Tumor Heterogeneity Predicts Metastatic Potential in Colorectal Cancer

• Published in: Clinical cancer research 2017-12, Vol.23 (23), p.7209-7216
• Main Authors: Joung, Je-Gun, Oh, Bo Young, Hong, Hye Kyung, Al-Khalidi, Hisham, Al-Alem, Faisal, Lee, Hae-Ock, Bae, Joon Seol, Kim, Jinho, Cha, Hong-Ui, Alotaibi, Maram, Cho, Yong Beom, Hassanain, Mazen, Park, Woong-Yang, Lee, Woo Yong
• Format: Article
• Language: English
• Subjects: Adenomatous polyposis coli; Adenomatous Polyposis Coli Protein - genetics; Aged; Cancer; Class I Phosphatidylinositol 3-Kinases - genetics; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Experimental design; Female; Gene Frequency; Genetic Heterogeneity; Heterogeneity; Humans; K-Ras protein; Liver; Liver Neoplasms - genetics; Liver Neoplasms - secondary; Male; Metastases; Metastasis; Middle Aged; Mutation; p53 Protein; Patients; Proto-Oncogene Proteins p21(ras) - genetics; Receptor, Notch1 - genetics; Sequences; Tumor Suppressor Protein p53 - genetics; Tumors; Whole Exome Sequencing - methods
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-17-0306

Tumors continuously evolve to maintain growth; secondary mutations facilitate this process, resulting in high tumor heterogeneity. In this study, we compared mutations in paired primary and metastatic colorectal cancer tumor samples to determine whether tumor heterogeneity can predict tumor metastasis. Somatic variations in 46 pairs of matched primary-liver metastatic tumors and 42 primary tumors without metastasis were analyzed by whole-exome sequencing. Tumor clonality was estimated from single-nucleotide and copy-number variations. The correlation between clinical parameters of patients and clonal heterogeneity in liver metastasis was evaluated. Tumor heterogeneity across colorectal cancer samples was highly variable; however, a high degree of tumor heterogeneity was associated with a worse disease-free survival. Highly heterogeneous primary colorectal cancer was correlated with a higher rate of liver metastasis. Recurrent somatic mutations in , and were frequently detected in highly heterogeneous colorectal cancer. The variant allele frequency of these mutations was high, while somatic mutations in other genes such as and were low. The number and distribution of primary colorectal cancer subclones were preserved in metastatic tumors. Heterogeneity of primary colorectal cancer tumors can predict the potential for liver metastasis and thus, clinical outcome of patients. .