scholarly journals An Apoptosis-Related Gene Prognostic Index for Colon Cancer

Author(s):  
Hanmin Tang ◽  
Jing Wang ◽  
Xuehui Luo ◽  
Qi Wang ◽  
Jie Chen ◽  
...  

Purpose: To construct an apoptosis-related gene prognostic index (ARGPI) for colon cancer, and clarify the molecular and immune characteristics of the risk subgroup as defined by the prognostic index and the benefits of adjuvant chemotherapy. Integrating the prognostic index and clinicopathological risk factors to better evaluate the prognosis of patients with colon cancer.Methods: Based on the colon adenocarcinoma data in the TCGA database, 20 apoptosis-related hub genes were screened by weighted gene co-expression network analysis (WGCNA). Five genes constituting the prognosis model were determined by Cox regression and verified by the Gene Expression Omnibus (GEO) dataset. Then the molecular and immune characteristics of risk subgroups defined by the prognostic index and the benefits of adjuvant chemotherapy were analyzed. Finally, nomograms integrating ARGPI and four clinicopathological risk factors were used to evaluate the prognosis of patients with colon cancer.Results: The ARGPI was constructed based on the FAS, VWA5A, SPTBN2, PCK1, and TIMP1 genes. In the TCGA cohort, patients in the low-risk subgroup had a longer progression-free interval (PFI) than patients in the high-risk subgroup, which coincided with the results of the GEO cohort. The comprehensive results showed that the high-risk score was related to the enrichment of the cell cycle pathway, high mutation rate of TP53 and KRAS, high infiltration of T regulatory cells (Tregs), immunosuppressive state, and less chemotherapeutic benefit. However, low-risk scores are related to drug metabolism-related pathways, low TP53 and KRAS mutation rates, high infiltration of plasma cells, more resting CD4 memory cells and eosinophils, active immune function, and better chemotherapeutic benefits. Receiver operating characteristic curve of two-year progress prediction evaluation showed that the ARGPI had higher prognostic accuracy than TNM staging. Nomograms integrating ARGPI and clinicopathological risk factors can better evaluate the prognosis of patients with colon cancer.Conclusions: The ARGPI is a promising biomarker for determining risk of colon cancer progression, molecular and immune characteristics, and chemotherapeutic benefit. This is a reliable method to predict the prognosis of colon cancer patients. It also can assist doctors in formulating more effective treatment strategies.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 118-118
Author(s):  
Ofer Margalit ◽  
Ben Boursi ◽  
Manel Rakez ◽  
Thierry André ◽  
Greg Yothers ◽  
...  

118 Background: The IDEA pooled analysis compared 3 to 6 months of adjuvant chemotherapy for stage III colon cancer. The overarching goal was to reduce chemotherapy-related toxicity, mainly oxaliplatin-induced neuropathy. Patients were classified into low-risk and high-risk, suggesting low-risk patients may be offered only 3 months of treatment. In our previously published analysis using retrospective data from the National Cancer Database (NCDB) we showed similar benefit for oxaliplatin in both low and high IDEA risk groups. In the current study, we aimed to test our hypothesis using data from the two large clinical trials assessing the benefit of oxaliplatin in the adjuvant setting, namely, MOSAIC and C-07. Methods: Using the MOSAIC and C-07 previously published studies, we identified 1,754 low-risk and 1,302 high-risk individuals with stage III colon cancer, according to the IDEA classification. We used multivariate COX regression to evaluate the magnitude of survival differences between IDEA risk groups, according to oxaliplatin use. The analysis was adjusted for age, primary tumor sidedness, tumor stage, tumor grade and lymph node ratio. Results: Individuals with IDEA low-risk derived overall survival (OS), disease-free survival (DFS) and recurrence-free survival (RFS) benefit from the addition of oxaliplatin to adjuvant chemotherapy, with adjusted hazard ratios (HRs) of 0.78 (0.65-0.94), 0.75 (0.63-0.89) and 0.74 (0.62-0.90). Similarly, individuals with IDEA high-risk derived OS, DFS and RFS benefit from the addition of oxaliplatin to adjuvant chemotherapy, with adjusted HRs of 0.84 (0.71-0.99), 0.81 (0.69-0.95) and 0.82 (0.69-0.97). Conclusions: IDEA risk classification per se does not predict benefit from addition of oxaliplatin to adjuvant chemotherapy in stage III colon cancer, according to analysis of the MOSAIC and C-07 studies. Funding: NCI U10CA-180868, NCI U10CA-180822.


