Clonal Hematopoiesis and Liquid Biopsy in Gastrointestinal Cancers.
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ABSTRACT:
SUBMITTER: Croitoru VM
PROVIDER: S-EPMC8814311 | biostudies-literature | 2021
REPOSITORIES: biostudies-literature
Publications
Clonal Hematopoiesis and Liquid Biopsy in Gastrointestinal Cancers.
Croitoru Vlad M VM Cazacu Irina M IM Popescu Ionut I Paul Doru D Dima Simona Olimpia SO Croitoru Adina Emilia AE Tanase Alina Daniela AD
Frontiers in medicine 20220121
The use of blood liquid biopsy is increasingly being incorporated into the clinical setting of gastrointestinal cancers care. Clonal hematopoiesis (CH) occurs naturally as a result of the accumulation of somatic mutations and the clonal proliferation of hematopoietic stem cells with normal aging. The identification of CH-mutations has been described as a source of biological noise in blood liquid biopsy. Incorrect interpretation of CH events as cancer related can have a direct impact on cancer d ...[more]
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Project description:ImportanceClonal hematopoiesis (CH) has been associated with development of atherosclerosis and leukemia and worse survival among patients with cancer; however, the association with cancer therapy efficacy, in particular immune checkpoint blockade (ICB), and toxicity has not yet been established. Given the widespread use of ICB and the critical role hematopoietic stem cell-derived lymphocytes play in mediating antitumor responses, CH may be associated with therapeutic efficacy and hematologic toxicity.ObjectiveTo determine the association between CH and outcomes, hematologic toxicity, and therapeutic efficacy in patients with metastatic gastrointestinal tract cancers being treated with systemic therapy, both in the first-line metastatic treatment setting and in ICB.Design, setting, and participantsThis retrospective cohort study included 633 patients with stage IV colorectal (CRC) and esophagogastric (EGC) cancer who were treated with first-line chemotherapy and/or ICB at Memorial Sloan Kettering Cancer Center. Patients underwent matched tumor and peripheral blood DNA sequencing using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets next-generation sequencing assay between January 1, 2006, and December 31, 2020.ExposuresClonal hematopoiesis-related genetic alterations were identified by next-generation sequencing of patients' tumor and normal blood buffy coat samples, with a subset of these CH alterations annotated as likely putative drivers (CH-PD) based upon previously established criteria.Main outcomes and measuresPatients with CH and CH-PD in peripheral blood samples were identified, and these findings were correlated with survival outcomes (progression-free survival [PFS] and overall survival [OS]) during first-line chemotherapy and ICB, as well as baseline white blood cell levels and the need for granulocyte colony-stimulating factor (G-CSF) support.ResultsAmong the 633 patients included in the study (390 men [61.6%]; median age, 58 [IQR, 48-66] years), the median age was 52 (IQR, 45-63) years in the CRC group and 61 (IQR, 53-69) years in the EGC group. In the CRC group, 161 of 301 patients (53.5%) were men, compared with 229 of 332 patients (69.0%) in the EGC group. Overall, 62 patients (9.8%) were Asian, 45 (7.1%) were Black or African American, 482 (76.1%) were White, and 44 (7.0%) were of unknown race or ethnicity. Presence of CH was identified in 115 patients with EGC (34.6%) and 83 with CRC (27.6%), with approximately half of these patients harboring CH-PD (CRC group, 44 of 83 [53.0%]; EGC group, 55 of 115 [47.8%]). Patients with EGC and CH-PD exhibited a significantly worse median OS of 16.0 (95% CI, 11.6-22.3) months compared with 21.6 (95% CI, 19.6-24.3) months for those without CH-PD (P = .01). For patients with CRC and EGC, CH and CH-PD were not associated with PFS differences in patients undergoing ICB or first-line chemotherapy. Neither CH nor CH-PD were correlated with baseline leukocyte levels or increased need for G-CSF support.Conclusions and relevanceThese findings suggest CH and CH-PD are not directly associated with the treatment course of patients with metastatic gastrointestinal tract cancer receiving cancer-directed therapy.
| S-EPMC9896303 | biostudies-literature
Project description:The use of blood liquid biopsy is being gradually incorporated into the clinical setting of cancer management. The minimally invasive nature of the usage of cell-free DNA (cfDNA) and its ability to capture the molecular alterations of tumors are great advantages for their clinical applications. However, somatic mosaicism in plasma remains an immense challenge for accurate interpretation of liquid biopsy results. Clonal hematopoiesis (CH) is part of the normal process of aging with the accumulation of somatic mutations and clonal expansion of hematopoietic stem cells. The detection of these non-tumor derived CH-mutations has been repeatedly reported as a source of biological background noise of blood liquid biopsy. Incorrect classification of CH mutations as tumor-derived mutations could lead to inappropriate therapeutic management. CH has also been associated with an increased risk of developing cardiovascular disease and hematological malignancies. Cancer patients, who are CH carriers, are more prone to develop therapy-related myeloid neoplasms after chemotherapy than non-carriers. The detection of CH mutations from plasma cfDNA analysis should be cautiously evaluated for their potential pathological relevance. Although CH mutations are currently considered as "false-positives" in cfDNA analysis, future studies should evaluate their clinical significance in healthy individuals and cancer patients.
| S-EPMC7463455 | biostudies-literature
Project description:As the use of next-generation sequencing (NGS) for plasma cell-free DNA (cfDNA) continues to expand in clinical settings, accurate identification of circulating tumor DNA mutations is important to validate its use in the clinical management for cancer patients. Here, we aimed to characterize mutations including clonal hematopoiesis (CH)-related mutations in plasma cfDNA and tumor tissues using the same ultradeep NGS assay and evaluate the clinical significance of CH-related mutations on the interpretation of liquid biopsy results. Ultradeep targeted NGS using Oncomine Pan-Cancer Panel was performed on matched surgically resected tumor tissues, peripheral blood cells (PBCs), and 120 plasma cfDNA samples from 38 colorectal cancer patients. The clinical significance of the CH-related mutations in plasma cfDNA was evaluated by longitudinal monitoring of the postoperative plasma samples. Among the 38 patients, 74 nonsynonymous mutations were identified from tumor tissues and 64 mutations from the preoperative plasma samples. Eleven (17%) of the 64 mutations identified in plasma cfDNA were also detected in PBC DNA and were identified to be CH-related mutations. Overall, 11 of 38 (29%) patients in this cohort harbored at least one CH-related mutation in plasma cfDNA. These CH-related mutations were continuously detected in subsequent postoperative plasma samples from three patients which could be misinterpreted as the presence of residual disease or as lack of treatment response. Our results indicated that it is essential to integrate the mutational information of PBCs to differentiate tumor-derived from CH-related mutations in liquid biopsy analysis. This would prevent the misinterpretation of results to avoid misinformed clinical management for cancer patients.
| S-EPMC7400786 | biostudies-literature
Project description:Room for improvement exists regarding recommendations for screening, staging, therapy selection, and frequency of surveillance of gastrointestinal cancers. Screening is costly and invasive, improved staging demands increased sensitivity and specificity to better guide therapy selection. Surveillance requires increased sensitivity for earlier detection and precise management of recurrences. Peripherally collected blood-based liquid biopsies enrich and analyze circulating tumor cells and/or somatic genomic material, including circulating tumor DNA along with various subclasses of RNA. Such assays have the potential to impact clinical practice at multiple stages of management in gastrointestinal cancers. This review summarizes current basic and clinical evidence for the utilization of liquid biopsy in cancers of the esophagus, pancreas, stomach, colon, and rectum. Technical aspects of various liquid biopsy methodologies and targets are reviewed and evidence supporting current commercially available assays is examined. Finally, current clinical applicability, potential future uses, and pitfalls of applying liquid biopsy to the screening, staging and therapeutic management of these diseases are discussed.
