Dataset Information

Sequential and co-occurring DNA damage response genetic mutations impact survival in stage III colorectal cancer patients receiving adjuvant oxaliplatin-based chemotherapy.

ABSTRACT:

Background

Certain sequences of genomic mutations can lead to cancer formation and affect treatment outcomes and drug resistance. We constructed a cancer evolutionary tree using bulk-targeted deep sequencing to explore the impact of sequential and co-occurring somatic mutations on patients with stage III colorectal cancer (CRC).

Methods

A total of 108 stage III CRC patients from National Cheng Kung University Hospital (NCKUH) were recruited for this study between Jan. 2014 and Jan. 2019. Clinical information and tumor-targeted deep sequencing data were collected. Phylogenetic trees were reconstructed for evolutionary trajectories. We used a machine learning model for survival analysis.

Results

Six sequential somatic mutations stratified patients into seven subgroups based on survival. Patients carrying sequential germline followed by DNA damage response-related ATM or BRCA2 somatic mutations or non-TP53, APC somatic mutations had a better outcome than those without such mutations. The 4-year recurrence-free survival (RFS) probability was 88% in the low-risk group (G1) and 46% in the high-risk group (G2) (log-rank p-value 2e-05). The predictive efficacy by the area under the curve (AUC) was 0.73, 0.7, 0.797, and 0.88 at 2, 4, 6, and 8?years, respectively. The mutation status of mismatch repair (MMR) genes was not associated with RFS. Different genomic features were found between the groups. The orders of APC, KRAS and APC, BRCA2 sequential somatic mutations were associated with clinical outcomes. The occurrence of somatic mutations in BRCA2, such as TP53 somatic mutations, affected recurrence-free survival.

Conclusions

According to the evolution model, DNA damage response (DDR)-related ATM or BRCA2 somatic mutations are promising biomarkers for assessing the response of stage III CRC patients to oxaliplatin-based chemotherapy. The sequential order and co-occurring DDR somatic mutations are associated with recurrence-free survival.

SUBMITTER: Lin PC

PROVIDER: S-EPMC7923464 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Publications

Sequential and co-occurring DNA damage response genetic mutations impact survival in stage III colorectal cancer patients receiving adjuvant oxaliplatin-based chemotherapy.

Lin Peng-Chan PC Yeh Yu-Min YM Chan Ren-Hao RH Lin Bo-Wen BW Chen Po-Chuan PC Pan Chien-Chang CC Shen Meng-Ru MR

BMC cancer 20210302 1

<h4>Background</h4>Certain sequences of genomic mutations can lead to cancer formation and affect treatment outcomes and drug resistance. We constructed a cancer evolutionary tree using bulk-targeted deep sequencing to explore the impact of sequential and co-occurring somatic mutations on patients with stage III colorectal cancer (CRC).<h4>Methods</h4>A total of 108 stage III CRC patients from National Cheng Kung University Hospital (NCKUH) were recruited for this study between Jan. 2014 and Jan ...[more]

PMID: 33653301

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Project description:BackgroundThere are robust data supporting the contribution of oxaliplatin (L-OHP) regarding clinical outcomes for colorectal cancer (CRC) in an adjuvant setting in European and US trials; however, there is no Japanese clinical evidence although L-OHP has been approved since 2009. We examined the transition of adjuvant chemotherapy for stage III colorectal cancer in our institute.MethodsA total of 642 patients with histopathologically confirmed stage III CRC underwent curative surgery from 2005 to 2010. We examined disease free survival (DFS), overall survival (OS) and prognostic factors for stage III CRC patients who underwent adjuvant chemotherapy.ResultsA total of 509 patients received adjuvant chemotherapy. 3-year DFS and 5-year OS rates were 74.5% and 87.5%, respectively. The frequency of inclusion of L-OHP as adjuvant chemotherapy was increased after 2008. A total of 189 patients received adjuvant chemotherapy from 2005 to 2007 increasing to 320 patients from 2008 to 2010; the 5-year OS rates were 82.4% and 91.5%, respectively, and the 3-year DFS rates were 69.2% and 76.6%, respectively (OS, P = 0.007; DFS, P = 0.023). In univariate analysis, adjuvant chemotherapy including L-OHP was no significant deference compared to FU monotherapy. (OS: HR 0.88, 95%CI 0.4-1.91, p = 0.75, DFS: HR 0.78, 95%CI 0.21-2.3, p = 0.29). In multivariate analysis, the OS was predicted by means of N stage (HR = 2; 95%CI, 1.1-3.8; P = 0.02) and pathology (HR = 0.28; 95%CI, 0.13-0.59; P = 0.0008). The DFS was predicted by means of N stage (HR = 2.67; 95%CI, 1.82-3.9; P < 0.05), T stage (HR = 1.61; 95%CI, 1.1-2.3; P = 0.01) pathology (HR = 0.47; 95%CI, 0.29-0.75; P < 0.05) and venous invasion (HR = 2.06; 95%CI, 1.12-3.77; P = 0.01).ConclusionsClinical outcomes of stage III CRC patients receiving adjuvant chemotherapy improved. The frequency of L-OHP usage was increasing annually, however it was no influence for clinical outcomes in this study. It will be necessary to reevaluate additional effect of L-OHP with more patients.

Dataset Information

Sequential and co-occurring DNA damage response genetic mutations impact survival in stage III colorectal cancer patients receiving adjuvant oxaliplatin-based chemotherapy.

Background

Methods

Results

Conclusions

Publications

Sequential and co-occurring DNA damage response genetic mutations impact survival in stage III colorectal cancer patients receiving adjuvant oxaliplatin-based chemotherapy.

Similar Datasets

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