2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Dakui Luo ◽  
Zezhi Shan ◽  
Qi Liu ◽  
Sanjun Cai ◽  
Qingguo Li ◽  
...  

A metabolic disorder is considered one of the hallmarks of cancer. Multiple differentially expressed metabolic genes have been identified in colon cancer (CC), and their biological functions and prognostic values have been well explored. The purpose of the present study was to establish a metabolic signature to optimize the prognostic prediction in CC. The related data were downloaded from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx) database, and Gene Expression Omnibus (GEO) combined with GSE39582 set, GSE17538 set, GSE33113 set, and GSE37892 set. The differentially expressed metabolic genes were selected for univariate Cox regression and lasso Cox regression analysis using TCGA and GTEx datasets. Finally, a seventeen-gene metabolic signature was developed to divide patients into a high-risk group and a low-risk group. Patients in the high-risk group presented poorer prognosis compared to the low-risk group in both TCGA and GEO datasets. Moreover, gene set enrichment analyses demonstrated multiple significantly enriched metabolism-related pathways. To sum up, our study described a novel seventeen-gene metabolic signature for prognostic prediction of colon cancer.


2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4036-4036
Author(s):  
A. M. Glas ◽  
P. Roepman ◽  
R. Salazar ◽  
G. Capella ◽  
V. Moreno ◽  
...  

4036 Background: Between 25 and 35% of stage II CRC patients will experience a recurrence of their disease and may benefit from adjuvant chemotherapy. Official guidelines give suggestions but no clear recommendation for best risk stratification. Here we describe the development a robust signature that predicts disease relapse and can assist in treatment decisions. Methods: Fresh frozen tumor tissues from 180 patients with stage I, II and III colorectal cancer undergoing surgery were analyzed using high density Agilent 44K oligonucleotide arrays. Median FU was 70.2 months; 85% of patients did not receive adjuvant chemotherapy. Unsupervised hierarchical clustering based on full-genome gene expression measurement indicated the existence of 3 main colon molecular subclasses. Survival analysis of the 3 classes showed that subtype C (n= 27) had a poor outcome and subtype A (n= 48) good outcome. Only the intermediate group B (n=104) was used to develop a signature by using a cross validation procedure to score all genes for their association with 5-yr distant metastasis free survival (DMFS) and subsequently applied to all samples (n=180). The obtained gene signature was further validated on an independent cohort of 178 stage II + III colon samples. Results: A set of 38 prognosis related gene probes showed robust DMFS association in over 50% of all iterations in the Training Set of 180 samples. The gene signature was validated on an independent cohort of 178 samples from stage II + III colon cancer patients. The profile classified 61% of the validation samples as low-risk and 39% as high-risk. The low- and high-risk samples showed a significant difference in DMFS with a HR of 3.19 (P= 8.5e-4). Five-year DMFS rates were 89% (95%CI 83–95) for low-risk and 62% (95%CI 50–77) for high-risk samples. Moreover, the profile showed a significant performance within stage II (P=0.0058) and III (P=0.036) only samples. The performance of the profile was significant for both untreated (P=0.0082) and treated patients (P=0.016) suggesting that its power is independent of treatment benefits. Conclusions: ColoPrint is able to predict the prognosis of stage II and III colon cancer patients and facilitates the identification of patients who would benefit from adjuvant chemotherapy. [Table: see text]


2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 378-378 ◽  
Author(s):  
Scott Kopetz ◽  
Zhi-Qin Jiang ◽  
Michael J. Overman ◽  
Christa Dreezen ◽  
Sun Tian ◽  
...  

