Dataset Information

Tumor LINE-1 methylation level and colorectal cancer location in relation to patient survival.

ABSTRACT: Colorectal tumors arise with genomic and epigenomic alterations through interactions between neoplastic cells, immune cells, and microbiota that vary along the proximal to distal axis of colorectum. Long interspersed nucleotide element-1 (LINE-1) hypomethylation in colorectal cancer has been associated with worse clinical outcome. Utilizing 1,317 colon and rectal carcinoma cases in two U.S.-nationwide prospective cohort studies, we examined patient survival according to LINE-1 methylation level stratified by tumor location. Cox proportional hazards model was used to assess a statistical interaction between LINE-1 methylation level and tumor location in colorectal cancer-specific mortality analysis, controlling for potential confounders including microsatellite instability, CpG island methylator phenotype, and KRAS, BRAF, and PIK3CA mutations. A statistically significant interaction was found between LINE-1 methylation level and tumor location in colorectal cancer-specific mortality analysis (Pinteraction = 0.011). The association of LINE-1 hypomethylation with higher colorectal cancer-specific mortality was stronger in proximal colon cancers (multivariable hazard ratio [HR], 1.66; 95% confidence interval [CI], 1.21 to 2.28) than in distal colon cancers (multivariable HR, 1.18; 95% CI, 0.81 to 1.72) or rectal cancers (multivariable HR, 0.87; 95% CI, 0.57 to 1.34). Our data suggest the interactive effect of LINE-1 methylation level and colorectal cancer location on clinical outcome.

SUBMITTER: Mima K

PROVIDER: S-EPMC5342404 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Tumor LINE-1 methylation level and colorectal cancer location in relation to patient survival.

Mima Kosuke K Nowak Jonathan A JA Qian Zhi Rong ZR Cao Yin Y Song Mingyang M Masugi Yohei Y Shi Yan Y da Silva Annacarolina A Gu Mancang M Li Wanwan W Hamada Tsuyoshi T Zhang Xuehong X Wu Kana K Meyerhardt Jeffrey A JA Baba Hideo H Giovannucci Edward L EL Chan Andrew T AT Fuchs Charles S CS Ogino Shuji S Nishihara Reiko R

Oncotarget 20160801 34

Colorectal tumors arise with genomic and epigenomic alterations through interactions between neoplastic cells, immune cells, and microbiota that vary along the proximal to distal axis of colorectum. Long interspersed nucleotide element-1 (LINE-1) hypomethylation in colorectal cancer has been associated with worse clinical outcome. Utilizing 1,317 colon and rectal carcinoma cases in two U.S.-nationwide prospective cohort studies, we examined patient survival according to LINE-1 methylation level ...[more]

PMID: 27391152

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Project description:Recent studies suggest that long-interspersed nucleotide element-1 (LINE-1) hypomethylation is commonly found in colorectal cancer (CRC), and is associated with worse prognosis. However, the utility of LINE-1 methylation on the prognosis of CRC is still controversial, and may be due to the fact that some clinical and pathological features may affect LINE-1 methylation. Thus, the aim of this study was to assess the prognostic value of tumor LINE-1 methylation in CRC, through their association with the CRC clinical and pathological characteristics. Survival of sixty-seven CRC patients was evaluated according to the median of tumor LINE-1 methylation, as well as pathological and oncological variables. We also studied the association between LINE-1 methylation and pathological features, and finally, we assessed the overall and disease-free survival of LINE1 methylation, stratified by neoadjuvant treatment and further checked by multivariate Cox regression to assess the statistical interactions. LINE-1 was hypomethylated in the CRC tumor with respect to the tumor adjacent-free area (p < 0.05), without association with any other clinical and oncological features, nor with overall and disease-free survival rates for CRC. Relevantly, in neoadjuvant treatment, LINE-1 methylation was associated with survival rates. Thus, disease-free and overall survival rates of treated CRC patients were worse in the hypomethylated LINE-1 tumors than those with normal LINE-1 methylation (p = 0.004 and 0.0049, respectively). Indeed, LINE-1 was hypermethylated more in the treated patients than in the non-treated patients (p < 0.05). The present study showed that tumor LINE-1 hypomethylation was associated with worse survival rates in only treated patients. Our data suggest an interactive effect of neoadjuvant treatment and tumor LINE-1 methylation, which could be a specific-tissue biomarker to predict survival of the treated patients, and help to personalize treatment in CRC.

