RGD Reference Report - Genomic Landscape of Esophageal Squamous Cell Carcinoma in a Japanese Population. - Rat Genome Database

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Genomic Landscape of Esophageal Squamous Cell Carcinoma in a Japanese Population.

Authors: Sawada, Genta  Niida, Atsushi  Uchi, Ryutaro  Hirata, Hidenari  Shimamura, Teppei  Suzuki, Yutaka  Shiraishi, Yuichi  Chiba, Kenichi  Imoto, Seiya  Takahashi, Yusuke  Iwaya, Takeshi  Sudo, Tomoya  Hayashi, Tomoatsu  Takai, Hiroki  Kawasaki, Yoshihiro  Matsukawa, Takashi  Eguchi, Hidetoshi  Sugimachi, Keishi  Tanaka, Fumiaki  Suzuki, Hiromichi  Yamamoto, Ken  Ishii, Hideshi  Shimizu, Makiko  Yamazaki, Hiroshi  Yamazaki, Makoto  Tachimori, Yuji  Kajiyama, Yoshiaki  Natsugoe, Shoji  Fujita, Hiromasa  Mafune, Kenichi  Tanaka, Yoichi  Kelsell, David P  Scott, Claire A  Tsuji, Shoji  Yachida, Shinichi  Shibata, Tatsuhiro  Sugano, Sumio  Doki, Yuichiro  Akiyama, Tetsu  Aburatani, Hiroyuki  Ogawa, Seishi  Miyano, Satoru  Mori, Masaki  Mimori, Koshi 
Citation: Sawada G, etal., Gastroenterology. 2016 May;150(5):1171-1182. doi: 10.1053/j.gastro.2016.01.035. Epub 2016 Feb 10.
RGD ID: 150429656
Pubmed: PMID:26873401   (View Abstract at PubMed)
DOI: DOI:10.1053/j.gastro.2016.01.035   (Journal Full-text)


BACKGROUND & AIMS: Esophageal squamous cell carcinoma (ESCC) is the predominant form of esophageal cancer in Japan. Smoking and drinking alcohol are environmental risk factors for ESCC, whereas single nucleotide polymorphisms in ADH1B and ALDH2, which increase harmful intermediates produced by drinking alcohol, are genetic risk factors. We conducted a large-scale genomic analysis of ESCCs from patients in Japan to determine the mutational landscape of this cancer.
METHODS: We performed whole-exome sequence analysis of tumor and nontumor esophageal tissues collected from 144 patients with ESCC who underwent surgery at 5 hospitals in Japan. We also performed single-nucleotide polymorphism array-based copy number profile and germline genotype analyses of polymorphisms in ADH1B and ALDH2. Polymorphisms in CYP2A6, which increase harmful effects of smoking, were analyzed. Functions of TET2 mutants were evaluated in KYSE410 and HEK293FT cells.
RESULTS: A high proportion of mutations in the 144 tumor samples were C to T substitution in CpG dinucleotides (called the CpG signature) and C to G/T substitutions with a flanking 5' thymine (called the APOBEC signature). Based on mutational signatures, patients were assigned to 3 groups, which associated with environmental (drinking and smoking) and genetic (polymorphisms in ALDH2 and CYP2A6) factors. Many tumors contained mutations in genes that regulate the cell cycle (TP53, CCND1, CDKN2A, FBXW7); epigenetic processes (MLL2, EP300, CREBBP, TET2); and the NOTCH (NOTCH1, NOTCH3), WNT (FAT1, YAP1, AJUBA) and receptor-tyrosine kinase-phosphoinositide 3-kinase signaling pathways (PIK3CA, EGFR, ERBB2). Mutations in EP300 and TET2 correlated with shorter survival times, and mutations in ZNF750 associated with an increased number of mutations of the APOBEC signature. Expression of mutant forms of TET2 did not increase cellular levels of 5-hydroxymethylcytosine in HEK293FT cells, whereas knockdown of TET2 increased the invasive activity of KYSE410 ESCC cells. Computational analyses associated the mutations in NFE2L2 we identified with transcriptional activation of its target genes.
CONCLUSIONS: We associated environmental and genetic factors with base substitution patterns of somatic mutations and provide a registry of genes and pathways that are disrupted in ESCCs. These findings might be used to design specific treatments for patients with esophageal squamous cancers.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
esophagus squamous cell carcinoma severityIAGP 150429656DNA:mutationsRGD 
esophagus squamous cell carcinoma severityISOTET2 (Homo sapiens)150429656; 150429656DNA:mutationsRGD 

Objects Annotated

Genes (Rattus norvegicus)
Tet2  (tet methylcytosine dioxygenase 2)

Genes (Mus musculus)
Tet2  (tet methylcytosine dioxygenase 2)

Genes (Homo sapiens)
TET2  (tet methylcytosine dioxygenase 2)


Additional Information