378 Background: Although the benefit of chemotherapy in stage II and III colon cancer patients is significant, many patients might not need adjuvant chemotherapy because they have a good prognosis even without additional treatment. ColoPrint is a gene expression classifier that distinguish patients with low or high risk of disease relapse. It was developed using whole genome expression data and has been validated in public datasets, independent European patient cohorts and technical studies (Salazar 2011 JCO, Maak 2012 Ann Surg). Methods: In this study, the commercial ColoPrint test was validated in stage II (n=96) and III patients (n=95) treated at the MD Anderson Cancer Center from 2003 to 2009. Frozen tissue specimen, clinical parameters, MSI-status and follow-up data (median follow-up 64 months) were available. The 64-gene MSI-signature developed to identify patients with deficient mismatch repair system (Tian 2012 J Path) was evaluated for its accuracy to identify MSI patients and also for prognosis. Results: In this cohort, ColoPrint classified 56% of stage II and III patients as being at low risk. The 3-year Relapse-Free-Survival (RFS) was 90.6% for Low Risk and 78.4% for High Risk patients with a HR of 2.33 (p=0.025). In uni-and multivariate analysis ColoPrint and stage were the only significant factors to predict outcome. The MSI-signature classified 47 patients (24.6%) as MSI-H and most MSI-H patients were ColoPrint low risk (81%). Patients who were ColoPrint low risk and MSI-H by signature had the best outcome with a 3-year RFS of 95% while patients with ColoPrint high risk had a worse outcome independently of the MSI-status. Low risk ColoPrint patients had a good outcome independent of stage or chemotherapy treatment (90.1% 3-year RFS for treated patients, 91.4% for untreated patients) while ColoPrint high risk patients treated with adjuvant chemotherapy had 3-year RFS of 84%, compared to 70.1% 3-year RFS in untreated patients (p=0.026). Conclusions: The combination of ColoPrint and MSI-Print improves the prognostic accuracy in stage II and stage III patients and may help the identification of patients at higher risk who are more likely to benefit from additional treatment


2021 ◽  
Vol 12 ◽  
Author(s):  
Qian Zhang ◽  
Liping Lv ◽  
Ping Ma ◽  
Yangyang Zhang ◽  
Jiang Deng ◽  
...  

BackgroundPancreatic adenocarcinoma (PAAD) spreads quickly and has a poor prognosis. Autophagy research on PAAD could reveal new biomarkers and targets for diagnosis and treatment.MethodsAutophagy-related genes were translated into autophagy-related gene pairs, and univariate Cox regression was performed to obtain overall survival (OS)-related IRGPs (P<0.001). LASSO Cox regression analyses were performed to construct an autophagy-related gene pair (ARGP) model for predicting OS. The Cancer Genome Atlas (TCGA)-PAAD cohort was set as the training group for model construction. The model predictive value was validated in multiple external datasets. Receiver operating characteristic (ROC) curves were used to evaluate model performance. Tumor microenvironments and immune infiltration were compared between low- and high-risk groups with ESTIMATE and CIBERSORT. Differentially expressed genes (DEGs) between the groups were further analyzed by Gene Ontology biological process (GO-BP) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses and used to identify potential small-molecule compounds in L1000FWD.ResultsRisk scores were calculated as follows: ATG4B|CHMP4C×(-0.31) + CHMP2B|MAP1LC3B×(0.30) + CHMP6|RIPK2 ×(-0.33) + LRSAM1|TRIM5×(-0.26) + MAP1LC3A|PAFAH1B2×(-0.15) + MAP1LC3A|TRIM21×(-0.08) + MET|MFN2×(0.38) + MET|MTDH×(0.47) + RASIP1|TRIM5×(-0.23) + RB1CC1|TPCN1×(0.22). OS was significantly shorter in the high-risk group than the low-risk group in each PAAD cohort. The ESTIMATE analysis showed no difference in stromal scores but a significant difference in immune scores (p=0.0045) and ESTIMATE scores (p=0.014) between the groups. CIBERSORT analysis showed higher naive B cell, Treg cell, CD8 T cell, and plasma cell levels in the low-risk group and higher M1 and M2 macrophage levels in the high-risk group. In addition, the results showed that naive B cells (r=-0.32, p<0.001), Treg cells (r=-0.31, p<0.001), CD8 T cells (r=-0.24, p=0.0092), and plasma cells (r=-0.2, p<0.026) were statistically correlated with the ARGP risk score. The top 3 enriched GO-BPs were signal release, regulation of transsynaptic signaling, and modulation of chemical synaptic transmission, and the top 3 enriched KEGG pathways were the insulin secretion, dopaminergic synapse, and NF-kappa B signaling pathways. Several potential small-molecule compounds targeting ARGs were also identified.ConclusionOur results demonstrate that the ARGP-based model may be a promising prognostic indicator for identifying drug targets in patients with PAAD.


2020 ◽  
Vol 4 (22) ◽  
pp. 5762-5771
Author(s):  
Ho-Young Yhim ◽  
Yael Eshet ◽  
Ur Metser ◽  
Chae-Hong Lim ◽  
Katherine Lajkosz ◽  
...  