Project description:BackgroundLong interspersed nucleotide element 1 (LINE-1) hypomethylation is suggested to play a role in the progression of colorectal cancer (CRC). To assess intra-patient heterogeneity of LINE-1 methylation in CRC and to understand its biological relevance in invasion and metastasis, we evaluated the LINE-1 methylation at multiple tumor sites. In addition, the influence of stromal cell content on the measurement of LINE-1 methylation in tumor tissue was analyzed.MethodsFormalin-fixed paraffin-embedded primary tumor tissue was obtained from 48 CRC patients. Matched adjacent normal colon tissue, lymph node metastases and distant metastases were obtained from 12, 18 and 7 of these patients, respectively. Three different areas were microdissected from each primary tumor and included the tumor center and invasive front. Normal mucosal and stromal cells were also microdissected for comparison with the tumor cells. The microdissected samples were compared in LINE-1 methylation level measured by multicolor MethyLight assay. The assay results were also compared between microdissected and macrodissected tissue samples.ResultsLINE-1 methylation within primary tumors showed no significant intra-tumoral heterogeneity, with the tumor center and invasive front showing identical methylation levels. Moreover, no difference in LINE-1 methylation was observed between the primary tumor and lymph node and distant metastases from the same patient. Tumor cells showed significantly less LINE-1 methylation compared to adjacent stromal and normal mucosal epithelial cells. Consequently, LINE-1 methylation was significantly lower in microdissected samples compared to macrodissected samples. A trend for less LINE-1 methylation was also observed in more advanced stages of CRC.ConclusionsLINE-1 methylation shows little intra-patient tumor heterogeneity, indicating the suitability of its use for molecular diagnosis in CRC. The methylation is relatively stable during CRC progression, leading us to propose a new concept for the association between LINE-1 methylation and disease stage.

Project description:Purpose:KRAS mutations and tumor location have been associated with response to targeted therapy among patients with stage IV colorectal cancer (CRC) in various trials. This study performed the first population-based examination of associations between KRAS mutations, tumor location, and survival, and assessed factors associated with documented KRAS testing. Methods: Patients with stage IV adenocarcinoma of the colon/rectum diagnosed from 2010 to 2013 were extracted from SEER data. Analyses of patient characteristics, KRAS testing, and tumor location were conducted using logistic regression. Cox proportional hazards models assessed relationships between KRAS mutations, tumor location, and risk of all-cause death. Results: Of 22,542 patients, 30% received KRAS testing, and 44% of these had mutations. Those tested tended to be younger, married, and metropolitan area residents, and have private insurance or Medicare. Rates of KRAS testing also varied by registry (range, 20%-46%). Patients with right-sided colon cancer (vs left-sided) tended to be older, female, and black; have mucinous, KRAS-mutant tumors; and have a greater risk of death (hazard ratio [HR], 1.27; 95% CI, 1.22-1.32). KRAS mutations were not associated with greater risk of death in the overall population; however, they were associated with greater risk of death among patients with left-sided colon cancer (HR, 1.19; 95% CI, 1.05-1.33). Conclusions: This large population-based study showed that among patients initially diagnosed with stage IV CRC, right-sided colon cancer was associated with greater risk of death compared with left-sided cancer, and KRAS mutations were only associated with risk of death in left-sided colon cancer. An unexpected finding was that among patients with stage IV disease, right-sided cancer was more commonly seen in black patients versus whites. Future studies should further explore these associations and determine the role of biology versus treatment differences. In addition, use of KRAS testing is increasing, but there is wide geographic variation wherein disparities related to insurance coverage and rurality may warrant further study.

Project description:Objective: The location of the primary tumor in colorectal cancer (CRC) could be a prognostic factor related to survival. However, its usefulness has not been sufficiently analyzed. The results in patients with tumors in initial stages are very limited, and there are descriptive parameters of survival that have not been analyzed in detail. In this study, the relationship between primary tumor location and survival in CRC patients was analyzed. Materials And Methods: This was a retrospective observational study. All patients treated consecutively for CRC between January 2005 and December 2019 in the same hospital center were included. Overall survival (OS), cancer-related survival (CRS), time to recurrence (TTR), relapse-free survival (RFS) and postrecurrence survival (PRS) were analyzed, and the results were classified by tumor stage. The results were compared among patients with right colon (RS), left colon (LS) and rectal tumors. Results: In the entire cohort, patients with RS tumors had lower OS and lower CRS at 60 months after diagnosis than did patients with LS or rectal tumors. In the regression analysis, the localization of the primary tumor was an independent prognostic indicator for OS and CRS. Analysis by tumor stage showed that patients with RS stage III tumors had lower OS and lower CRS at 60 months than did patients with LS and rectal tumors (42%, 59% and 53%, respectively, p = 0.006; and 48%, 63% and 57%, respectively, p = 0.025). Additionally, patients with RS Stage IV tumors had lower OS and lower CRS at 36 months than did patients with LS and rectal tumors (9%, 24%, 24%, respectively, p < 0.001; and 10%, 24% and 24%, respectively, p < 0.001). No differences were found in TTR and RFS among patients with stage I and II RS, LS, and rectal tumors. In contrast, patients with stage RS III tumors had significantly poorer PRS (9% for RS tumors, 13% for LS tumors, and 22% for rectal tumors) (p < 0.001). Conclusion: The location of the primary tumor in patients with CRC is related to survival. The effect of laterality is more marked in patients with stage III and IV tumors. Patients with RS tumors had lower OS and CRS due to the lower survival of patients with stage IV RS tumors and lower PRS for patients with stage III tumors.

Dataset Information

Tumor LINE-1 methylation level and colorectal cancer location in relation to patient survival.

Publications

Tumor LINE-1 methylation level and colorectal cancer location in relation to patient survival.

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