noninvasively screen for CRC through, for example, the use of blood- or stool-based testing, with high specificity. Tests are also available that can provide prognostic information beyond traditional clinicopathologic factors such as tumor size, grade, and nodal status, which can enable clinicians to more accurately risk stratify patients for recurrence. Lastly, in the setting of resected CRC, tests are now available that can detect circulating tumor DNA as a means for noninvasive minimal/molecular residual disease monitoring, thereby potentially guiding the use of adjuvant chemotherapy and/or escalating or de-escalating ...
Clinical Cancer Research, 2021
Purpose: Detection of persistent circulating tumor DNA (ctDNA) after curative-intent surgery can identify patients with minimal residual disease (MRD) who will ultimately recur. Most ctDNA MRD assays require tumor sequencing to identify tumor-derived mutations to facilitate ctDNA detection, requiring tumor and blood. We evaluated a plasma-only ctDNA assay integrating genomic and epigenomic cancer signatures to enable tumor-uninformed MRD detection. Experimental Design: A total of 252 prospective serial plasma specimens from 103 patients with colorectal cancer undergoing curative-intent surgery were analyzed and correlated with recurrence. Results: Of 103 patients, 84 [stage I (9.5%), II (23.8%), III (47.6%), IV (19%)] had evaluable plasma drawn after completion of definitive therapy, defined as surgery only (n = 39) or completion of adjuvant therapy (n = 45). In “landmark” plasma drawn 1-month (median, 31.5 days) after definitive therapy and >1 year follow-up, 15 patients had det...
Circulating cell-free DNA in serum as a biomarker of colorectal cancer
Journal of Clinical Pathology, 2013
Background: To verify whether the concentrations and integrity index of circulating cell-free DNA (ccf-DNA) in serum may be clinically useful for the diagnosis and progression monitoring of colorectal cancer (CRC) patients. Methods: Serum samples were collected from 104 with primary CRC, 85 with operated CRC, 16 with recurrent/metastatic CRC, 63 patients with intestinal polyps and 110 normal controls. Long (247 bp) and short (115 bp) DNA fragments in serum were detected by real-time quantitative PCR by amplifying the ALU repeats (ALU-qPCR). Serum carcinoembryonic antigen (CEA) level was detected by ARCHITECT assay. Results: The median absolute serum ALU115 and ALU247/115 in primary CRC group was significantly higher than those in intestinal polyp and normal control groups (both Po0.0001), in recurrent/metastatic CRC was significantly higher compared with primary CRC (P ¼ 0.0021, P ¼ 0.0018) or operated CRC (Po0.0001, respectively) and during follow-up, ALU115 and ALU247/115 were increased before surgery and decreased significantly after surgery. Conclusions: Combined detection of ALU115, ALU247/115 and CEA could improve the diagnostic efficiency for CRC. Serum DNA concentrations and integrity index may be valuable in early complementary diagnosis and monitoring of progression and prognosis of CRC. Colorectal cancer (CRC) is the third most common newly diagnosed cancer and the third most common cause of cancer death among US men and women. It is also a worldwide problem, with an annual incidence of one million cases and an annual mortality of more than 500 000 cases (Ferlay et al, 2010; Jemal et al, 2011). The overall survival of CRC tends to be poor, mainly because most CRC cases are in late stages at the time of diagnosis, and thus losing the opportunity for access to timely and standard treatment. Approximately 50% of CRC patients ultimately died from distant metastasis (Mutch, 2007). Therefore, the key to CRC treatment is early detection and diagnosis. Multiple serum markers including carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) have been well recognised as tumour markers for CRC. However, not all CRC cases can be diagnosed by CEA or CA19-9 alone owing to unstable detection and incremental concentrations in benign diseases (Ludwig and Weinstein, 2005), and CEA only has a sensitivity of 43% (Keesee et al, 1996). Therefore, there is an urgent need to find a noninvasive biomarker that can be commonly applied for screening diagnosis, 'early' adjuvant detection of recurrence and monitoring of metastatic CRC (MCRC). Circulating cell-free DNA (ccf-DNA) in serum or plasma is a promising candidate biomarker for detection, monitoring and prognostic prediction of malignant tumours (Taback and Hoon 2004a, b; Fujimoto et al, 2004; Chan et al, 2008). A study by Leon et al (1977) suggested that the ccf-DNA concentration was significantly increased in cancer patients compared with that in healthy individuals, which was also confirmed by other studies