Abstract There are limited data regarding the combined value of the pretransplant Deauville score (DS) from a positron emission tomography scan and clinical risk factors in patients with relapsed/refractory aggressive non-Hodgkin lymphoma (NHL). We performed a retrospective analysis to assess the prognostic role of pretransplant DS in patients with relapsed/refractory aggressive NHL who underwent salvage chemotherapy and autologous stem cell transplantation (ASCT). We identified 174 eligible patients between January 2013 and March 2019. In multivariable analysis, pretransplant DS, B symptoms, and secondary International Prognostic Index (sIPI) were independent risk factors for event-free survival (EFS). These variables were used to derive an integrated risk score that categorized 166 patients with available information for all risk factors into 3 groups: low (n = 92; 55.4%), intermediate (n = 48; 28.9%), and high (n = 26; 15.7%). The new prognostic index showed a strong association with EFS (low-risk vs intermediate-risk hazard ratio [HR], 3.94; 95% confidence interval [CI], 2.16-7.17; P < .001; low-risk vs high-risk HR, 10.83; 95% CI, 5.81-20.19; P < .001) and outperformed models based on clinical risk factors or DS alone. These results were validated in 60 patients from an independent external cohort (low-risk vs intermediate-risk HR, 4.04; 95% CI, 1.51-10.82; P = .005; low-risk vs high-risk HR, 10.49; 95% CI, 4.11-26.73; P < .001). We propose and validate a new prognostic index that risk-stratifies patients undergoing salvage chemotherapy followed by ASCT, thereby identifying patients at high risk for posttransplant treatment failure.


2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15139-e15139
Author(s):  
M. Piperdi ◽  
V. Velagapudi ◽  
G. Ayata ◽  
J. Simons ◽  
J. F. Tseng ◽  
...  

e15139 Background: Preop-CRT followed by surgical resection is the standard for LARC. LARC patients (pts) treated with preop-CRT have 60–70% 5-year survival. Several pathologic features including T stage (yT), lymph node (N) ratio (# of positive N (Np) / # of N examined (Ne)) and tumor regression grade (TRG) have been shown to be independent prognostic markers. We developed a prognostic score to determine pts with low risk of recurrence after preop-CRT. Methods: Our sample set consists of 20 pts treated on in house trial of preop-CRT with paclitaxel. All pts had R0 resections and received 4 months of 5-FU based adjuvant chemotherapy. All pathology slides were independently reviewed by GI pathologist. RPI scale of -4 to 14 was developed based on the formula: RPI = T (1–4) + (Np/Ne x 10) - TRG (0–4). The low, intermediate and high risk for recurrence were predefined as RPI (≤1), (>1 and <5), (≥5). Results: Between 1999–2003, 20 pts were treated on the trial and had R0 resection. The data is summarized in table 1 . The 5yr disease-free (DFS) and overall survival (OS) rate of all pts were 62 and 77%. Two pts (10%) achieved complete pathological response. Low, intermediate and high risk RPI was noted in 50, 35, and 15 % of pts. The 5yr DFS and OS for low, intermediate and high risk groups were 75, 42, 33 % and 86, 71 and 33% respectively.Conclusions: RPI can accurately predict a subset of pts with low risk of recurrence after preop-CRT. Majority of pts in this cohort have low risk RPI and have a favorable outcome (5yr survival rate of 86%). RPI could be very helpful in designing future trials tailoring adjuvant chemotherapy based on risk of recurrence. We are validating this data with a larger, independent group of LARC patients from our cancer registry (N=30) and this data will be available for presentation. Since RPI only requires the final pathology after CRT, it should be readily reproducible in future prospective studies across different institutions. [Table: see text] No significant financial relationships to disclose.


2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 156-156
Author(s):  
Pengfei Yu

