title: 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 ofTP53,CDKN2A,NFE2L2,CHEK2,NOTCH1,FAT1, andFBXW7. 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.affiliation: Department of Genetics.|Department of Medicine.|The Lineberger Comprehensive Cancer Center.
authors.forename: Wenjin
authors.initials: W
authors.lastname: Liu
authors.affiliation: The Lineberger Comprehensive Cancer Center.|Program in Bioinformatics and Computational Biology.|Program in Molecular and Cellular Biophysics.
authors.forename: Jeff M
authors.initials: JM
authors.lastname: Snell
authors.affiliation: Department of Genetics.|The Lineberger Comprehensive Cancer Center.
authors.forename: William R
authors.initials: WR
authors.lastname: Jeck
authors.affiliation: Department of Genetics.|The Lineberger Comprehensive Cancer Center.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Hoadley
authors.affiliation: Department of Genetics.|The Lineberger Comprehensive Cancer Center.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Wilkerson
authors.affiliation: Department of Genetics.|The Lineberger Comprehensive Cancer Center.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Parker
authors.affiliation: The Lineberger Comprehensive Cancer Center.|Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Nirali
authors.initials: N
authors.lastname: Patel
authors.affiliation: Department of Medicine, University of Malawi College of Medicine, Blantyre, Malawi.
authors.forename: Yohannie B
authors.initials: YB
authors.lastname: Mlombe
authors.affiliation: Department of Surgery, Kamuzu Central Hospital, Lilongwe, Malawi.
authors.forename: Gift
authors.initials: G
authors.lastname: Mulima
authors.affiliation: UNC Project-Malawi, Lilongwe, Malawi.
authors.forename: N George
authors.initials: NG
authors.lastname: Liomba
authors.affiliation: UNC Project-Malawi, Lilongwe, Malawi.|Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Lindsey L
authors.initials: LL
authors.lastname: Wolf
authors.affiliation: The Lineberger Comprehensive Cancer Center.|Department of Otolaryngology/Head and Neck Surgery.
authors.forename: Carol G
authors.initials: CG
authors.lastname: Shores
authors.affiliation: Department of Medicine.|The Lineberger Comprehensive Cancer Center.|Department of Medicine, University of Malawi College of Medicine, Blantyre, Malawi.|UNC Project-Malawi, Lilongwe, Malawi.|Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Satish
authors.initials: S
authors.lastname: Gopal
authors.affiliation: Department of Genetics.|Department of Medicine.|The Lineberger Comprehensive Cancer Center.
authors.forename: Norman E
authors.initials: NE
authors.lastname: Sharpless
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000145:classification*; D004252:DNA Mutational Analysis; D004938:Esophageal Neoplasms / Q000145:classification*; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D018628:Gene Dosage; D006801:Humans; D008295:Malawi; D008297:Male; D008875:Middle Aged; D009154:Mutation; D014157:Transcription Factors / Q000235:genetics; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: C495901:TP53 protein, human; C115051:TP63 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins