Multiple gene promoter methylation and clinical stage in adjacent normal tissues: Effect on prognosis of colorectal cancer in Taiwan

AbstractThis study provide an insight that the panel genes methylation status in different clinical stage tended to reflect a different prognosis even in matched normal tissues, to clinical recommendation. We enrolled 153 colorectal cancer patients from a medical center in Taiwan and used the candidate gene approach to select five genes involved in carcinogenesis pathways. We analyzed the relationship between DNA methylation with different cancer stages and the prognostic outcome. There were significant trends of increasing risk of 5-year time to progression and event-free survival of subjects with raising number of hypermethylation genes both in normal tissue and tumor tissue. The group with two or more genes with aberrant methylation in the advanced cancer stages (Me/advanced) had lower 5-year event-free survival among patients with colorectal cancer in either normal or tumor tissue. The adjusted hazard ratios in the group with two or more genes with aberrant methylation with advanced cancer stages (Me/advanced) were 8.04 (95% CI, 2.80–23.1; P for trend <0.01) and 8.01 (95% CI, 1.92–33.4; P for trend <0.01) in normal and tumor tissue, respectively. DNA methylation status was significantly associated with poor prognosis outcome. This finding in the matched normal tissues of colorectal cancer patients could be an alternative source of prognostic markers to assist clinical decision making.

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Clinical stage and risk of recurrence and mortality: interaction of DNA methylation factors in patients with colorectal cancer

Journal of Investigative Medicine ◽

10.1136/jim-2016-000086 ◽

2016 ◽

Vol 64 (7) ◽

pp. 1200-1207 ◽

Cited By ~ 3

Author(s):

Hsien-Feng Chang ◽

Chang-Chieh Wu ◽

Chien-An Sun ◽

Chi-Ming Chu ◽

Fu-Gong Lin ◽

...

Keyword(s):

Colorectal Cancer ◽

Dna Methylation ◽

Clinical Stage ◽

Methylation Status ◽

Clinical Pathology ◽

Cancer Staging ◽

Joint Effect ◽

Candidate Gene Approach ◽

Risk Of Recurrence ◽

Normal Tissues

Aberrant DNA methylation plays a crucial role in cancer development; however, prospective evidence of an interaction between molecular biomarkers and cancer staging for predicting the prognosis of colorectal cancer (CRC) is still limited. We examined DNA methylation in tumors and adjacent normal tissues from patients who underwent CRC surgical resection, and evaluated the interaction between cancer staging (advanced vs local) and DNA methylation to predict the prognosis of CRC. We recruited 132 patients with CRC from Tri-Service General Hospital in Taiwan and used the candidate gene approach to select 3 tumor suppressor genes involved in carcinogenesis pathways. ORs and 95% CIs were computed using logistic regression analyses while adjusting for potential covariates. Advanced cancer stage was correlated with cancer recurrence (OR 7.22, 95% CI 2.82 to 18.45; p<0.001). In addition, after stratification by promoter methylation in 3 combined genes in the matched normal tissues, we observed a joint effect after adjusting for sex, age at surgery, and adjuvant chemotherapy, yielding a significant OR of 20.35 (95% CI 4.16 to 99.57; p<0.001). DNA methylation status would significantly increase the recurrence risk of CRC with a significant impact on joint effect between DNA methylation and clinical stage, particularly in matched normal tissues. This was attributed to molecular changes that could not be examined on the basis of clinical pathology. Our interaction results may serve as a reference marker for evaluating the risk of recurrence in future studies.

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Progressive alteration of DNA methylation of Alu, MGMT, MINT2, and TFPI2 genes in colonic mucosa during colorectal cancer development

Cancer Biomarkers ◽

10.3233/cbm-203259 ◽

2021 ◽

pp. 1-6

Author(s):

Ben Kang ◽

Hyun Seok Lee ◽

Seong Woo Jeon ◽

Soo Yeun Park ◽

Gyu Seog Choi ◽

...

Keyword(s):

Colorectal Cancer ◽

Dna Methylation ◽

Healthy Subjects ◽

Large Scale ◽

Methylation Status ◽

Clinical Information ◽

Field Cancerization ◽

Aberrant Methylation ◽

Clinical Value ◽

Mortality And Morbidity

BACKGROUND: Colorectal cancer (CRC) is one of the leading causes of mortality and morbidity in the world. It is characterized by different pathways of carcinogenesis and is a heterogeneous disease with diverse molecular landscapes that reflect histopathological and clinical information. Changes in the DNA methylation status of colon epithelial cells have been identified as critical components in CRC development and appear to be emerging biomarkers for the early detection and prognosis of CRC. OBJECTIVE: To explore the underlying disease mechanisms and identify more effective biomarkers of CRC. METHODS: We compared the levels and frequencies of DNA methylation in 11 genes (Alu, APC, DAPK, MGMT, MLH1, MINT1, MINT2, MINT3, p16, RGS6, and TFPI2) in colorectal cancer and its precursor adenomatous polyp with normal tissue of healthy subjects using pyrosequencing and then evaluated the clinical value of these genes. RESULTS: Aberrant methylation of Alu, MGMT, MINT2, and TFPI2 genes was progressively accumulated during the normal-adenoma-carcinoma progression. Additionally, CGI methylation occurred either as an adenoma-associated event for APC, MLH1, MINT1, MINT31, p16, and RGS6 or a tumor-associated event for DAPK. Moreover, relatively high levels and frequencies of DAPK, MGMT, and TFPI2 methylation were detected in the peritumoral nonmalignant mucosa of cancer patients in a field-cancerization manner, as compared to normal mucosa from healthy subjects. CONCLUSION: This study identified several biomarkers associated with the initiation and progression of CRC. As novel findings, they may have important clinical implications for CRC diagnostic and prognostic applications. Further large-scale studies are needed to confirm these findings.

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Distinct epigenetic features of tumor-reactive CD8+ T cells in colorectal cancer patients revealed by genome-wide DNA methylation analysis

Genome Biology ◽

10.1186/s13059-019-1921-y ◽

2019 ◽

Vol 21 (1) ◽

Cited By ~ 4

Author(s):

Rui Yang ◽

Sijin Cheng ◽

Nan Luo ◽

Ranran Gao ◽

Kezhuo Yu ◽

...

Keyword(s):

Colorectal Cancer ◽

Dna Methylation ◽

T Cells ◽

T Cell ◽

Cancer Patients ◽

Cd8 T Cells ◽

Methylation Status ◽

Effector Memory ◽

Binding Motif ◽

Colorectal Cancer Patients

Abstract Background Tumor-reactive CD8+ tumor-infiltrating lymphocytes (TILs) represent a subtype of T cells that can recognize and destroy tumor specifically. Understanding the regulatory mechanism of tumor-reactive CD8+ T cells has important therapeutic implications. Yet the DNA methylation status of this T cell subtype has not been elucidated. Results In this study, we segregate tumor-reactive and bystander CD8+ TILs, as well as naïve and effector memory CD8+ T cell subtypes as controls from colorectal cancer patients, to compare their transcriptome and methylome characteristics. Transcriptome profiling confirms previous conclusions that tumor-reactive TILs have an exhausted tissue-resident memory signature. Whole-genome methylation profiling identifies a distinct methylome pattern of tumor-reactive CD8+ T cells, with tumor-reactive markers CD39 and CD103 being specifically demethylated. In addition, dynamic changes are observed during the transition of naïve T cells into tumor-reactive CD8+ T cells. Transcription factor binding motif enrichment analysis identifies several immune-related transcription factors, including three exhaustion-related genes (NR4A1, BATF, and EGR2) and VDR, which potentially play an important regulatory role in tumor-reactive CD8+ T cells. Conclusion Our study supports the involvement of DNA methylation in shaping tumor-reactive and bystander CD8+ TILs, and provides a valuable resource for the development of novel DNA methylation markers and future therapeutics.

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The Differential DNA Hypermethylation Patterns of microRNA-137 and microRNA-342 Locus in Early Colorectal Lesions and Tumours

Biomolecules ◽

10.3390/biom9100519 ◽

2019 ◽

Vol 9 (10) ◽

pp. 519

Author(s):

Elham Kashani ◽

Mahrooyeh Hadizadeh ◽

Vahid Chaleshi ◽

Reza Mirfakhraie ◽

Chris Young ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Patients ◽

Methylation Status ◽

Dna Hypermethylation ◽

Normal Colon Mucosa ◽

Normal Tissues ◽

Diagnosis And Prognosis ◽

Adjacent Mucosa ◽

Prediction And Prevention ◽

Colorectal Cancer Patients

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, representing 13% of all cancers. The role of epigenetics in cancer diagnosis and prognosis is well established. MicroRNAs in particular influence numerous cancer associated processes including apoptosis, proliferation, differentiation, cell-cycle controls, migration/invasion and metabolism. MiRNAs-137 and 342 are exon- and intron-embedded, respectively, acting as tumour-suppressive microRNA via hypermethylation events. Levels of miRNAs 137 and 342 have been investigated here as potential prognostic markers for colorectal cancer patients. The methylation status of miRNA-137 and miRNA-342 was evaluated using methylation-specific (MSP) polymerase chain reaction (PCR) on freshly frozen tissue derived from 51 polyps, 8 tumours and 14 normal colon mucosa specimens. Methylation status of miRNA-137 and miRNA-342 was significantly higher in tumour lesions compared to normal adjacent mucosa. Surprisingly, the methylation frequency of miR-342 (76.3%) among colorectal cancer patients was significantly higher compared to miR-137 (18.6%). Furthermore, normal tissues, adjacent to the lesions (N-Cs), displayed no observable methylation for miRNA-137, whereas 27.2% of these N-Cs showed miRNA-342 hypermethylation. MiRNA-137 hypermethylation was significantly higher in male patients and miR-342 hypermethylation correlated with patient age. Methylation status of miRNA-137 and miRNA-342 has both diagnostic and prognostic value in CRC prediction and prevention.

