TY - JOUR
T1 - Mutational Landscape of Esophageal Squamous Cell Carcinoma in an Indian Cohort
AU - Mangalaparthi, Kiran K.
AU - Patel, Krishna
AU - Khan, Aafaque A.
AU - Manoharan, Malini
AU - Karunakaran, Coral
AU - Murugan, Sakthivel
AU - Gupta, Ravi
AU - Gupta, Rohit
AU - Khanna-Gupta, Arati
AU - Chaudhuri, Amitabha
AU - Kumar, Prashant
AU - Nair, Bipin
AU - Kumar, Rekha V.
AU - Prasad, T. S.Keshava
AU - Chatterjee, Aditi
AU - Pandey, Akhilesh
AU - Gowda, Harsha
N1 - Funding Information:
KM was a recipient of Junior Research Fellowship from University Grants Commission (UGC). KP was the recipient of Senior Research Fellow from Council of Scientific and Industrial Research (CSIR). HG was supported by career development fellowship from NHMRC (APP1148551). Funding. This work was supported by the Wellcome Trust/DBT India Alliance Margdarshi Fellowship (grant number IA/M/15/1/502023) awarded to AP. We thank the Department of Biotechnology (DBT), Government of India for research support to the Institute of Bioinformatics (IOB), Bangalore. IOB was supported by DBT Program Support on Neuroproteomics and infrastructure for proteomic data analysis (BT/01/COE/08/05).
Publisher Copyright:
© Copyright © 2020 Mangalaparthi, Patel, Khan, Manoharan, Karunakaran, Murugan, Gupta, Gupta, Khanna-Gupta, Chaudhuri, Kumar, Nair, Kumar, Prasad, Chatterjee, Pandey and Gowda.
PY - 2020/8/20
Y1 - 2020/8/20
N2 - Esophageal squamous cell carcinoma (ESCC) is the most common histological subtype of esophageal cancer in India. Cigarette smoking and chewing tobacco are known risk factors associated with ESCC. However, genomic alterations associated with ESCC in India are not well-characterized. In this study, we carried out exome sequencing to characterize the mutational landscape of ESCC tumors from subjects with a varied history of tobacco usage. Whole exome sequence analysis of ESCC from an Indian cohort revealed several genes that were mutated or had copy number changes. ESCC from tobacco chewers had a higher frequency of C:G > A:T transversions and 2-fold enrichment for mutation signature 4 compared to smokers and non-users of tobacco. Genes, such as TP53, CSMD3, SYNE1, PIK3CA, and NOTCH1 were found to be frequently mutated in Indian cohort. Mutually exclusive mutation patterns were observed in PIK3CA–NOTCH1, DNAH5–ZFHX4, MUC16–FAT1, and ZFHX4–NOTCH1 gene pairs. Recurrent amplifications were observed in 3q22-3q29, 11q13.3-q13.4, 7q22.1-q31.1, and 8q24 regions. Approximately 53% of tumors had genomic alterations in PIK3CA making this pathway a promising candidate for targeted therapy. In conclusion, we observe enrichment of mutation signature 4 in ESCC tumors from patients with a history of tobacco chewing. This is likely due to direct exposure of esophagus to tobacco carcinogens when it is chewed and swallowed. Genomic alterations were frequently observed in PIK3CA-AKT pathway members independent of the history of tobacco usage. PIK3CA pathway can be potentially targeted in ESCC which currently has no effective targeted therapeutic options.
AB - Esophageal squamous cell carcinoma (ESCC) is the most common histological subtype of esophageal cancer in India. Cigarette smoking and chewing tobacco are known risk factors associated with ESCC. However, genomic alterations associated with ESCC in India are not well-characterized. In this study, we carried out exome sequencing to characterize the mutational landscape of ESCC tumors from subjects with a varied history of tobacco usage. Whole exome sequence analysis of ESCC from an Indian cohort revealed several genes that were mutated or had copy number changes. ESCC from tobacco chewers had a higher frequency of C:G > A:T transversions and 2-fold enrichment for mutation signature 4 compared to smokers and non-users of tobacco. Genes, such as TP53, CSMD3, SYNE1, PIK3CA, and NOTCH1 were found to be frequently mutated in Indian cohort. Mutually exclusive mutation patterns were observed in PIK3CA–NOTCH1, DNAH5–ZFHX4, MUC16–FAT1, and ZFHX4–NOTCH1 gene pairs. Recurrent amplifications were observed in 3q22-3q29, 11q13.3-q13.4, 7q22.1-q31.1, and 8q24 regions. Approximately 53% of tumors had genomic alterations in PIK3CA making this pathway a promising candidate for targeted therapy. In conclusion, we observe enrichment of mutation signature 4 in ESCC tumors from patients with a history of tobacco chewing. This is likely due to direct exposure of esophagus to tobacco carcinogens when it is chewed and swallowed. Genomic alterations were frequently observed in PIK3CA-AKT pathway members independent of the history of tobacco usage. PIK3CA pathway can be potentially targeted in ESCC which currently has no effective targeted therapeutic options.
KW - esophageal cancer
KW - mutation signatures
KW - squamous cell carcinoma
KW - tobacco
KW - whole exome sequencing
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UR - http://www.scopus.com/inward/citedby.url?scp=85090299012&partnerID=8YFLogxK
U2 - 10.3389/fonc.2020.01457
DO - 10.3389/fonc.2020.01457
M3 - Article
AN - SCOPUS:85090299012
SN - 2234-943X
VL - 10
JO - Frontiers in Oncology
JF - Frontiers in Oncology
M1 - 1457
ER -