Context-dependent effects of CDKN2A and other 9p21 gene losses during the evolution of esophageal cancer
Ganguli P., Basanta CC., Acha-Sagredo A., Misetic H., Armero M., Mendez A., Zahra A., Devonshire G., Kelly G., Freeman A., Green M., Nye E., Bichisecchi A., Bonfanti P., Bartlett F., Petty RD., Coleman H., McManus D., Turkington R., Grabowska A., Moorthy K., Peters CJ., Hanna GB., Lishman S., Sothi S., Scott M., Haidry R., Lovat L., Saunders J., Kaye P., Soomro I., Parsons SL., Sreedharan L., Kumar B., Cheong E., Chan D., Berrisford R., Sanders G., Ciccarelli FD., Goh V., Mahadeva U., Chang F., Davies A., Gossage J., Lagergren J., Grace BL., Walker RC., Underwood TJ., Contino G., Puig S., Taniere P., Beggs A., Tucker O., O’Neill JR., Hupp TR., Skipworth RJE., Save V., Bagwan I., Preston SR., Sharrocks A., Ang Y., Hayes SJ., Sujendran V., Hindmarsh A., Safranek P., Hardwick RH., Carroll N., Crichton C., Davies J., Secrier M., Eldridge M., Millington C., Coles H., Tripathi M., Malhotra S., Miremadi A., O’Donovan M., Smyth EC., Freeman A., Abbas S., Loreno C., Redmond AM., Nutzinger B., Grehan N., Edwards PAW., Fitzgerald RC., Rodriguez-Justo M., Spencer J., Fitzgerald RC., Ciccarelli FD.
CDKN2A is a tumor suppressor located in chromosome 9p21 and frequently lost in Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC). How CDKN2A and other 9p21 gene co-deletions affect EAC evolution remains understudied. We explored the effects of 9p21 loss in EACs and cancer progressor and non-progressor BEs with matched genomic, transcriptomic and clinical data. Despite its cancer driver role, CDKN2A loss in BE prevents EAC initiation by counterselecting subsequent TP53 alterations. 9p21 gene co-deletions predict poor patient survival in EAC but not BE through context-dependent effects on cell cycle, oxidative phosphorylation and interferon response. Immune quantifications using bulk transcriptome, RNAscope and high-dimensional tissue imaging showed that IFNE loss reduces immune infiltration in BE, but not EAC. Mechanistically, CDKN2A loss suppresses the maintenance of squamous epithelium, contributing to a more aggressive phenotype. Our study demonstrates context-dependent roles of cancer genes during disease evolution, with consequences for cancer detection and patient management.