Integrated clinical and genomic analysis identifies driver events and molecular evolution of colitis-associated cancers

Walid K. Chatila, Henry Walch, Jaclyn F. Hechtman, Sydney M. Moyer, Valeria Sgambati, David M. Faleck, Amitabh Srivastava, Laura Tang, Jamal Benhamida, Dorina Ismailgeci, Carl Campos, Fan Wu, Qing Chang, Efsevia Vakiani, Elisa Stanchina, Martin R. Weiser, Maria Widmar, Rhonda K. Yantiss, Manish A. Shah, Adam J. Bass, Zsofia K. Stadler, Lior H. Katz, Ingo K. Mellinghoff, Nilay S. Sethi, Nikolaus Schultz, Karuna Ganesh, David Kelsen and Rona Yaeger ()
Additional contact information
Walid K. Chatila: Weill Cornell Medicine
Henry Walch: Memorial Sloan Kettering Cancer Center
Jaclyn F. Hechtman: Memorial Sloan Kettering Cancer Center
Sydney M. Moyer: Dana-Farber Cancer Institute
Valeria Sgambati: Memorial Sloan Kettering Cancer Center
David M. Faleck: Memorial Sloan Kettering Cancer Center
Amitabh Srivastava: Memorial Sloan Kettering Cancer Center
Laura Tang: Memorial Sloan Kettering Cancer Center
Jamal Benhamida: Memorial Sloan Kettering Cancer Center
Dorina Ismailgeci: Memorial Sloan Kettering Cancer Center
Carl Campos: Memorial Sloan Kettering Cancer Center
Fan Wu: Memorial Sloan Kettering Cancer Center
Qing Chang: Memorial Sloan Kettering Cancer Center
Efsevia Vakiani: Memorial Sloan Kettering Cancer Center
Elisa Stanchina: Memorial Sloan Kettering Cancer Center
Martin R. Weiser: Memorial Sloan Kettering Cancer Center
Maria Widmar: Memorial Sloan Kettering Cancer Center
Rhonda K. Yantiss: Weill Cornell Medicine
Manish A. Shah: Weill Cornell Medicine
Adam J. Bass: Columbia University Irving Medical Center
Zsofia K. Stadler: Memorial Sloan Kettering Cancer Center
Lior H. Katz: Gastroenterology Institute, Sheba Medical Center, Tel Hashomer
Ingo K. Mellinghoff: Memorial Sloan Kettering Cancer Center
Nilay S. Sethi: Dana-Farber Cancer Institute
Nikolaus Schultz: Memorial Sloan Kettering Cancer Center
Karuna Ganesh: Memorial Sloan Kettering Cancer Center
David Kelsen: Memorial Sloan Kettering Cancer Center
Rona Yaeger: Memorial Sloan Kettering Cancer Center

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Inflammation has long been recognized to contribute to cancer development, particularly across the gastrointestinal tract. Patients with inflammatory bowel disease have an increased risk for bowel cancers, and it has been posited that a field of genetic changes may underlie this risk. Here, we define the clinical features, genomic landscape, and germline alterations in 174 patients with colitis-associated cancers and sequenced 29 synchronous or isolated dysplasia. TP53 alterations, an early and highly recurrent event in colitis-associated cancers, occur in half of dysplasia, largely as convergent evolution of independent events. Wnt pathway alterations are infrequent, and our data suggest transcriptional rewiring away from Wnt. Sequencing of multiple dysplasia/cancer lesions from mouse models and patients demonstrates rare shared alterations between lesions. These findings suggest neoplastic bowel lesions developing in a background of inflammation experience lineage plasticity away from Wnt activation early during tumorigenesis and largely occur as genetically independent events.

Date: 2023
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DOI: 10.1038/s41467-022-35592-9

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