Colorectal Cancer Genetic Heterogeneity Delineated by Multi-Region Sequencing

PLoS One. 2016 Mar 29;11(3):e0152673. doi: 10.1371/journal.pone.0152673. eCollection 2016.

Abstract

Intratumor heterogeneity (ITH) leads to an underestimation of the mutational landscape portrayed by a single needle biopsy and consequently affects treatment precision. The extent of colorectal cancer (CRC) genetic ITH is not well understood in Chinese patients. Thus, we conducted deep sequencing by using the OncoGxOne™ Plus panel, targeting 333 cancer-specific genes in multi-region biopsies of primary and liver metastatic tumors from three Chinese CRC patients. We determined that the extent of ITH varied among the three cases. On average, 65% of all the mutations detected were common within individual tumors. KMT2C aberrations and the NCOR1 mutation were the only ubiquitous events. Subsequent phylogenetic analysis showed that the tumors evolved in a branched manner. Comparison of the primary and metastatic tumors revealed that PPP2R1A (E370X), SETD2 (I1608V), SMAD4 (G382T), and AR splicing site mutations may be specific to liver metastatic cancer. These mutations might contribute to the initiation and progression of distant metastasis. Collectively, our analysis identified a substantial level of genetic ITH in CRC, which should be considered for personalized therapeutic strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Colorectal Neoplasms / genetics*
  • Female
  • Genetic Heterogeneity*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • INDEL Mutation / genetics
  • Male
  • Middle Aged
  • Neoplasm Metastasis
  • Phylogeny
  • Polymorphism, Single Nucleotide / genetics
  • Sequence Analysis, DNA / methods*

Grants and funding

This work was supported by Foundation of Medical Leading Talent of Yunnan Province (No. L-201205) KHW, Foundation of Yunnan Institute of Digestive Disease (No. 2014NS122) KHW, Department of Science and Technology of Yunnan Province—Kunming Medical University (NO. 2015FB100) HFZ, National Natural Science Foundation of China (81460007) XYK. http://www.nsfc.gov.cn/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.