Neoantigens and genome instability: impact on immunogenomic phenotypes and immunotherapy response

被引:85
作者
Mardis, Elaine R. [1 ]
机构
[1] Ohio State Univ, Inst Genom Med, Coll Med, Nationwide Childrens Hosp, Childrens Dr, Columbus, OH 43205 USA
关键词
MISMATCH REPAIR-DEFICIENCY; DNA-POLYMERASE EPSILON; T-CELL EPITOPES; COLORECTAL-CANCER; PD-1; BLOCKADE; SOMATIC MUTATIONS; CTLA-4; GENE-MUTATIONS; DOUBLE-BLIND; GENERATION;
D O I
10.1186/s13073-019-0684-0
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
The resurgence of immune therapies in cancer medicine has elicited a corresponding interest in understanding the basis of patient response or resistance to these treatments. One aspect of patient response clearly lies in the genomic alterations that are associated with cancer onset and progression, including those that contribute to genomic instability and the resulting creation of novel peptide sequences that may present as neoantigens. The immune reaction to these unique 'non-self' peptides is frequently suppressed by the tumor itself, but the use of checkpoint blockade therapies, personalized vaccines, or a combination of these treatments may elicit a tumor-specific immune response that results in cell death. Massively parallel sequencing, coupled with different computational analyses, provides unbiased identification of the germline and somatic alterations that drive cancer development, and of those alterations that lead to neoantigens. These range from simple point mutations that change single amino acids to complex alterations, such as frameshift insertion or deletion mutations, splice-site alterations that lead to exon skipping, structural alterations that lead to the formation of fusion proteins, and other forms of collateral damage caused by genome instability that result in new protein sequences unique to the cancer. The various genome instability phenotypes can be identified as alterations that impact DNA replication or mismatch repair pathways or by their genomic signatures. This review provides an overview of current knowledge regarding the fundamentals of genome replication and of both germline and somatic alterations that disrupt normal replication, leading to various forms of genomic instability in cancers, to the resulting generation of neoantigens and, ultimately, to immune-responsive and resistant phenotypes.
引用
收藏
页数:12
相关论文
共 91 条
[1]   Signatures of mutational processes in human cancer [J].
Alexandrov, Ludmil B. ;
Nik-Zainal, Serena ;
Wedge, David C. ;
Aparicio, Samuel A. J. R. ;
Behjati, Sam ;
Biankin, Andrew V. ;
Bignell, Graham R. ;
Bolli, Niccolo ;
Borg, Ake ;
Borresen-Dale, Anne-Lise ;
Boyault, Sandrine ;
Burkhardt, Birgit ;
Butler, Adam P. ;
Caldas, Carlos ;
Davies, Helen R. ;
Desmedt, Christine ;
Eils, Roland ;
Eyfjord, Jorunn Erla ;
Foekens, John A. ;
Greaves, Mel ;
Hosoda, Fumie ;
Hutter, Barbara ;
Ilicic, Tomislav ;
Imbeaud, Sandrine ;
Imielinsk, Marcin ;
Jaeger, Natalie ;
Jones, David T. W. ;
Jones, David ;
Knappskog, Stian ;
Kool, Marcel ;
Lakhani, Sunil R. ;
Lopez-Otin, Carlos ;
Martin, Sancha ;
Munshi, Nikhil C. ;
Nakamura, Hiromi ;
Northcott, Paul A. ;
Pajic, Marina ;
Papaemmanuil, Elli ;
Paradiso, Angelo ;
Pearson, John V. ;
Puente, Xose S. ;
Raine, Keiran ;
Ramakrishna, Manasa ;
Richardson, Andrea L. ;
Richter, Julia ;
Rosenstiel, Philip ;
Schlesner, Matthias ;
Schumacher, Ton N. ;
Span, Paul N. ;
Teague, Jon W. .
NATURE, 2013, 500 (7463) :415-+
[2]   MHC-II neoantigens shape tumour immunity and response to immunotherapy [J].
Alspach, Elise ;
Lussier, Danielle M. ;
Miceli, Alexander P. ;
Kizhvatov, Ilya ;
DuPage, Michel ;
Luoma, Adrienne M. ;
Meng, Wei ;
Lichti, Cheryl F. ;
Esaulova, Ekaterina ;
Vomund, Anthony N. ;
Runci, Daniele ;
Ward, Jeffrey P. ;
Gubin, Matthew M. ;
Medrano, Ruan F. V. ;
Arthur, Cora D. ;
White, J. Michael ;
Sheehan, Kathleen C. F. ;
Chen, Alex ;
Wucherpfennig, Kai W. ;
Jacks, Tyler ;
Unanue, Emil R. ;
Artyomov, Maxim N. ;
Schreiber, Robert D. .
NATURE, 2019, 574 (7780) :696-+
[3]   Mutator phenotypes due to DNA replication infidelity [J].
Arana, Mercedes E. ;
Kunkel, Thomas A. .
SEMINARS IN CANCER BIOLOGY, 2010, 20 (05) :304-311
[4]  
Bassani-Sternberg M, 2018, METHODS MOL BIOL, V1719, P209, DOI 10.1007/978-1-4939-7537-2_14
[5]  
Bebenek K, 2004, ADV PROTEIN CHEM, V69, P137
[6]   Randomized, Double-Blind, Phase III Trial of Ipilimumab Versus Placebo in Asymptomatic or Minimally Symptomatic Patients With Metastatic Chemotherapy-Naive Castration-Resistant Prostate Cancer [J].
Beer, Tomasz M. ;
Kwon, Eugene D. ;
Drake, Charles G. ;
Fizazi, Karim ;
Logothetis, Christopher ;
Gravis, Gwenaelle ;
Ganju, Vinod ;
Polikoff, Jonathan ;
Saad, Fred ;
Humanski, Piotr ;
Piulats, Josep M. ;
Gonzalez Mella, Pablo ;
Ng, Siobhan S. ;
Jaeger, Dirk ;
Parnis, Francis X. ;
Franke, Fabio A. ;
Puente, Javier ;
Carvajal, Roman ;
Sengelov, Lisa ;
McHenry, M. Brent ;
Varma, Arvind ;
van den Eertwegh, Alfonsus J. ;
Gerritsen, Winald .
JOURNAL OF CLINICAL ONCOLOGY, 2017, 35 (01) :40-+
[7]   The emerging clinical relevance of genomics in cancer medicine [J].
Berger, Michael F. ;
Mardis, Elaine R. .
NATURE REVIEWS CLINICAL ONCOLOGY, 2018, 15 (06) :353-365
[8]  
Billingsley C., 2014, CANCER, V121, P386, DOI [10.1002/cncr.29046, 10.1002/cncr.290461:CAS:528:DC%2BC2MXhslams7c%3D, DOI 10.1002/CNCR.29046]
[9]   Immune Checkpoint Inhibition for Hypermutant Glioblastoma Multiforme Resulting From Germline Biallelic Mismatch Repair Deficiency [J].
Bouffet, Eric ;
Larouche, Valerie ;
Campbell, Brittany B. ;
Merico, Daniele ;
de Borja, Richard ;
Aronson, Melyssa ;
Durno, Carol ;
Krueger, Joerg ;
Cabric, Vanja ;
Ramaswamy, Vijay ;
Zhukova, Nataliya ;
Mason, Gary ;
Farah, Roula ;
Afzal, Samina ;
Yalon, Michal ;
Rechavi, Gideon ;
Magimairajan, Vanan ;
Walsh, Michael F. ;
Constantini, Shlomi ;
Dvir, Rina ;
Elhasid, Ronit ;
Reddy, Alyssa ;
Osborn, Michael ;
Sullivan, Michael ;
Hansford, Jordan ;
Dodgshun, Andrew ;
Klauber-Demore, Nancy ;
Peterson, Lindsay ;
Patel, Sunil ;
Lindhorst, Scott ;
Atkinson, Jeffrey ;
Cohen, Zane ;
Laframboise, Rachel ;
Dirks, Peter ;
Taylor, Michael ;
Malkin, David ;
Albrecht, Steffen ;
Dudley, Roy W. R. ;
Jabado, Nada ;
Hawkins, Cynthia E. ;
Shlien, Adam ;
Tabori, Uri .
JOURNAL OF CLINICAL ONCOLOGY, 2016, 34 (19) :2206-+
[10]   Risk of colorectal cancer for carriers of a germ-line mutation in POLE or POLD1 [J].
Buchanan, Daniel D. ;
Stewart, Jenna R. ;
Clendenning, Mark ;
Rosty, Christophe ;
Mahmood, Khalid ;
Pope, Bernard J. ;
Jenkins, Mark A. ;
Hopper, John L. ;
Southey, Melissa C. ;
Macrae, Finlay A. ;
Winship, Ingrid M. ;
Win, Aung Ko .
GENETICS IN MEDICINE, 2018, 20 (08) :890-895