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Multiregion ultra-deep sequencing reveals early intermixing and variable levels of intratumoral heterogeneity in colorectal cancer.

Publication ,  Journal Article
Suzuki, Y; Ng, SB; Chua, C; Leow, WQ; Chng, J; Liu, SY; Ramnarayanan, K; Gan, A; Ho, DL; Ten, R; Su, Y; Lezhava, A; Lai, JH; Koh, D; Tan, P ...
Published in: Mol Oncol
February 2017

Intratumor heterogeneity (ITH) contributes to cancer progression and chemoresistance. We sought to comprehensively describe ITH of somatic mutations, copy number, and transcriptomic alterations involving clinically and biologically relevant gene pathways in colorectal cancer (CRC). We performed multiregion, high-depth (384× on average) sequencing of 799 cancer-associated genes in 24 spatially separated primary tumor and nonmalignant tissues from four treatment-naïve CRC patients. We then used ultra-deep sequencing (17 075× on average) to accurately verify the presence or absence of identified somatic mutations in each sector. We also digitally measured gene expression and copy number alterations using NanoString assays. We identified the subclonal point mutations and determined the mutational timing and phylogenetic relationships among spatially separated sectors of each tumor. Truncal mutations, those shared by all sectors in the tumor, affected the well-described driver genes such as APC, TP53, and KRAS. With sequencing at 17 075×, we found that mutations first detected at a sequencing depth of 384× were in fact more widely shared among sectors than originally assessed. Interestingly, ultra-deep sequencing also revealed some mutations that were present in all spatially dispersed sectors, but at subclonal levels. Ultra-high-depth validation sequencing, copy number analysis, and gene expression profiling provided a comprehensive and accurate genomic landscape of spatial heterogeneity in CRC. Ultra-deep sequencing allowed more sensitive detection of somatic mutations and a more accurate assessment of ITH. By detecting the subclonal mutations with ultra-deep sequencing, we traced the genomic histories of each tumor and the relative timing of mutational events. We found evidence of early mixing, in which the subclonal ancestral mutations intermixed across the sectors before the acquisition of subsequent nontruncal mutations. Our findings also indicate that different CRC patients display markedly variable ITH, suggesting that each patient's tumor possesses a unique genomic history and spatial organization.

Duke Scholars

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Published In

Mol Oncol

DOI

EISSN

1878-0261

Publication Date

February 2017

Volume

11

Issue

2

Start / End Page

124 / 139

Location

United States

Related Subject Headings

  • Oncology & Carcinogenesis
  • Neoplasm Proteins
  • Mutation
  • Male
  • Humans
  • High-Throughput Nucleotide Sequencing
  • Genes, Neoplasm
  • Female
  • Colorectal Neoplasms
  • 3211 Oncology and carcinogenesis
 

Citation

APA
Chicago
ICMJE
MLA
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Suzuki, Y., Ng, S. B., Chua, C., Leow, W. Q., Chng, J., Liu, S. Y., … Tan, I. B. (2017). Multiregion ultra-deep sequencing reveals early intermixing and variable levels of intratumoral heterogeneity in colorectal cancer. Mol Oncol, 11(2), 124–139. https://doi.org/10.1002/1878-0261.12012
Suzuki, Yuka, Sarah Boonhsi Ng, Clarinda Chua, Wei Qiang Leow, Jermain Chng, Shi Yang Liu, Kalpana Ramnarayanan, et al. “Multiregion ultra-deep sequencing reveals early intermixing and variable levels of intratumoral heterogeneity in colorectal cancer.Mol Oncol 11, no. 2 (February 2017): 124–39. https://doi.org/10.1002/1878-0261.12012.
Suzuki Y, Ng SB, Chua C, Leow WQ, Chng J, Liu SY, et al. Multiregion ultra-deep sequencing reveals early intermixing and variable levels of intratumoral heterogeneity in colorectal cancer. Mol Oncol. 2017 Feb;11(2):124–39.
Suzuki, Yuka, et al. “Multiregion ultra-deep sequencing reveals early intermixing and variable levels of intratumoral heterogeneity in colorectal cancer.Mol Oncol, vol. 11, no. 2, Feb. 2017, pp. 124–39. Pubmed, doi:10.1002/1878-0261.12012.
Suzuki Y, Ng SB, Chua C, Leow WQ, Chng J, Liu SY, Ramnarayanan K, Gan A, Ho DL, Ten R, Su Y, Lezhava A, Lai JH, Koh D, Lim KH, Tan P, Rozen SG, Tan IB. Multiregion ultra-deep sequencing reveals early intermixing and variable levels of intratumoral heterogeneity in colorectal cancer. Mol Oncol. 2017 Feb;11(2):124–139.

Published In

Mol Oncol

DOI

EISSN

1878-0261

Publication Date

February 2017

Volume

11

Issue

2

Start / End Page

124 / 139

Location

United States

Related Subject Headings

  • Oncology & Carcinogenesis
  • Neoplasm Proteins
  • Mutation
  • Male
  • Humans
  • High-Throughput Nucleotide Sequencing
  • Genes, Neoplasm
  • Female
  • Colorectal Neoplasms
  • 3211 Oncology and carcinogenesis