Expression and methylation profiles associated with recurrent mutations in stage II colorectal cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e14613-e14613
Author(s):  
Laia Pare-Brunet ◽  
Rebeca Sanz-Pamplona ◽  
Adriana Lopez-Doriga ◽  
Antoni Berenguer-Llergo ◽  
Susanna Ausso ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Methylation ◽  
Molecular Subtypes ◽  
Expression Patterns ◽  
Stage Ii ◽  
Molecular Heterogeneity ◽  
Rna Expression ◽  
Gene Methylation ◽  
Recurrent Mutations ◽  
Combining Data

e14613 Background: Aberration of normal genetic and epigenetic patterns occurs at early stages of colorectal cancer (CRC) and accumulates throughout cancer progression. To characterize pre-metastatic tumors, a series of stage II, microsatellite stable, colon tumors and their paired mucosa were profiled on RNA expression and DNA methylation microarrays ( www.colonomics.org ). Our aim is to define molecular subtypes based on recurrent gene mutations, methylation and expression profiles, and explore if these molecular subtypes are associated to patients’ prognosis. Methods: We have sequenced exomes (Illumina Genome Analyzer) of a subset of 42 COLONOMICS normal-tumor paired samples (21 good and 21 bad prognosis). Variants identified in normal tissue were used to filter SNPs. DNA methylation (Infinium Human Methylation 450k) and RNA expression (Affymetrix U219) data from those samples were used in this analysis. Correlation was used to assess the association between tumor mutations and differentially expressed/methylated genes. Significant genes were subsequently used to perform tumor clustering. Results: Exome analysis revealed a mean of 150 somatic mutations per sample. From these, 12 variants were recurrently mutated (KRAS, TP53, etc) in more than 3 tumors that were used to define tumor subtypes based on gene methylation/expression patterns. We obtained 12 profiles that clearly identified the cluster of mutated samples. For some profiles, the cluster only includes those tumors with the mutation. Interestingly, some clusters included the mutated samples and additional tumors showing the same phenotype despite not having the mutation. For each mutation, the overlapping between the differently methylated/expressed genes ranged from 14 to 200 common genes. When combining data from the three platforms two main CRC molecular subtypes emerge; each of which shows molecular heterogeneity but no association with prognosis. Conclusions: Mutational status is associated with gene methylation and expression patterns in CRC patients. Although none of these clusters was associated with prognosis, different groups of tumors could be related to distinctive pathways, which may reveal useful as therapeutic targets.

scholarly journals Expression Patterns of Microenvironmental Factors and Tenascin-C at the Invasive Front of Stage II And III Colorectal Cancer: Novel Tumor Prognostic Markers

2021 ◽  
Author(s):  
Mai Hashimoto ◽  
Noriyuki Uesugi ◽  
Mitsumasa Osaka ◽  
Naoki Yanagawa ◽  
Koki Otsuka ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Prognostic Markers ◽  
Multivariate Analyses ◽  
Expression Patterns ◽  
Stage Ii ◽  
High Expression ◽  
Disease Stage ◽  
Neoplastic Progression ◽  
Tenascin C

Abstract Background. Biological markers expressed in cancer cells and the surrounding cancer-associated fibroblasts (CAF) can be used for prediction of patient prognosis in colorectal cancer (CRC). Here, we used immunohistochemical techniques to evaluate cancer cells’ expression of specific biomarkers that are closely associated with neoplastic progression. Patients and Methods. Immunohistochemical markers included Ki-67, p53, β-catenin, MMP7, E-cadherin and HIF1-α. We also characterized microenvironmental markers expressed by CAF, including expression of α-smooth muscle actin, CD10, podoplanin, fibroblast specific protein 1, platelet derived growth factor β, fibroblast association protein, tenascin-C (TNC), ZEB1 and TWIST1. The study population consisted of 286 CRC patients with stage II and III disease. Stage II and III CRC were divided into a first and a second cohort (for validation). The CRCs were stratified using cluster analysis. To identify the utility of prognostic markers in stage II and III CRC, univariate and multivariate analyses were performed in both cohorts. Results. Stage II and III CRCs were stratified into 3 subgroups. Specific subgroups were significantly correlated to disease-free survival using univariate and multivariate analyses in the first cohort. High expression of TNC was identified as a single prognostic marker in both cohorts by univariate and multivariate analyses. Conclusions. We suggest that the presence of a specific subgroup defined by multiple markers can be used for prediction of CRC outcome in stages II and III. In addition, we showed that high expression of TNC was correlated with a poorer prognosis in stages II and III of CRC.

