Genome-Wide Scan for Copy Number Alteration Association with Relapse-Free Survival in Colorectal Cancer with Liver Metastasis Patients

Abstract

Predicting a patient's risk of recurrence after the resection of liver metastases from colorectal cancer is critical for evaluating and selecting therapeutic approaches. Clinical and pathologic parameters have shown limited accuracy thus far. Therefore, we combined the clinical status with a genomic approach to stratify relapse-free survival in colorectal cancer liver metastases patients. To identify new molecular and genetic signatures specific to colorectal cancer with liver metastasis (CRCLM) patients, we conducted DNA copy number profiling on a cohort of 21 Taiwanese CRCLM patients using a comparative genomic hybridization (CGH) array. We identified a three-gene signature based on differential copy number alteration between patients with different statuses of (1) recurrence and (2) synchronous metastasis. In relapse hotspot regions, only three genes (S100PBP, CSMD2, and TGFBI) were significantly associated with the synchronous liver metastasis factor. A final set of three genes-S100PBP, CSMD2, TGFBI-significantly predicted relapse-free survival in our cohort (p = 0.04) and another CRCLM cohort (p = 0.02). This three-gene signature is the first genomic signature validated for relapse-free survival in post-hepatectomy CRCLM patients. Our three-gene signature was developed using a whole-genome CGH array and has a good prognostic position for the relapse-free survival of CRCLM patients after hepatectomy.

Keywords: biomarker; colorectal cancer liver metastases; copy number alteration; gene signature; relapse-free survival.

Figure 1

Frequency plots of DNA copy number aberrations in 8 patients without recurrence and 13 patients with recurrence.

Figure 2

Flowchart of gene selection and analysis procedures.

Figure 3

The circos plot of relapse hotspot regions in the CRCLM cohort. Outside to inside: synchronous metastasis (yes vs no); recurrence (yes vs no); copy number alteration in 21 CRCLM patients.

Figure 4

(A) The recurrence-associated region on chromosome 1. (B) The recurrence-associated region on chromosome 5.

Figure 4

(A) The recurrence-associated region on chromosome 1. (B) The recurrence-associated region on chromosome 5.

Figure 5

Heatmap for expression analysis in disease and functions.

Figure 6

(A) Kaplan–Meier relapse-free survival curves of three genes’ copy number variation in 21 CRCLM patients. (B) Kaplan–Meier overall survival curves of three genes’ copy number variation in 21 CRCLM patients. (C) Kaplan–Meier relapse-free survival curves of three genes’ copy number variation in 45 CRCLM patients. (D) Kaplan–Meier overall survival curves of three genes’ copy number variation in 45 CRCLM patients.

Figure 6

(A) Kaplan–Meier relapse-free survival curves of three genes’ copy number variation in 21 CRCLM patients. (B) Kaplan–Meier overall survival curves of three genes’ copy number variation in 21 CRCLM patients. (C) Kaplan–Meier relapse-free survival curves of three genes’ copy number variation in 45 CRCLM patients. (D) Kaplan–Meier overall survival curves of three genes’ copy number variation in 45 CRCLM patients.

Figure 6

(A) Kaplan–Meier relapse-free survival curves of three genes’ copy number variation in 21 CRCLM patients. (B) Kaplan–Meier overall survival curves of three genes’ copy number variation in 21 CRCLM patients. (C) Kaplan–Meier relapse-free survival curves of three genes’ copy number variation in 45 CRCLM patients. (D) Kaplan–Meier overall survival curves of three genes’ copy number variation in 45 CRCLM patients.