Histopathological characteristics and artificial intelligence for predicting tumor mutational burden-high colorectal cancer

Abstract Background Tumor mutational burden (TMB) is a promising predictor, which could stratify colorectal cancer (CRC) patients based on the response to immune checkpoint inhibitors (ICIs). MicroRNAs (miRNAs) act as the key regulators of anti-cancer immune response. However, the relationship between TMB and miRNA expression profiles is not elucidated in CRC. Methods Differentially expressed miRNAs (DE miRNAs) between the TMBhigh group and the TMBlow group were identified for the CRC cohort of the TCGA database. In the training cohort, a miRNA-related expression signature for predicting TMB level was developed by the least absolute shrinkage and selection operator (LASSO) method and tested with reference to its discrimination, calibration, and decision curve analysis (DCA) in the validation cohort. Functional enrichment analysis of these TMB-related miRNAs was performed. The correlation between this miRNA-related expression signature and three immune checkpoints was analyzed. Results Twenty-one out of 43 DE miRNAs were identified as TMB-related miRNAs, which were used to develop a miRNA-related expression signature. This TMB-related miRNA signature demonstrated great discrimination (AUCtest set = 0.970), satisfactory calibration (P > 0.05), and clinical utility in the validation cohort. Functional enrichment results revealed that these TMB-related miRNAs were mainly involved in biological processes associated with immune response and signaling pathways related with cancer. This miRNA-related expression signature showed a median positive correlation with PD-L1 (R = 0.47, P < 0.05) and CTLA4 (R = 0.39, P < 0.05) and a low positive correlation with PD-1 (R = 0.16, P < 0.05). Conclusion This study presents a miRNA-related expression signature which could stratify CRC patients with different TMB levels.

Download Full-text

Abstract 5379: Stratification of colorectal cancer patients based on various sequencing platforms and tumor mutational burden

10.1158/1538-7445.am2018-5379 ◽

2018 ◽

Author(s):

Fang Yin Lo ◽

Claire Olson ◽

Kerry Deutsch ◽

Tuuli Saloranta ◽

Inah Golez ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Patients ◽

Mutational Burden ◽

Tumor Mutational Burden ◽

Sequencing Platforms ◽

Colorectal Cancer Patients

Download Full-text

Mutational Analysis of Patients With Colorectal Cancer in CALGB/SWOG 80405 Identifies New Roles of Microsatellite Instability and Tumor Mutational Burden for Patient Outcome

Journal of Clinical Oncology ◽

10.1200/jco.18.01798 ◽

2019 ◽

Vol 37 (14) ◽

pp. 1217-1227 ◽

Cited By ~ 69

Author(s):

Federico Innocenti ◽

Fang-Shu Ou ◽

Xueping Qu ◽

Tyler J. Zemla ◽

Donna Niedzwiecki ◽

...

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Metastatic Colorectal Cancer ◽

Mutational Analysis ◽

Gene Mutations ◽

Phase Iii ◽

First Line ◽

Mutational Burden ◽

Significant Difference ◽

Tumor Mutational Burden

PURPOSE CALGB/SWOG 80405 was a randomized phase III trial that found no statistically significant difference in overall survival (OS) in patients with first-line metastatic colorectal cancer treated with chemotherapy plus either bevacizumab or cetuximab. Primary tumor DNA from 843 patients has been used to discover genetic markers of OS. PATIENTS AND METHODS Gene mutations were determined by polymerase chain reaction. Microsatellite status was determined by genotyping of microsatellites. Tumor mutational burden (TMB) was determined by next-generation sequencing. Cox proportional hazard models were used, with adjusting factors. Interaction of molecular alterations with either the bevacizumab or the cetuximab arms was tested. RESULTS Patients with high TMB in their tumors had longer OS than did patients with low TMB (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.95]; P = .02). In patients with microsatellite instability–high (MSI-H) tumors, longer OS was observed in the bevacizumab arm than in the cetuximab arm (HR, 0.13 [95% CI, 0.06 to 0.30]; interaction P < .001 for interaction between microsatellite status and the two arms). Patients with BRAF mutant tumors had shorter OS than did patients with wild-type (WT) tumors (HR, 2.01 [95% CI, 1.49 to 2.71]; P < .001). Patients with extended RAS mutant tumors had shorter OS than did patients with WT tumors (HR, 1.52 [95% CI, 1.26 to 1.84]; P < .001). Patients with triple-negative tumors (WT for NRAS/ KRAS/ BRAF) had a median OS of 35.9 months (95% CI, 33.0 to 38.8 months) versus 22.2 months (95% CI, 19.6 to 24.4 months ) in patients with at least one mutated gene in their tumors ( P < .001). CONCLUSION In patients with metastatic colorectal cancer treated in first line, low TMB, and BRAF and RAS mutations are negative prognostic factors. Patients with MSI-H tumors benefited more from bevacizumab than from cetuximab, and studies to confirm this effect of MSI-H are warranted.

