A qualitative transcriptional signature for predicting microsatellite instability status of right-sided Colon Cancer

Abstract Background: Microsatellite instability (MSI) accounts for about 15% of colorectal cancer and is associated with prognosis. Today, MSI is usually detected by polymerase chain reaction amplification of specific microsatellite markers. However, the instability is identified by comparing the length of microsatellite repeats in tumor and normal samples. In this work, we developed a qualitative transcriptional signature to individually predict MSI status for right-sided colon cancer (RCC) based on tumor samples. Results: Using RCC samples, based on the relative expression orderings (REOs) of gene pairs, we extracted a signature consisting of 10 gene pairs (10-GPS) to predict MSI status for RCC through a feature selection process. A sample is predicted as MSI when the gene expression orderings of at least 7 gene pairs vote for MSI; otherwise the microsatellite stability (MSS). The classification performance reached the largest F-score in the training dataset. This signature was verified in four independent datasets of RCCs with the F-scores of 1, 0.9630, 0.9412 and 0.8798, respectively. Additionally, the hierarchical clustering analyses and molecular features also supported the correctness of the reclassifications of the MSI status by 10-GPS. Conclusions: The qualitative transcriptional signature can be used to classify MSI status of RCC samples at the individualized level.

Download Full-text

A Qualitative Transcriptional Signature for Predicting Microsatellite Instability Status of Right-sided Colon Cancer

10.21203/rs.2.10681/v1 ◽

2019 ◽

Author(s):

Yelin Fu ◽

Lishuang Qi ◽

Wenbing Guo ◽

Liangliang Jin ◽

Kai Song ◽

...

Keyword(s):

Colon Cancer ◽

Microsatellite Instability ◽

Selection Process ◽

Polymerase Chain Reaction Amplification ◽

Classification Performance ◽

Training Dataset ◽

Transcriptional Signature ◽

Gene Pairs ◽

Molecular Features ◽

Relative Expression Orderings

Abstract Background: Microsatellite instability (MSI) accounts for about 15% of colorectal cancer and is associated with prognosis. Today, MSI is usually detected by polymerase chain reaction amplification of specific microsatellite markers. However, the instability is identified by comparing the length of microsatellite repeats in tumor and normal samples. In this work, we developed a qualitative transcriptional signature to individually predict MSI status for right-sided colon cancer (RCC) based on tumor samples. Results: Using RCC samples, based on the relative expression orderings (REOs) of gene pairs, we extracted a signature consisting of 10 gene pairs (10-GPS) to predict MSI status for RCC through a feature selection process. A sample is predicted as MSI when the gene expression orderings of at least 7 gene pairs vote for MSI; otherwise the microsatellite stability (MSS). The classification performance reached the largest F-score in the training dataset. This signature was verified in four independent datasets of RCCs with the F-scores of 1, 0.9630, 0.9412 and 0.8798, respectively. Additionally, the hierarchical clustering analyses and molecular features also supported the correctness of the reclassifications of the MSI status by 10-GPS. Conclusions: The qualitative transcriptional signature can be used to classify MSI status of RCC samples at the individualized level.

Download Full-text

A qualitative transcriptional signature for predicting CpG island methylator phenotype status of the right-sided colon cancer

10.21203/rs.2.17598/v1 ◽

2019 ◽

Author(s):

Tianyi You ◽

wenyuan Zhao ◽

Zheng Guo ◽

Kai Song ◽

Wenbing Guo ◽

...

Keyword(s):

Colon Cancer ◽

Cpg Island ◽

Selection Process ◽

Cpg Islands ◽

Stage Ii ◽

Cpg Island Methylator Phenotype ◽

Transcriptional Signature ◽

Gene Pairs ◽

Methylator Phenotype ◽

The Right

Abstract Background: A part of colorectal cancer which is characterized by simultaneous numerous hypermethylation CpG islands sites is defined as CpG island methylator phenotype (CIMP) status. Stage II and III CIMP-positive (CIMP+) right-sided colon cancer (RCC) patients have a better prognosis than CIMP-negative (CIMP-) RCC treated with surgery alone. However, there is no gold standard available in defining CIMP status. In this work, we developed a transcriptional qualitative signature to individually predict CIMP status for stage II and III RCC. Results: Based on the relative expression orderings (REOs) of gene pairs, a signature composed of 19 gene pairs was developed to predict the CIMP status of RCC through a feature selection process. A sample is predicted as CIMP+ when the gene expression orderings of at least 12 gene pairs vote for CIMP+; otherwise the CIMP-. The difference of prognosis between the predicted CIMP+ and CIMP- groups was more significantly different than the original CIMP status groups. There were more differential methylation and expression characteristics between the two predicted groups. The hierarchical clustering analysis showed that the signature could perform better for predicting CIMP status of RCC than current methods. Conclusions: The qualitative transcriptional signature for classifying CIMP status at the individualized level can predict outcome and guide therapy for RCC patients.

Download Full-text

Association of microsatellite instability with prognosis in the pathologic N2 colon cancer patients treated with adjuvant FOLFOX chemotherapy.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.3568 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 3568-3568

Author(s):

Jeong Eun Kim ◽

Hwa Jung Kim ◽

Yong Sang Hong ◽

Jae-Lyun Lee ◽

Kyu-Pyo Kim ◽

...