156 Background: Postoperative adjuvant chemotherapy was beneficial for some patients,however, it may increase the treatment burden and reduce the immunity of other patients. Screening appropriate patients based on molecular markers for individualized adjuvant chemotherapy was necessary. Methods: Between June 2002 to June 2004, 119 patients who underwent radical gastrectomy were retrospectively analyzed. 61 patients had adjuvant chemotherapy based on platinum and 5-FU for 4 to 6 cycles. ToPo II negative, MRP positive and GST-π positive were regarded as three risk factors which may be associated with chemotherapy resistance and poor prognosis. Patients were divided into two groups: high-risk group (≥2 risk factors) and the low-risk group (<2 risk factors), and the tumor recurrence and patients’ survival time of the two groups were analyzed. Results: The average recurrence time of the low-risk group was significantly longer than that of the high-risk group (21.29 ± 11.10 VS 15.16 ± 8.05 months ,p<0.01).The 3-year and 5-year survival rate of the high-risk group was 57.4% and 42.6%, however, it had no significant difference compared to 66.2% and 58.5% of the low-risk group (P> 0.05). In the high-risk group, the 3-year survival rate of patients with/without chemotherapy were 62.1% and 52.0%, 5-year survival rates were 44.8% and 40.0%, but the difference was not statistically significant (P> 0.05). In the low-risk group, the 3-year survival rate of patients with/without chemotherapy were 81.2% and 51.5%, 5-year survival rates were 71.9% and 45.5%, and the difference was statistically significant (p<0.05). Conclusions: Combined determination of MDR-related proteins ToPo II, MRP and GST-π may be prospectively valuable for optimizing the chemotherapy regimes, and further predicting the outcomes of gastric cancer patients.


2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 845-845
Author(s):  
Ofer Margalit ◽  
Ronac Mamtani ◽  
Yu-Xiao Yang ◽  
Kim Anna Reiss ◽  
Talia Golan ◽  
...  

845 Background: The IDEA pooled analysis compared 3 to 6 months of adjuvant chemotherapy for newly defined low- and high-risk stage III colon cancer patients, suggesting low-risk patients may be offered only 3 months of treatment. We aimed to evaluate the benefit of monotherapy vs doublet chemotherapy in low and high IDEA risk groups. Methods: Using the NCDB (2004-2014) we identified 56,728 and 47,557 individuals as low and high IDEA risk groups, respectively. We used multivariate COX regression to evaluate the magnitude of survival differences between IDEA risk groups, according to treatment intensity (doublet vs monotherapy). In a secondary analysis, we examined the predictive value of subgroups of age. Results: Low and high IDEA risk groups derived similar benefit from doublet chemotherapy compared to monotherapy, with hazard ratios of 0.83 (95%CI 0.79-0.86) and 0.80 (95%CI 0.78-0.83), respectively. The only subpopulations that did not benefit from doublet chemotherapy were low-risk patients above the age of 72 (HR = 0.95, 95%CI 0.90-1.01) and high-risk patients above the age of 85 (HR = 0.90, 95%CI 0.77-1.05). Conclusions: IDEA risk classification does not predict benefit from doublet chemotherapy in stage III colon cancer. However, omission of oxaliplatin can be considered in IDEA low-risk patients above the age of 72.


2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 620-620
Author(s):  
Jianmin Xu ◽  
Qingyang Feng ◽  
Wenju Chang ◽  
Ye Wei ◽  
Li Ren ◽  
...  

620 Background: For stage II colon cancer, the effect of postoperative adjuvant chemotherapy is still controversial. It is well known that tumor-associated macrophages (TAMs) play an important role in tumor progression. The aim of this study is to determine the effect of TAMs as predictor for adjuvant chemotherapy for stage II colon cancer. Methods: From July 2009 to June 2012, 521 patients with pathological stage II colon cancer were included. TAMs were detected using tissue microarray and immunohistochemistry (all TAMs detected by CD68; M2 subtype detected by CD206). The density of CD68+ TAMs, CD206+ TAMs and the ratio of CD206+ TAMs / CD68+ TAMs (CD206 / CD68 ratio) were calculated. The cut-off values were defined using X-Tile software. Results: High CD206+ TAMs density and high CD206 / CD68 ratio were significantly associated with reduced disease-free survival (DFS, P < 0.001 and P < 0.001, respectively) and overall survival (OS, P < 0.001 and P < 0.001, respectively). And CD206 / CD68 ratio had a better prognostic power. Furthermore, for patients with low CD206 / CD68 ratio, adjuvant chemotherapy made no benefit. But for high CD206 / CD68 ratio, adjuvant chemotherapy significantly improved DFS and OS (as shown in Table 1). In subgroup analysis, for T3 with high-risk factors or T4 tumors, CD206 / CD68 ratio was also a significant predictor for adjuvant chemotherapy (interaction P = 0.024 in DFS). Conclusions: For stage II colon cancer, CD206 / CD68 ratio was a good prognostic and predictive biomarker for adjuvant chemotherapy. Together with clinicopathological high-risk factors, it might facilitate patient counselling and individualise management. [Table: see text]


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