| S-EPMC6721625 | biostudies-literature
Project description:Cancer has emerged as a leading cause of mortality worldwide, claiming more than 8 million lives annually. Gastrointestinal cancers account for about 35% of these mortalities. Recent advances in diagnostic and treatment strategies have reduced mortality among patients with gastrointestinal cancer, yet a significant number of patients still develop late-stage cancer, where treatment options are inadequate. Emerging interests in "liquid biopsies" have encouraged investigators to identify and develop clinically relevant noninvasive genomic and epigenomic signatures that can be exploited as biomarkers capable of detecting premalignant and early-stage cancers. In this context, microRNAs (miRNA), which are small, noncoding RNAs that are frequently dysregulated in cancers, have emerged as promising entities for such diagnostic purposes. Even though the future looks promising, current approaches for detecting miRNAs in blood and other biofluids remain inadequate. This review summarizes existing efforts to exploit circulating miRNAs as cancer biomarkers and evaluates their potential and challenges as liquid biopsy-based biomarkers for gastrointestinal cancers. Clin Cancer Res; 23(10); 2391-9. ©2017 AACR.
| S-EPMC5433899 | biostudies-literature
Project description:During cancer therapy, tumor heterogeneity can drive the evolution of multiple tumor subclones harboring unique resistance mechanisms in an individual patient1-3. Previous case reports and small case series have suggested that liquid biopsy (specifically, cell-free DNA (cfDNA)) may better capture the heterogeneity of acquired resistance4-8. However, the effectiveness of cfDNA versus standard single-lesion tumor biopsies has not been directly compared in larger-scale prospective cohorts of patients following progression on targeted therapy. Here, in a prospective cohort of 42 patients with molecularly defined gastrointestinal cancers and acquired resistance to targeted therapy, direct comparison of postprogression cfDNA versus tumor biopsy revealed that cfDNA more frequently identified clinically relevant resistance alterations and multiple resistance mechanisms, detecting resistance alterations not found in the matched tumor biopsy in 78% of cases. Whole-exome sequencing of serial cfDNA, tumor biopsies and rapid autopsy specimens elucidated substantial geographic and evolutionary differences across lesions. Our data suggest that acquired resistance is frequently characterized by profound tumor heterogeneity, and that the emergence of multiple resistance alterations in an individual patient may represent the 'rule' rather than the 'exception'. These findings have profound therapeutic implications and highlight the potential advantages of cfDNA over tissue biopsy in the setting of acquired resistance.
| S-EPMC6741444 | biostudies-literature
Project description:Circulating tumor DNA (ctDNA) analysis is a promising non-invasive technique for active surveillance after chemoradiotherapy for locally advanced resectable esophageal carcinoma. In other malignancies false-positive results in ctDNA analysis have been reported due to clonal hematopoiesis. In this case, we present a 66-year-old male who had adenocarcinoma of the gastroesophageal junction for which he received neoadjuvant chemoradiotherapy and underwent a transhiatal esophagectomy. Postoperatively our patient received follow-up with ctDNA analysis using next generation sequencing (NGS) and droplet digital PCR (ddPCR). This case report illustrates a number of the current challenges in ctDNA diagnostics in esophageal carcinoma. Firstly, the TP53 c.524G>A; p.R175H mutation that was found in preoperative tumor biopsies became detectable in ctDNA only after distant metastases had already been confirmed by clinical symptoms and standard imaging- and biopsy techniques. Secondly our patient repeatedly had false-positive outcomes of ctDNA analysis. Genomic analysis of white blood cells revealed that the origin of these discordant mutations lies in clonal hematopoiesis. Failure to detect TP53 c.524G>A; p.R175H in cell-free DNA (cfDNA) is most likely due to the amount of ctDNA in the cfDNA fraction being below the limit of detection for NGS and ddPCR analyses. Clinicians should be aware of the possibility of finding mutations originating from clonal hematopoiesis when using ctDNA analysis during active surveillance for esophageal carcinoma. We recommend correlation of mutations in cfDNA with mutations in tumor biopsies.
