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Mutational signatures in esophageal squamous cell carcinoma from eight countries with varying incidence
Nature Genetics  (IF38.33),  Pub Date : 2021-10-18, DOI: 10.1038/s41588-021-00928-6
Sarah Moody, Sergey Senkin, S. M. Ashiqul Islam, Jingwei Wang, Dariush Nasrollahzadeh, Ricardo Cortez Cardoso Penha, Stephen Fitzgerald, Erik N. Bergstrom, Joshua Atkins, Yudou He, Azhar Khandekar, Karl Smith-Byrne, Christine Carreira, Valerie Gaborieau, Calli Latimer, Emily Thomas, Irina Abnizova, Pauline E. Bucciarelli, David Jones, Jon W. Teague, Behnoush Abedi-Ardekani, Stefano Serra, Jean-Yves Scoazec, Hiva Saffar, Farid Azmoudeh-Ardalan, Masoud Sotoudeh, Arash Nikmanesh, Hossein Poustchi, Ahmadreza Niavarani, Samad Gharavi, Michael Eden, Paul Richman, Lia S. Campos, Rebecca C. Fitzgerald, Luis Felipe Ribeiro, Sheila Coelho Soares-Lima, Charles Dzamalala, Blandina Theophil Mmbaga, Tatsuhiro Shibata, Diana Menya, Alisa M. Goldstein, Nan Hu, Reza Malekzadeh, Abdolreza Fazel, Valerie McCormack, James McKay, Sandra Perdomo, Ghislaine Scelo, Estelle Chanudet, Laura Humphreys, Ludmil B. Alexandrov, Paul Brennan, Michael R. Stratton

Esophageal squamous cell carcinoma (ESCC) shows remarkable variation in incidence that is not fully explained by known lifestyle and environmental risk factors. It has been speculated that an unknown exogenous exposure(s) could be responsible. Here we combine the fields of mutational signature analysis with cancer epidemiology to study 552 ESCC genomes from eight countries with varying incidence rates. Mutational profiles were similar across all countries studied. Associations between specific mutational signatures and ESCC risk factors were identified for tobacco, alcohol, opium and germline variants, with modest impacts on mutation burden. We find no evidence of a mutational signature indicative of an exogenous exposure capable of explaining differences in ESCC incidence. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC)-associated mutational signatures single-base substitution (SBS)2 and SBS13 were present in 88% and 91% of cases, respectively, and accounted for 25% of the mutation burden on average, indicating that APOBEC activation is a crucial step in ESCC tumor development.