Genomic Instability and Cancer Genetics

GENOMIC INSTABILITY AND CANCER GENETICS PROGRAM PROJECT SUMMARY/ABSTRACT The overall goals of the Genomic Instability and Cancer Genetics (GICG) Program are to determine the mechanisms by which genome stability is maintained to prevent tumorigenesis, to define the landscapes of cancer genomes, and to expose the therapeutic vulnerability of cancer due to genomic alterations. The GICG Program is organized around three themes: 1) fundamental mechanisms of genome maintenance in DNA repair, replication fidelity, and cell cycle control; 2) modifying and regulatory factors of tumorigenesis; and 3) genomic alterations in cancer. The GICG Program is composed of a highly qualified and collaborative team of 40 Members with diverse and complementary expertise from 21 departments, nine schools, three universities, and one institute. Our research is currently supported by $10.8 million in cancer-relevant funding ($4.6 million annual direct funds from NCI), 32 cancer-focused NIH R01 or equivalent research grants to 21 independent PD/PIs and 14 multi-PI awards including one P01 award. Productivity and collaboration within GICG are evident from the 523 cancer-focused publications during 11/2017-10/2022 (compared to 483 during 11/2012-10/2017), 33% being collaborative publications including 11% intra- and 28% interprogrammatic, 63% multi-institutional collaborative publications, and 38% of the publications are in journals with impact factor (IF) of 10 or greater. Examples of impactful science during the current grant period are exemplified by the application of an innovative single-cell based CRISPR screen of ~450 DNA repair genes to decipher the in-depth mechanisms of DNA repair; the demonstration of critical roles of BRCA1-PALB2-BRCA2 interactions and associated factors in replication fidelity, cell cycle checkpoint control and tumor suppression; the identification of a new mechanism of mitotic spindle assembly; the discovery of novel functions of TP53 and its regulated genes in a diverse array of activities that modulate tumor development; identification of new pathways in cell fate determination after DNA damage; new findings on the relationship between tissue homeostasis and tumorigenesis; identification of distinct subgroups of neuroendocrine tumors, and identification and validation of fibroblast growth factor receptor 2 (FGFR2) mutant targetable drivers; and the development of numerous genomic tools for precision oncology. Examples of outstanding programmatic accomplishments and impact include the forward and reverse translation of the mechanistic and genomic studies, the catchment relevance of GICG research to a broad range of cancer types as well as key cancer risk factors, the Program participation in community outreach activities, training of scientists from under-represented groups, and the highly collaborative and synergistic team science as reflected by multi-PI awards and a new P01 program project grant.