Abstract 2200: NF1 copy number alterations in clinically-defined subsets of high-grade serous ovarian cancers
Authors: Sanghoon Lee, Li Zhao, Joseph Celestino, Richard A. Hajek, Margaret B. Morgan, Mark S. Kim, Shannon N. Westin, Amir A. Jazaeri, Nicole D. Fleming, Jinsong Liu, Jianhua Zhang, P Andrew Futreal, Anil K. Sood
Journal: Cancer Research (2021)

Abstract Background: While high-grade serous ovarian cancers (HGSC) look alike at a histological level, there is marked variation in clinical outcomes; however, the underlying mechanisms are not well understood. We previously highlighted significant distinct molecular and cellular characteristics in highly clinically annotated HGSC tumor samples from patients who underwent complete gross resection (R0) or received neoadjuvant chemotherapy (NACT). Neurofibromatosis type 1 (NF1) is known to negatively regulate the Ras/MAPK signaling pathways and tumorigenesis. Here, we specifically validate the higher loss of NF1 copy number exhibited in the R0 compared to the NACT groups in patients with HGSC. Methods: Fresh-frozen tumor biopsies were collected from patients with HGSC treated under a systematic surgical algorithm: complete gross resection after primary surgery (R0, n=40); poor tumor response to NACT (NACT-PR, n=26); excellent tumor response to NACT with carboplatin and paclitaxel (NACT-ER, n=14). Primary or metastatic tumor sites for each patient were obtained pre-treatment and subjected to high-depth targeted DNA sequencing. Results: The average coverage of 568X for tumors and 291X for germline controls (matched blood samples) was obtained by targeted sequencing for each sample from the entire cohort. The median numbers of non-synonymous somatic mutations identified in the panel sequencing were 5 in R0, 3 in NACT-ER, and 5 in NACT-PR. Sixty-nine of the 80 samples (86.25%) had alterations in at least one of the ovarian cancer-related genes. The most frequently altered genes including somatic mutations and copy number variations were TP53 (68%), NF1 (65%) and ERBB2 (62%) in the R0 group whereas TP53 (50%), AKT1 (48%) and TERT (42%) in the NACT group. Gene alteration enrichment was evaluated by comparing between two groups. 17 genes were found to be enriched for alterations in the R0 group comparing to the NACT group; MLH3 (OR= 15.03, p&amp;lt;0.001), CDK13 (OR=11.08, p&amp;lt;0.001), GOPC (OR=9.96, p=0.0015), and NF1 (OR=4.25, p=0.0033). Importantly, among all the significantly enriched gene alterations, NF1 and CSMD3 were observed with consistent enrichment in the R0 versus the NACT group as we previously observed (Lee et al, Cell Reports, 2011). Conclusions: Our findings, using an independent validation cohort of patients, verified the higher loss of NF1 copy number in the R0 versus the NACT group. These findings could have major implications for clinical decision making and developing novel therapies for patients with HGSC. Citation Format: Sanghoon Lee, Li Zhao, Joseph Celestino, Richard A. Hajek, Margaret B. Morgan, Mark S. Kim, Shannon N. Westin, Amir A. Jazaeri, Nicole D. Fleming, Jinsong Liu, Jianhua Zhang, P Andrew Futreal, Anil K. Sood. NF1 copy number alterations in clinically-defined subsets of high-grade serous ovarian cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2200.