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Genome-wide analysis identifies critical DNA methylations within NTRKs genes in colorectal cancer

Journal of Translational Medicine ◽

10.1186/s12967-021-02740-6 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Zijian Chen ◽

Zenghong Huang ◽

Yanxin Luo ◽

Qi Zou ◽

Liangliang Bai ◽

...

Keyword(s):

Colorectal Cancer ◽

Dna Methylation ◽

Promoter Methylation ◽

Expression Profiles ◽

Methylation Status ◽

Gene Promoter ◽

Normal Mucosa ◽

Suppressor Gene ◽

Survival Outcome ◽

Prognostic Models

Abstract Background Neurotrophic tropomyosin receptor kinases (NTRKs) are a gene family function as oncogene or tumor suppressor gene in distinct cancers. We aimed to investigate the methylation and expression profiles and prognostic value of NTRKs gene in colorectal cancer (CRC). Methods An analysis of DNA methylation and expression profiles in CRC patients was performed to explore the critical methylations within NTRKs genes. The methylation marker was validated in a retrospectively collected cohort of 229 CRC patients and tested in other tumor types from TCGA. DNA methylation status was determined by quantitative methylation-specific PCR (QMSP). Results The profiles in six CRC cohorts showed that NTRKs gene promoter was more frequently methylated in CRC compared to normal mucosa, which was associated with suppressed gene expression. We identified a specific methylated region within NTRK3 promoter targeted by cg27034819 and cg11525479 that best predicted survival outcome in CRC. NTRK3 promoter methylation showed independently predictive value for survival outcome in the validation cohort (P = 0.004, HR 2.688, 95% CI [1.355, 5.333]). Based on this, a nomogram predicting survival outcome was developed with a C-index of 0.705. Furthermore, the addition of NTRK3 promoter methylation improved the performance of currently-used prognostic model (AIC: 516.49 vs 513.91; LR: 39.06 vs 43.64, P = 0.032). Finally, NTRK3 promoter methylation also predicted survival in other tumors, including pancreatic cancer, glioblastoma and stomach adenocarcinoma. Conclusions This study highlights the essential value of NTRK3 methylation in prognostic evaluation and the potential to improve current prognostic models in CRC and other tumors.

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Outcome of Radical Surgery for Simultaneous Liver and Lung Metastases Synchronous with Primary Colorectal Cancer

Indian Journal of Surgery ◽

10.1007/s12262-021-02848-5 ◽

2021 ◽

Author(s):

Franz Xaver Singhartinger ◽

Martin Varga ◽

Tarkan Jäger ◽

Adam Dinnewitzer ◽

Oliver Koch ◽

...

Keyword(s):

Colorectal Cancer ◽

Lung Metastases ◽

Primary Tumour ◽

Median Number ◽

R0 Resection ◽

Curative Intent ◽

Median Hospital Stay ◽

Free Survival ◽

Colorectal Cancer Patients ◽

Primary Tumour Site

Abstract Background Colorectal cancer (CRC) leads to metastatic disease in approximately 30% of patients. In patients with newly diagnosed CRC with both liver and lung metastases, curative resection is rarely possible. The aim of this study is to evaluate the overall (OS) and relapse-free survival (RFS) rates of these patients after resection with curative intent. Methods This study is a retrospective analysis of colorectal cancer patients (n=8, median age 54.3 years) with simultaneous liver and lung metastasis undergoing resection with curative intent between May 1st, 2002, to December 31st, 2016, at our institution. Results Colon was the primary tumour site in 2 patients and rectum in 6 patients. The median number of liver and lung metastases was 3 and 2, respectively. Patients received various treatment sequences individualized on tumour disease burden. R0 resection was achieved after all but one procedure. Two severe Clavien-Dindo grade IIIb complications were present. Median hospital stay was 9 (3–24) days per procedure. Tumour relapse was observed in all patients with median RFS of 9 (3–28) months and median OS of 40 (17–52) months. In 4 cases, where repeated resection of recurrent metastases (3 liver and 1 lung) was possible, the median OS was 43 months. Conclusion Our data suggests that patients seem to benefit from resection with curative intent, with tendency to prolonged OS and with acceptable complication rate. Tumour recurrence occurred in all patients. Repeated resection was beneficial and led to further prolonged OS.

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