Impact of uncommon genomic alterations on outcomes in metastatic colorectal cancer patients Restricted; Files Only

Liang, Tao (Spring 2019)

Permanent URL: https://etd.library.emory.edu/concern/etds/sf268624x?locale=en
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Abstract

Background: Metastatic colorectal cancer(mCRC) remains to be deadly and there are limited actionable genes to develop targeted therapies. Accumulating studies have shown that patients with specific mutations, such as KRAS, are more likely to be insensitive to anti-epidermal growth factor receptor (anti-EGFR) targeted therapies than patients with wild-type genes. However, there are still many patients with wild-type KRAS but nonresponding to anti-EGFR therapies. This suggests that there are other genetic determinants play roles in this process.

Methods and Materials: Records of 161 mCRC patients who underwent molecular profiling for mutations status of 30 genes were reviewed, including 116 patients with records of surgery date. Genes that are related to primary tumor side are determined by Chi-square test or Fisher Exact test. Univariate survival analysis with Cox model was used to determine genes that are related to poor survival outcome, and multivariate Cox model was used to adjust potential confounders. Overall survival and progression-free survival were assessed separately.

Results: TET2 (P=0.0280), FAM123B (P=0.0011), PTEN (P=0.0244), and BCOR (P=0.0212) were associated with the primary tumor side. After adjusting for patient characteristics, BRCA1/2 (OR, 6.98; HR, 1.05 to 46.45; P=0.0444), FLT3 (OR, 7.55; HR, 1.436 to 39.74; P=0.0170), SOX9 (OR, 10.23; HR, 1.61 to 65.24; P=0.0139) and IRS2 (OR, 31.63; HR, 4.55 to 219.92; P=0.0005) are associated with worse overall survival, CDK8 (OR, 3.122; HR, 1.337 to 7.291; P=0.0044) is associated with worse progression-free survival. More interestingly, we found that females (OR, 10.74; HR, 3.080 to 37.43; P< .0001) bearing mutated CDK8 have worse progression-free survival outcome than males (OR, 1.24; HR, 0.31 to 4.94; P=0.7621) bearing mutated CDK8.

Conclusion: Overall, we found that TET2, FAM123B, PTEN and BCOR are associated with primary side of tumor which is an indicator of worse survival outcome in colorectal cancer. Mutated BRCA1/2, FLT3, SOX9, IRS3 and CDK8 are plausible prognostic predictors for mCRC survival. However, these results need to be confirmed by investigation on separate cohorts.  

Table of Contents

Contents

Introduction. 1

Method. 3

2.1 Study Design. 3

2.2 Descriptive Characteristic and Association Study. 3

2.3 Survival Analysis. 4

Results. 6

3.1 Patients Characteristics and Mutation-associated Features. 6

3.2 Overall Survival 7

3.3 Progression-free Survival 8

3.4 Results Interpretation and Clinical Validity. 9

Discussion. 11

4.1 Main Conclusions. 11

4.2 Limitations. 11

Reference. 13

Tables and Figures. 15

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