A panel of DNA methylation markers for the classification of consensus molecular subtypes 2 and 3 in patients with colorectal cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3545-3545
Author(s):  
Inge van Den Berg ◽  
Marcel Smid ◽  
Robert R.J. Coebergh van den Braak ◽  
Mark A van de Wiel ◽  
Carolien H. M. Van Deurzen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Methylation ◽  
Prediction Models ◽  
Molecular Subtypes ◽  
Cpg Island ◽  
Methylation Marker ◽  
Marker Selection ◽  
Fresh Frozen ◽  
Classification Tool

3545 Background: Consensus molecular subtypes (CMSs) can guide precision treatment of colorectal cancer (CRC). Currently available assays can identify CMS1 and CMS4 cases well, while a dedicated test to distinguish CMS2 and 3 is lacking. This study aimed to identify a panel of methylation markers to distinguish between CMS2 and 3 in patients with CRC. Methods: Fresh-frozen tumor tissue of 239 patients with stage I-III CRC was included. CMS classification was performed on RNA-seq data using the single-sample-prediction parameter from the “CMSclassifier” package. Methylation profiles were obtained using the Infinium HumanMethylation450 BeadChip. We performed adaptive group-regularised logistic ridge-regression with post-hoc group-weighted elastic net marker selection to build prediction models for classification of CMS2 and CMS3 based on 15, 10 or 5 markers. Data from TCGAwas used for validation. Results: Overall methylation profiles differed between CMS2 and CMS3. Group-regularisation of the probes was done based on their location either relative to a CpG island or relative to a gene present in the CMS classifier resulting in two different prediction models and subsequently different marker panels. For both panels, even when using only 5 markers, sensitivity, specificity, and accuracy were > 90%. Validation showed comparable performances. Conclusions: Our highly sensitive and specific methylation marker panel can be used to distinguish CMS2 and 3. This enables development of a qPCR DNA methylation assay in patients with CRC to provide a specific and non-invasive classification tool.

Stratification of patients with colorectal cancer of UICC stage II using prognostic mutations signatures obtained by deep amplicon sequencing of cancer genes.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 377-377
Author(s):  
Andre Rosenthal ◽  
Karsten Ridwelski ◽  
Frank Marusch ◽  
Matthias Pross ◽  
Rene Mantke ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adjuvant Therapy ◽  
Deep Sequencing ◽  
Predictive Value ◽  
Amplicon Sequencing ◽  
Stage Ii ◽  
Rna Expression ◽  
Uicc Stage ◽  
Cancer Genes ◽  
Primary Tumors

377 Background: Assignment of patients (pts) with UICC-stage II colorectal cancer (CRC) to adjuvant therapy remains controversial. The clinical utility of histo-pathological parameters (pT4, L+, V+) as well as tumor RNA expression signatures like Oncotype Dx Colon Cancer Assay, ColoPrint, or Predictor C is low given their positive predictive value (PPV) of 0.13, 0.22, 0.19, and 0.33, respectively, when adjusted to an incidence of 10% for occurrence of metastatic disease (mets) within 3 years after diagnosis. Methods: We applied deep amplicon sequencing of 48 well-known cancer genes to DNA samples of primary tumors from 173 pts with UICC-stage II CRC using the Illumina MiSeq technology. Patients were selected from a prospective, multicenter clinical diagnostic study named MSKK. More than 6,500 patients with CRC have been recruited into this study conducted by 39 hospitals in Germany. 79 of the 173 pts had progression of disease events within 3 years after R0 resection including 40 pts with mets, 12 pts with local recurrences, and 27 pts with secondary malignancies. 94 pts remained progression-free. Results: Deep sequencing revealed a total of 2,221 sequence variations (SV) including missense, stop, InDel, noncoding, nonsense SV. 401 SV were in COSMIC, 750 SV in normal tissue. The remaining 1471 SV served as basis for development of SV-signatures (SVS) for prediction of progression events in a classical double-nested bootstrap approach in order to generate second order unbiased estimates of performance of SVS, namely sensitivity(S+), specificity (S-), PPV, and negative predictive value (NPV). The best SVS for prediction of metastases contained SV in less than 15 genes and has a S+ of 0.41, S- of 0.93, PPV of 0.40, and NPV of 0.93 (incidence of metastasis: 10%). The best SVS for prediction any progression event has a S+ of 0.33, S- of 0.93, PPV of 0.54, and NPV of 0.84 (incidence for any progression = 20.5%). Conclusions: This deep sequencing based prognostic tissue test with a PPV of 40% and a NPV of 93% represents a milestone over prognostic tests based on RNA expression. The increased PPV leads to more patients being treated correctly with adjuvant therapy.

Regulation of gene expression by DNA methylation with cytotoxic T lymphocytes evaluation in consensus molecular subtypes of colorectal cancer.

2020 ◽  
Vol 38 (5_suppl) ◽  
pp. 25-25
Author(s):  
Yuanyuan Shen ◽  
Justin Hummel ◽  
Isabel Cristina Trindade ◽  
Christos Papageorgiou ◽  
Chi-Ren Shyu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Dna Methylation ◽  
Molecular Subtypes ◽  
Epigenetic Modification ◽  
Pearson Correlation ◽  
Critical Role ◽  
Regulation Of Gene Expression ◽  
The Cancer Genome Atlas ◽  
Highly Correlated

25 Background: Low cytotoxic T lymphocyte (CTLs) infiltration in colorectal cancer (CRC) tumors is a challenge to treatment with immune checkpoint inhibitors. Consensus molecular subtypes (CMS) classify patients based on tumor attributes, and CMS1 patients include the majority of patients with high CTL infiltration and “inflamed” tumors. Epigenetic modification plays a critical role in gene expression and therapy resistance. Therefore, in this study we compared DNA methylation, gene expression, and CTL infiltration of CMS1 patients to other CMS groups to determine targets for improving immunotherapy in CRC. Methods: RNA-seq (n = 511) and DNA methylation (n = 316) from The Cancer Genome Atlas databases were used to determine gene expression and methylation profiles based on CMSs. CMS1 was used as a reference and compared to other subtypes (CMS2-4). Microenvironment Cell Populations- counter (MCPcounter) was used to determine tumor CTL infiltration. Genes with significantly different expression (p < 0.01, LogFC≥|1.5|) and difference of mean methylation β value ≥|0.25| were integrated for Pearson correlation coefficient analysis with MCPcounter score (r > |0.7|). Results: Comparing CMS1 and CMS2, ARHGAP9, TBX21, and LAG3 were differentially methylated and correlated with CTL scores. ARHGAP9 and TBX21 were decreased and hypomethylated in CMS2. Comparing CMS1 and CMS3, ARHGAP9, TBX21, FMNL1, HLA-DPB1, and STX11 were downregulated in CMS3 and highly correlated with CTL scores. ARHGAP9, FMNL1, HLA-DPB1, and STX11 were hypomethylated in CMS3 and TBX21 was methylated in both, but had a higher methylation ratio in CMS1. Comparing CMS1 and CMS4, TBX21 was the only gene downregulated, hypomethylated, and highly correlated with CTL scores in CMS4 patients. Conclusions: We found six genes differentially expressed, differentially methylated, and highly correlated with CTL infiltration when comparing CMS1 to other CMS groups. Specifically, TBX21 was the only gene highly correlated with CTL scores with differential gene expression and methylation in CMS2-4 when compared to CMS1. Thus, T-bet may be a critical regulator of T cell responses in CRC.

Tumor sidedness and intrinsic subtypes in patients with stage II/III colon cancer: Analysis of NSABP C-07 (NRG Oncology).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3514-3514 ◽  
Author(s):  
S. Rim Kim ◽  
Nan Song ◽  
Greg Yothers ◽  
Patrick Gavin ◽  
Carmen Joseph Allegra ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Therapy Response ◽  
Stage Ii ◽  
Intrinsic Subtypes ◽  
Treatment Benefit ◽  
Cancer Subtypes ◽  
Metastatic Setting

3514 Background: The predictive value of tumor sidedness in colorectal cancer is currently of interest especially in metastatic setting for anti-EGFR therapy response. We tested whether intrinsic molecular subtype classification predictive of treatment benefit in stage II/III colon cancer is an independent novel marker in association with tumor sidedness. Methods: All available cases included in the NSABP/NRG C-07 trial for which we had both gene expression data and anatomical data (n=1603) were used to determine the molecular subtypes using the following classifiers; the Colorectal Cancer Assigner (CRCA), the Colon Cancer Subtypes (CCS) and the Consensus Molecular Subtypes (CMS). Frequency of tumor sidedness in each subtype and recurrence-free survival were analyzed. Results: Intrinsic subtypes were differentially distributed in right- and left-colon tumors with the exception of the stem-like or CMS4 (mesenchymal) subtype (Table 1). Sidedness was not associated with prognosis (p=0.82, HR: 1.022 [CI: 0.851-1.227]) or prediction of patients with greater benefit from oxaliplatin when combined with 5-Fu+LV (interaction p=0.484). Conclusions: Although tumor sidedness is associated with distribution of intrinsic subtypes in stage II/III colon cancer, it is not predictive of survival benefit from oxaliplatin in C-07. Support: -180868, -180822, U24-CA196067; HI13C2162; PA DOH; Sanofi-Synthelabo Clinical trial information: NCT00004931. [Table: see text]

