Abstract 6072: Chromosomal aneuploidy, whole-genome doubling and mutational signatures in NCI PDMR models

• Published in: Cancer research (Chicago, Ill.) Ill.), 2023-04, Vol.83 (7_Supplement), p.6072-6072
• Main Authors: Chen, Li, Das, Biswajit, Chang, Ting-Chia, Evrard, Yvonne A., Karlovich, Chris A., Chapman, Alyssa, Fullmer, Brandie, Hayes, Ashley, Thornton, Ruth, Nair, Nikitha, Jiwani, Shahanawaz, Dutko, Lindsay, Benauer, Kelly, Rivera, Gloryvee, Camalier, Corinne, Carter, John, Borgel, Suzanne, Miner, Tiffanie, McGlynn, Chelsea, Mills, Justine, Uzelac, Shannon, Shearer, Tia, Hicks, Lauren, Norris, Michelle, Border, Carley, Alcoser, Sergio, Walsh, Thomas, Mullendore, Michael, Eugeni, Michelle, Newton, Dianne, Hollingshead, Melinda G., Williams, P. Mickey, Doroshow, James H.
• Format: Article
• Language: English
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.AM2023-6072

Introduction: Structural variants (SVs) are a unique class of mutations which have certain therapeutic implications for the tumor. Certain SVs, such as chromosomal aneuploidy, whole-genome doubling (WGD), have specific therapeutic implications. The underlying cellular processes present in the tumor are reflected in mutational signatures. Here, we describe the landscape of chromosomal aneuploidy, WGD and mutational signatures in the National Cancer Institute’s Patient-Derived Models Repository (NCI PDMR) to facilitate the investigation of their roles in therapeutic responses of the preclinical models. Method: Chromosome arm-level aneuploidy was called by scoring at the individual arm level if >90% of the arm copy number (CN) was gained/lost based on whole-exome sequencing (WES) data. Aneuploidy score was defined as number of arms with aneuploidy. WGD was determined by derived allelic specific CN, purity and ploidy from tumor/normal matched samples and permutation test. Mutational signatures (COSMIC v3) including single base substitutions (SBS), doublet base substitutions (DBS), small insertions and deletions (ID) and CN signatures were derived using SigProfiler for specimens with somatic mutations and CNs. Results: A large fraction (85%) of patient-derived xenograft (PDX) models (N=755) have at least one arm -level aneuploidy. Certain chromosomes and arms (7, 8, 17p and 18) are more frequently aneuploid, which might be biased due to the overrepresentation of gastrointestinal cancer in the cohort. Histology specific differences were observed in the frequency of arm level aneuploidies. For example, synovial sarcoma (SYNS) and endometrioid carcinoma (UEC) have much lower level of aneuploidy than non-small cell lung cancer (NSCLC) or clear cell renal carcinoma (ccRCC) models. 61% of PDX models (N=277) have WGD, in which certain histologies have more WGD [NSCLC: 81%, head and neck squamous cell carcinomas (HNSCC): 71%] than others. Samples having WGD have a higher degree of aneuploidy and chromosomal instability. WGD and aneuploidy remain stable along the passages in 78% PDX models. Intra-model heterogeneity of WGD was observed due to lineage difference. Mutational signatures (SBS6,15,20) indicating concurrent DNA polymerase epsilon (POLE) mutation and defective DNA mismatch repair were highly enriched in microsatellite instability-high models (p