Download Full-text

Correlation of tumor mutational burden and treatment outcomes in patients with colorectal cancer

Journal of Gastrointestinal Oncology ◽

10.21037/jgo.2017.06.20 ◽

2017 ◽

Vol 8 (5) ◽

pp. 858-866 ◽

Cited By ~ 15

Author(s):

Sachin G. Pai ◽

Benedito A. Carneiro ◽

Young Kwang Chae ◽

Ricardo L. Costa ◽

Aparna Kalyan ◽

...

Keyword(s):

Colorectal Cancer ◽

Treatment Outcomes ◽

Mutational Burden ◽

Tumor Mutational Burden

Download Full-text

Targeted therapy for HER2 driven colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.3583 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 3583-3583 ◽

Cited By ~ 2

Author(s):

Jeffrey S. Ross ◽

Siraj Mahamed Ali ◽

Julia Andrea Elvin ◽

Alexa Betzig Schrock ◽

James Suh ◽

...

Keyword(s):

Colorectal Cancer ◽

Clinical Trials ◽

Genomic Profiling ◽

Hybrid Capture ◽

Mutational Burden ◽

Precision Therapy ◽

Comprehensive Genomic Profiling ◽

Tumor Mutational Burden ◽

Upper Gastrointestinal ◽

Colonic Adenocarcinomas

3583 Background: ERBB2 ( HER2) genomic alterations (GA) are evolving therapy taregets in metastatc coorectal cancer (mCRC). Methods: Hybrid capture based comprehensive genomic profiling (CGP) was performed on 8874 (9.6%) mCRC including both colonic adenocarcinomas (7587 cases; 85%) and rectal adenocarcinomas (1287 cases, 15%) Tumor mutational burden (TMB) was calculated from a minimum of 1.2 Mb of sequenced DNA. Results: ERBB2 amplifications or a short variant (SV) alterations or both were found in 433 (4.9%) of the total mCRC. 195 (45%) of the ERBB2 positive mCRC were female and 238 (55%) were male. Median age was 54 years (range 22 to 88 years). The most frequently co-altered genes were SV GA in TP53 (82%), APC (70%), KRAS (26%), SMAD4 (15%) and PIK3CA (13%). Clinically relevant GA significantly under-represented in ERBB2-altered CRC included significantly reduced GA in KRAS at 26% (p = 0.001) and BRAF at 4% (p = 0.003) as well as other kinases at 1% including EGFR, KIT, MET and RET. The frequency of TMB at > 10 mut/Mb (p < 0.0001), but at > 20 mut/Mb mCRC cases demonstrated virtually the same results regardless to ERBB2 status at a frequency of x%. The overall ERBB2 GA frequency at 5.3% in rectal mCRC is slightly higher than that seen in colonic mCRC at 4.9%, (p = 0.36). The frequency of TMB > 10 mut/Mb in ERBB2 WT mCRC is greater in the colonic mCRC than the rectal mCRC (p < 0.0001 for both comparisons). When > 20 mut/Mb is used as the cut-off, the greater frequency of TMB in colonic mCRC versus rectal mCRC remains significant (p < 0.0001). When the ERBB2altered mCRC cases are evaluated, the greater frequency of TMB > 10 mu/Mb in colonic mCRC versus rectal mCRC remains significant (p = 0.009), but the greater frequency in colonic verses rectal mCRC at the > 20 mut/Mb is not significant (p = 0.37). Conclusions: Although lower than observed in breast and upper gastrointestinal carcinomas where anti-HER2 therapies are approved indications, the frequency of ERBB2 GA in CRC at 4.9% is significant. Importantly, nearly half of CRC ERBB2 alterations are SVs, not detectable by routine IHC and FISH testing. However, the success of anti-HER2 therapies shown here and progress in on-going clinical trials indicates that targeting ERBB2 has potential to become an approved advance in precision therapy for mCRC patients.

Download Full-text