Muscle invasive bladder cancer (MIBC) demonstrates neoadjuvant cisplatin-based chemotherapy (NAC) related changes in molecular subtype and immune infiltration.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 443-443
Author(s):  
Samuel Aaron Funt ◽  
Alexander Solovyov ◽  
Bishoy Morris Faltas ◽  
Gopa Iyer ◽  
Mariel Elena Boyd ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Bladder Tumor ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Expression Patterns ◽  
The Cancer Genome Atlas ◽  
Rna Expression ◽  
Cancer Therapies ◽  
Primary Bladder ◽  
Muscle Invasive

443 Background: Defining the role of MIBC molecular subtypes and immune expression in determining clinical outcomes is an area of active investigation. However, changes in these transcriptomic profiles pre- and post-NAC have not been well characterized. Methods: This retrospective study reviewed 53 pts with MIBC treated with NAC, of whom 12 pts without complete pathological response had both pre- and post-NAC samples of sufficient quality. Post-NAC staging was > = pT2 in 11 pts and pT1 in 1 pt. We performed RNA expression analysis of matched pre-NAC transurethral resection of bladder tumor specimens and post-treatment radical cystectomy primary bladder tumor specimens. We used a customized NanoString panel incorporating previously reported immune signatures (Ayers, JCI 2017; O’Donnell, ASCO 2017) and additional genes to assign basal ( CD14, CD44, PDGFC, KRT14, KRT5) and luminal ( GATA3, PPARG, SHH, CD24, FOXA1, WNT7B, ERBB2) molecular subtypes. Results: We first classified the bladder cancer cohort of The Cancer Genome Atlas into basal and luminal subtypes using the BASE47 signature (Damrauer, PNAS 2014) and the NanoString panel and there was good agreement (Rand Index = 0.72). We then assigned subtypes using the NanoString panel on matched pre- and post-NAC samples and found marked subtype shift (Table). We identified two robust clusters of samples according to immune expression with a 3-fold change of immune expression between them (FDR = 0.0008). We found that 4 pts switched from the low to the high cluster, while 2 switched from the high to the low cluster after NAC (Table). Conclusions: MIBC molecular subtype membership is dynamic and is influenced by NAC. NAC can induce both enhanced and suppressed immune activity. These findings have implications on future studies exploring the predictive value of RNA expression patterns for bladder cancer therapies as well as post-NAC immunotherapy. [Table: see text]

scholarly journals GADD45B as a Prognostic and Predictive Biomarker in Stage II Colorectal Cancer

Genes ◽  
2018 ◽  
Vol 9 (7) ◽  
pp. 361 ◽  
Author(s):  
Zhixun Zhao ◽  
Yibo Gao ◽  
Xu Guan ◽  
Zheng Liu ◽  
Zheng Jiang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Damage ◽  
Adjuvant Chemotherapy ◽  
Prognostic Factor ◽  
Expression Patterns ◽  
Independent Prognostic Factor ◽  
Stage Ii ◽  
Free Survival ◽  
Cox Regression Analysis ◽  
Stage Ii Colorectal Cancer

GADD45B acts as a member of the growth arrest DNA damage-inducible gene family, which has demonstrated to play critical roles in DNA damage repair, cell growth, and apoptosis. This study aimed to explore the potential relationship between GADD45B expression and tumor progression and evaluate the clinical value of GADD45B in stage II colorectal cancer (CRC). The expression patterns and prognostic value of GADD45B in CRC were analyzed based on The Cancer Genomic Atlas (TCGA). GADD45B expression features of 306 patients with stage II CRC and 201 patients with liver metastasis of CRC were investigated using immunochemical staining on tissue microarrays. Afterward, survival analysis and stratification analysis were performed in stage II to explore the prognostic and predictive significance of GADD45B. Overexpressed GADD45B is associated with poorer prognosis for CRC patients both in overall survival (OS) (p < 0.001) and disease-free survival (DFS) (p = 0.001) based on the TCGA database. Analysis results according to the stage II CRC cohort and the liver metastatic CRC cohort revealed that GADD45B was gradually upregulated in normal mucosa including primary colorectal cancer (PCC). Colorectal liver metastases (CLM) tissues were arranged in order (normal tissue vs. PCC p = 0.005 and PCC vs. CLM p = 0.001). The low GADD45B group had a significantly longer five-year OS (p = 0.001) and progression-free survival (PFS) (p < 0.001) than the high GADD45B group for the stage II patients. The multivariate Cox regression analysis results proved that the expression level of GADD45B was an independent prognostic factor for stage II after radical surgery (OS: Hazard Ratio (HR) 0.479, [95% confidence interval (CI) 0.305–0.753] and PFS:HR 0.490, [95% CI 0.336–0.714]). In high GADD45B expression subgroup of stage II cohort, the patients who underwent adjuvant chemotherapy had longer PFS than those who did not (p = 0.008). High expression levels of GADD45B is an independent prognostic factor of decreased OS and PFS in stage II CRC patients. The stage II CRC patients with high GADD45B expression might benefit from adjuvant chemotherapy.

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