| S-EPMC8421960 | biostudies-literature
Project description:BackgroundPrecision medicine highlights the importance of incorporating molecular genetic testing into standard clinical care. Next-generation sequencing can detect cancer-specific gene mutations, and molecular-targeted drugs can be designed to be effective for one or more specific gene mutations. For patients with special site metastases, it is particularly important to use appropriate samples for genetic profiling. This study aimed to determine whether genomic profiling using ASC and PE is effective in detecting genetic mutations.MethodsTissues, plasma, ascites (ASC) supernatants, and pleural effusion (PE) samples from gastrointestinal cancer patients with peritoneal metastasis and lung cancer patients with pleural metastasis were collected for comprehensive genomic profiling. The samples were subjected to next-generation sequencing using a panel of 59 or 1021 cancer-relevant genes panel.ResultsA total of 156 tissues, 188 plasma samples, 45 ASC supernatants, and 1 PE samples from 304 gastrointestinal cancer patients and 446 PE supernatants, 122 tissues, 389 plasma samples, and 45 PE sediments from 407 lung cancer patients were analyzed. The MSAF was significantly higher in ASC and PE supernatant than that in plasma ctDNA (50.00% vs. 3.00%, p < 0.0001 and 28.5% vs. 1.30%, p < 0.0001, respectively). The ASC supernatant had a higher actionable mutation rate and more actionable alterations than the plasma ctDNA in 26 paired samples. The PE supernatant had a higher total actionable mutation rate than plasma (80.3% vs. 48.4%, p < 0.05). The PE supernatant had a higher frequency of uncommon variations than the plasma regardless of distant organ metastasis.ConclusionASC and PE supernatants could be better alternative samples when tumor tissues are not available, especially in patients with only peritoneal or pleural metastases.
| S-EPMC9513868 | biostudies-literature
Project description:Immunotherapy has shifted the therapeutic landscape in thoracic cancers. However, assessment of biomarkers for patient selection and disease monitoring remain challenging, especially considering the lack of tissue sample availability for clinical and research purposes. In this scenario, liquid biopsy (LB), defined as the study and characterization of biomarkers in body fluids, represents a useful alternative strategy. In other malignancies such as colorectal cancer, breast cancer or melanoma, the potential of LB has been more extensively explored for monitoring minimal residual disease or response to treatment, and to investigate mechanisms of resistance to targeted agents. Even if various experiences have already been published about the applications of LB in immunotherapy in thoracic cancers, the standardization of methodology and assessment of its clinical utility is still pending. In this review, the authors will focus on the applications of LB in immunotherapy in non-small cell lung cancer, small cell lung cancer, and malignant pleural mesothelioma, describing available data and future perspectives.
| S-EPMC9400760 | biostudies-literature
Project description:Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by detectable hematopoietic-associated gene mutations in a person without evidence of hematologic malignancy. We sought to identify additional cancer-presenting mutations useable for CHIP detection by performing a data mining analysis of 48 somatic mutation studies reporting mutations at diagnoses of 7,430 adult and pediatric patients with hematologic malignancies. Following extraction of 20,141 protein-altering mutations, we identified 434 significantly recurrent mutation hotspots, 364 of which occurred at loci confidently assessable for CHIP. We then performed an additional large-scale analysis of whole exome sequencing data from 4,538 persons belonging to three non-cancer cohorts for clonal mutations. We found the combined cohort prevalence of CHIP with mutations identical to those reported at blood cancer mutation hotspots to be 1.8%, and that some of these CHIP mutations occurred in children. Our findings may help to improve CHIP detection and pre-cancer surveillance for both children and adults.
| S-EPMC8133376 | biostudies-literature