In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 2500-2500
Abstract:
Carriers of pathogenic germline mutations in BRCA1/2 are highly predisposed to breast and ovarian cancers. Although their primary tumors respond to DNA-damaging agents, such as platinum-based chemotherapy and poly (ADP-ribose) polymerase inhibitors (PARPi), these malignancies often return as therapy-resistant recurrences. To identify genetic mechanisms of therapeutic resistance, we performed whole exome sequencing on 41 pairs of matched primary/recurrent breast and ovarian tumors from 27 BRCA1/2 mutation carriers. The cohort consisted of 14 ovarian cancer patients (nine BRCA1, five BRCA2) and 13 breast cancer patients (nine BRCA1, four BRCA2). Five patients received PARPi, 17 patients received platinums, and all patients received some type of chemotherapy prior to recurrence. First, we performed a segmentation analysis to assess copy number variation (CNVs) in each tumor. We calculated homologous recombination deficiency (HRD) scores for each tumor, but found no significant differences between matched primary/recurrent pairs. We noted that primary tumors had a relatively high average HRD score (55/100), which remained high in recurrences (52/100). Next, we totaled arm-level CNVs to generate aneuploidy scores for each tumor. Using a Wilcoxon signed rank test, we found that aneuploidy scores were significantly higher in recurrences than in matched primary tumors (p=0.007). This finding suggests that recurrences have more arm-level CNVs than primary tumors, but that acquired genomic abnormalities are not caused by HRD per se. Instead, arm-level CNVs indicate that replication errors or genome doubling events are more common in recurrences than in primary tumors. Lastly, we annotated all tumors' CNVs with genes to interrogate potential effects on signaling pathways, including CNVs exclusive to each recurrence. Using Gene Set Enrichment Analysis with Hallmark gene sets, we identified pathways significantly (FDR q & lt;0.30) affected by losses (CN≤1) and gains (CN≥4) from primary tumor CNVs, recurrent tumor CNVs, and recurrence-exclusive CNVs. All three CNV sets showed gains encompassing interferon gamma response genes and losses of Hedgehog signaling genes. Primary tumor losses were enriched for reactive oxygen species and cholesterol homeostasis genes. Recurrent tumor and recurrence-exclusive gains were enriched for UV-responsive and MTORC1 signaling gene sets, which may enhance survival in the presence of DNA-damaging or cytotoxic chemotherapies. These findings suggest that CNVs encompass different genes in recurrences compared to matched primary tumors. Further, differences in gene dosage and downstream signaling could represent novel therapeutic targets for recurrent tumors. Ultimately, we found that CNVs grant insights into the genomic and signaling processes that underlie acquired therapeutic resistance in BRCA1/2 mutation-associated cancers. Citation Format: Jennifer Brady Shah, Bradley Wubbenhorst, John Pluta, Caitlin Feltcher, Lauren Schmucker, Kurt D'Andrea, Heather Symecko, Catherine Ruan, Anupma Nayak, Kara N. Maxwell, Susan Domchek, Katherine L. Nathanson. Copy number variation in recurrent BRCA1/2 germline mutation-associated breast and ovarian cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2500.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2020-2500
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2020
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