Keyword(s):

Colon Cancer ◽

Microsatellite Instability ◽

Polymerase Chain Reaction Amplification ◽

Univariate Analysis ◽

Stage Iii ◽

Stage Iii Colon Cancer ◽

Folfox Chemotherapy ◽

Resected Stage ◽

The Impact ◽

Pathologic N2

3568 Background: The impact of microsatellite instability (MSI) on survival has been rarely explored, with controversy, in stage III colon cancer treated with adjuvant 5-flurouracil-oxaliplatin combination (FOLFOX) chemotherapy. We evaluated association between MSI and survival in this population. Methods: We analyzed 312 patients (pts) with curatively resected stage III colon cancer treated with adjuvant FOLFOX chemotherapy. We determined MSI status using polymerase chain reaction amplification as high levels of MSI (MSI-H, ≥ 2 unstable markers), low levels of MSI (MSI-L, 1 unstable marker), and microsatellite stable (MSS, no unstable marker). Results: Of 312 pts, 8.3% showed MSI-H and they were younger (median age, 51.5 vs. 58 years, p=0.018). MSI-H tumors were more commonly located ascending colon (46.2% vs. 23.1%, p=0.002) and had poorly differentiated features (30.8% vs. 5.2%, p<0.0001). After the median follow-up of 30.9 months, 3-year relapse-free (RFS) and overall survival (OS) rates were 76.1% and 91.7%, respectively. In univariate analysis, pathologic N2 (pN2) was associated with reduced RFS (p<0.0001) and OS (p=0.002), while MSI status did not affect either RFS (p=0.254) or OS (p=0.961). In patients with pN2 tumors, however, MSI-H was associated with better survival compared with MSS/MSI-L; the RFS and OS in pts with pN2/MSI-H were comparable to those in pts with pN1 tumors (table). Conclusions: MSI status alone did not affect survival in our population. However, pts with pN2/MSI-H showed favorable survival outcomes comparable to those with pN1, and MSS/MSI-L/pN2 was associated with worst survival, implicating that MSI-H modifies the inherent worse prognosis of pN2 tumors. [Table: see text]

Download Full-text

CpG Island Methylation, Microsatellite Instability, and BRAF Mutations and Their Clinical Application in the Treatment of Colon Cancer

Chemotherapy Research and Practice ◽

10.1155/2012/359041 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 2

Author(s):

Christina Wu ◽

Tanios Bekaii-Saab

Keyword(s):

Colon Cancer ◽

Microsatellite Instability ◽

Braf Mutation ◽

Cpg Island ◽

Growth Factor Receptor ◽

Future Research ◽

Braf Mutations ◽

Molecular Features ◽

Mutational Status ◽

Cpg Island Methylation

There have been significant developments in colon cancer research over the last few years, enabling us to better characterize tumors individually and classifying them according to certain molecular or genetic features. Currently, we are able to use KRAS mutational status as a guide to therapy with anti-epidermal growth factor receptor antibodies. Other molecular features under research include BRAF mutation, microsatellite instability, and CpG island methylation. These three molecular features are often associated with tumors that have overlapping phenotypes and can be present simultaneously in the same tumor. However, they carry different prognostic and predictive qualities, making analysis of their interaction relatively complex. Much research thus far has examined the clinical relevance of microsatellite instability in helping determine prognosis and the predictive value of adjuvant 5-fluorouracil chemotherapy in stages II and III colon cancers. BRAF mutation appears to be a biomarker for poor prognosis. CpG island methylation is tightly associated with microsatellite instable tumors and BRAF mutation, but its clinical utility remains uncertain. Hereby, we examine preclinical and clinical data that supports the utilization of all three phenotypes in future research applied to clinical practice.

Download Full-text

Prognostic and Predictive Cross-Roads of Microsatellite Instability and Immune Response to Colon Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms21249680 ◽

2020 ◽

Vol 21 (24) ◽

pp. 9680

Author(s):

Luigi Laghi ◽

Francesca Negri ◽

Federica Gaiani ◽

Tommaso Cavalleri ◽

Fabio Grizzi ◽

...

Keyword(s):

Colon Cancer ◽

Microsatellite Instability ◽

Adjuvant Treatment ◽

Early Stage ◽

Tumor Infiltrating Lymphocytes ◽

Staging System ◽

Risk Groups ◽

Tnm Staging ◽

Molecular Features ◽

Colon Cancers

Understanding molecular features of colon cancer has shed light on its pathogenesis and progression. Over time, some of these features acquired clinical dignity and were incorporated in decision making. Namely, microsatellite instability (MSI) due to mismatch repair of defects, which primarily was adopted for the diagnosis of Lynch syndrome, became recognized as the biomarker of a different disease type, showing a less aggressive behavior. MSI tumors harbor high amounts of tumor infiltrating lymphocytes (TILs) due to their peculiar load in neoantigens. However, microsatellite stable colon cancer may also show high amounts of TILs, and this feature is as well associated with better outcomes. High TIL loads are in general associated with a favorable prognosis, especially in stage II colon cancer, and therein identifies a patient subset with the lowest probability of relapse. With respect to post-surgical adjuvant treatment, particularly in stage III, TILs predictive ability seems to weaken along with the progression of the disease, being less evident in high risk patients. Moving from cohort studies to the analysis of a series from clinical trials contributed to increase the robustness of TILs as a biomarker. The employment of high TIL densities as an indicator of good prognosis in early-stage colon cancers is strongly advisable, while in late-stage colon cancers the employment as an indicator of good responsiveness to post-surgical therapy requires refinement. It remains to be clarified whether TILs could help in identifying those patients with node-positive cancers to whom adjuvant treatment could be spared, at least in low-risk groups as defined by the TNM staging system.

Download Full-text