Browsing by Author "Moore, Nathanael D."

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    Inherited DNA-Repair Defects in Colorectal Cancer
    (Elsevier, 2018-03-01) AlDubayan, Saud H.; Giannakis, Marios; Moore, Nathanael D.; Han, G. Celine; Reardon, Brendan; Hamada, Tsuyoshi; Mu, Xingmeng Jasmine; Nishihara, Reiko; Qian, Zhirong; Liu, Li; Yurgelun, Matthew B.; Syngal, Sapna; Garraway, Levi A.; Ogino, Shuji; Fuchs, Charles S.; Van Allen, Eliezer M.; Medicine, School of Medicine
    Colorectal cancer (CRC) heritability has been estimated to be around 30%. However, mutations in the known CRC-susceptibility genes explain CRC risk in fewer than 10% of affected individuals. Germline mutations in DNA-repair genes (DRGs) have recently been reported in CRC, but their contribution to CRC risk is largely unknown. We evaluated the gene-level germline mutation enrichment of 40 DRGs in 680 unselected CRC individuals and 27,728 ancestry-matched cancer-free adults. Significant findings were then examined in independent cohorts of 1,661 unselected CRC individuals and 1,456 individuals with early-onset CRC. Of the 680 individuals in the discovery set, 31 (4.56%) individuals harbored germline pathogenic mutations in known CRC-susceptibility genes, and another 33 (4.85%) individuals had DRG mutations that have not been previously associated with CRC risk. Germline pathogenic mutations in ATM and PALB2 were enriched in both the discovery (OR = 2.81 and p = 0.035 for ATM and OR = 4.91 and p = 0.024 for PALB2) and validation (OR = 2.97 and adjusted p = 0.0013 for ATM and OR = 3.42 and adjusted p = 0.034 for PALB2) sets. Biallelic loss of ATM was evident in all individuals with matched tumor profiling. CRC individuals also had higher rates of actionable mutations in the HR pathway, which can substantially increase the risk of developing cancers other than CRC. Our analysis provides evidence for ATM and PALB2 as CRC-risk genes, underscoring the importance of the homologous recombination pathway in CRC. In addition, we identified frequent complete homologous recombination deficiency in CRC tumors, representing a unique opportunity to explore targeted therapeutic interventions such as poly-ADP ribose polymerase inhibitor (PARPi).
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    Integrating molecular profiles into clinical frameworks through the Molecular Oncology Almanac to prospectively guide precision oncology
    (Springer Nature, 2021) Reardon, Brendan; Moore, Nathanael D.; Moore, Nicholas S.; Kofman, Eric; AlDubayan, Saud H.; Cheung, Alexander T.M.; Conway, Jake; Elmarakeby, Haitham; Imamovic, Alma; Kamran, Sophia C.; Keenan, Tanya; Keliher, Daniel; Konieczkowski, David J.; Liu, David; Mouw, Kent W.; Park, Jihye; Vokes, Natalie I.; Dietlein, Felix; Van Allen, Eliezer M.; Medicine, School of Medicine
    Tumor molecular profiling of single gene-variant ('first-order') genomic alterations informs potential therapeutic approaches. Interactions between such first-order events and global molecular features (for example, mutational signatures) are increasingly associated with clinical outcomes, but these 'second-order' alterations are not yet accounted for in clinical interpretation algorithms and knowledge bases. We introduce the Molecular Oncology Almanac (MOAlmanac), a paired clinical interpretation algorithm and knowledge base to enable integrative interpretation of multimodal genomic data for point-of-care decision making and translational-hypothesis generation. We benchmarked MOAlmanac to a first-order interpretation method across multiple retrospective cohorts and observed an increased number of clinical hypotheses from evaluation of molecular features and profile-to-cell line matchmaking. When applied to a prospective precision oncology trial cohort, MOAlmanac nominated a median of two therapies per patient and identified therapeutic strategies administered in 47% of patients. Overall, we present an open-source computational method for integrative clinical interpretation of individualized molecular profiles.