Subtyping sub-Saharan esophageal squamous cell carcinoma by comprehensive molecular analysis
Wenjin Liu, … , Satish Gopal, Norman E. Sharpless
Wenjin Liu, … , Satish Gopal, Norman E. Sharpless
Published October 6, 2016
Citation Information: JCI Insight. 2016;1(16):e88755. https://doi.org/10.1172/jci.insight.88755.
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Research Article Genetics Oncology

Subtyping sub-Saharan esophageal squamous cell carcinoma by comprehensive molecular analysis

Abstract

Esophageal squamous cell carcinoma (ESCC) is endemic in regions of sub-Saharan Africa (SSA), where it is the third most common cancer. Here, we describe whole-exome tumor/normal sequencing and RNA transcriptomic analysis of 59 patients with ESCC in Malawi. We observed similar genetic aberrations as reported in Asian and North American cohorts, including mutations of TP53, CDKN2A, NFE2L2, CHEK2, NOTCH1, FAT1, and FBXW7. Analyses for nonhuman sequences did not reveal evidence for infection with HPV or other occult pathogens. Mutational signature analysis revealed common signatures associated with aging, cytidine deaminase activity (APOBEC), and a third signature of unknown origin, but signatures of inhaled tobacco use, aflatoxin and mismatch repair were notably absent. Based on RNA expression analysis, ESCC could be divided into 3 distinct subtypes, which were distinguished by their expression of cell cycle and neural transcripts. This study demonstrates discrete subtypes of ESCC in SSA, and suggests that the endemic nature of this disease reflects exposure to a carcinogen other than tobacco and oncogenic viruses.

Authors

Wenjin Liu, Jeff M. Snell, William R. Jeck, Katherine A. Hoadley, Matthew D. Wilkerson, Joel S. Parker, Nirali Patel, Yohannie B. Mlombe, Gift Mulima, N. George Liomba, Lindsey L. Wolf, Carol G. Shores, Satish Gopal, Norman E. Sharpless

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Figure 1

Summary of patient characteristics and somatic point mutations.

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Summary of patient characteristics and somatic point mutations. Each col...
Each column represents 1 of 59 patient samples and columns are ordered based on RNA subtype (see Figure 4). The frequency of synonymous and nonsynonymous mutations per Mb sequenced (log scale) are stacked and shown at the top of the figure. Clinical and environmental characteristics of each sample are displayed in a matrix in the center of the figure, where each row is a single characteristic. Somatic single-nucleotide polymorphisms and copy number variations of each sample are displayed in a matrix in the bottom of the figure, where each row is a single mutated gene ordered top-to-bottom by decreasing percentage of the cohort with mutations in a given gene. Each mutation type is color coded and samples with 2 or more mutation types per gene are indicated by 2 or more colors. Percentage of the cohort with mutations in a given gene are shown in the bottom right of the figure.