RT Journal Article
SR Electronic
T1 Genomic analysis of response to neoadjuvant chemotherapy in esophageal adenocarcinoma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.03.26.437144
DO 10.1101/2021.03.26.437144
A1 Fereshteh Izadi
A1 Benjamin P. Sharpe
A1 Stella P. Breininger
A1 Maria Secrier
A1 Jane Gibson
A1 Robert Walker
A1 Saqib Rahman
A1 Ginny Devonshire
A1 Megan A Lloyd
A1 Zoë S. Walters
A1 Rebecca C. Fitzgerald
A1 Matthew J. J. Rose-Zerilli
A1 Tim J. Underwood
A1 on behalf of OCCAMS
YR 2021
UL http://biorxiv.org/content/early/2021/04/23/2021.03.26.437144.abstract
AB Neoadjuvant therapy followed by surgery is the standard of care for locally advanced esophageal adenocarcinoma (EAC). Unfortunately, response to neoadjuvant chemotherapy (NAC) is poor (<20%), as is the overall survival benefit at 5 years (5%). The EAC genome is complex and heterogeneous between patients, and it is not yet understood whether specific mutational patterns may result in chemotherapy sensitivity or resistance. To identify associations between genomic events and response to NAC in EAC, a comparative genomic analysis was performed in 65 patients with extensive clinical and pathological annotation using whole-genome sequencing (WGS). We defined response using Mandard Tumor Regression Grade (TRG), with responders classified as TRG1-2 (n=27) and non-responders classified as TRG4-5 (n=38). We report a higher non-synonymous mutation burden in responders (median 2.08/Mb vs 1.70/Mb, P=0.036) and elevated copy number variation in non-responders (282 vs 136/patient, P<0.001). We identified copy number variants unique to each group in our cohort, with cell cycle (CDKN2A, CCND1), c-Myc (MYC), RTK/PIK3 (KRAS, EGFR) and gastrointestinal differentiation (GATA6) pathway genes being specifically altered in non-responders. Of note, NAV3 mutations were exclusively present in the non-responder group with a frequency of 22%. Thus, lower mutation burden, higher chromosomal instability and specific copy number alterations are associated with resistance to NAC.Competing Interest StatementThe authors have declared no competing interest.