Jan 7, 2022

Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency

Nature medicine
Anirban Das, Sumedha Sudhaman, Daniel Morgenstern, Ailish Coblentz, Jiil Chung, Simone C Stone, Noor Alsafwani, Zhihui Amy Liu, Ola Abu Al Karsaneh, Shirin Soleimani, Hagay Ladany, David Chen, Matthew Zatzman, Vanja Cabric, Liana Nobre, Vanessa Bianchi, Melissa Edwards, Lauren C Sambira Nahum, Ayse B Ercan, Arash Nabbi, Shlomi Constantini, Rina Dvir, Michal Yalon-Oren, Gadi Abebe Campino, Shani Caspi, Valerie Larouche, Alyssa Reddy, Michael Osborn, Gary Mason, Scott Lindhorst, Annika Bronsema, Vanan Magimairajan, Enrico Opocher, Rebecca Loret De Mola, Magnus Sabel, Charlotta Frojd, David Sumerauer, David Samuel, Kristina Cole, Stefano Chiaravalli, Maura Massimino, Patrick Tomboc, David S Ziegler, Ben George, An Van Damme, Nobuko Hijiya, David Gass, Rose B McGee, Oz Mordechai, Daniel C Bowers, Theodore W Laetsch, Alexander Lossos, Deborah T Blumenthal, Tomasz Sarosiek, Lee Yi Yen, Jeffrey Knipstein, Anne Bendel, Lindsey M Hoffman, Sandra Luna-Fineman, Stefanie Zimmermann, Isabelle Scheers, Kim E Nichols, Michal Zapotocky, Jordan R Hansford, John M Maris, Peter Dirks, Michael D Taylor, Abhaya V Kulkarni, Manohar Shroff, Derek S Tsang, Anita Villani, Wei Xu, Melyssa Aronson, Carol Durno, Adam Shlien, David Malkin, Gad Getz, Yosef E Maruvka, Pamela S Ohashi, Cynthia Hawkins, Trevor J Pugh, Eric Bouffet, Uri Tabori
Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion-deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes...