Exploring the nuances between BRCA1 and 2: A multiomic analysis.

Authors

null

Radhika Gogoi

Wayne State University, Detroit, MI

Radhika Gogoi , Sharon Wu , Alex Farrell , Seongho Kim , John Wallbillich , Ira Seth Winer , Robert Morris , David Spetzler , Alberto Puccini , Nathaniel L. Jones , Thomas J. Herzog , Premal H. Thaker , Gil Mor , Ayesha Alvero

Organizations

Wayne State University, Detroit, MI, Caris Life Sciences, Phoenix, AZ, CARIS Life Sciences, Irving, TX, Karmanos Cancer Institute/Wayne State University, Detroit, MI, Wayne State University/Karmanos Cancer Center, Detroit, MI, Karmanos Cancer Institute, Detroit, MI, Harper Prof Bldg, Detroit, MI, Ospedale Policlinico San Martino, Genova, CA, Italy, Columbia University College of Physicians and Surgeons and New York Presbyterian Hospital, New York, NY, University of Cincinnati, University of Cincinnati Cancer Institute, Cincinnati, OH, Department of Gynecologic Oncology, Washington University School of Medicine, St. Louis, MO, C.S. Mott Center for Human Growth and Development, Detroit, MI

Research Funding

Other Foundation

Background: Emerging data suggests that key differences exist between BRCA1 and BRCA2 associated OC, including response to therapy and survival. The purpose of this study was to identify the gene expression profiles, interacting pathways and immune microenvironment of BRCA1 mutant (BRCA1mut), BRCA2 mutant (BRCA2mut) and homologous recombination wild-type (HRwt) associated high grade serous OC (HGSOC). Methods: Next-generation sequencing (592, NextSeq; WES, NovaSeq) and Whole Transcriptome Sequencing (NovaSeq) (Caris Life Sciences, Phoenix, AZ) were performed in 8196 OC tumors classified into 3 groups: BRCA1mt; BRCA2mt; and HRwt. BRCA mutations were defined as variants that result in loss-of-function of the BRCA protein and HRwt was defined as samples negative for aberrations in both BRCA1 and BRCA2, as well as for 28 other homologous recombination genes Microsatellite instability (MSI) was tested by fragment analysis, IHC and NGS. Tumor mutational burden (TMB) was measured by totaling somatic mutations (TMB-H: >10 mutations/MB). LOH cut-off >16%. Immune cell infiltrates were calculated by XCell. Differential gene expression was calculated using Limma. Significance was determined using chi-square and Wilcoxon rank sum test and adjusted for multiple comparisons (q-value < 0.05). Results: We identified 677 BRCA1mt, 439 BRCA2mt, and 7080 HRwt OC tumors. HGSOC made up the largest portion of BRCA1mt (523; 77%), BRCA2mt (306; 70%), and HRwt (4281; 60%) tumors. TP53 was most commonly mutated gene in all three groups. LOH (>16%) was highest in BRCA1mt (86.8%) compared to BRCA2mt (74.8%) and HRwt (38.4%). TMB-H was highest in BRCA2mt (6.29%) than in BRCA1mt (1.35%) and HRwt (0.91%) HGSOC (all q < 0.05). Expression of immune checkpoint genes CD80, CD86, CD274, CTLA4, HAVCR2/TIM3, IFNG, IDO1, LAG3, PDCD1 and PDCD1LG2 were significantly higher in BRCA1 and BRCA2 mt compared to HRwt HGSOC (FC: 1.12-1.59, q < 0.05). HRwt tumors had decreased infiltration of Activated Dendritic cells compared to BRCA1mt, and lower Macrophage M1 compared to both BRCA1mt and BRCA2mt (all q < 0.05). Additionally, T-inflamed score was higher in BRCA1mt compared to HRwt, while IFN score was higher in BRCA1mt compared to both BRCA2mt and HRwt (all q < 0.05). From 17,408 genes with measured expression. 522 (3.0%) differentially expressed genes (DEG) were found between BRCA2mt vs BRCA1mt; 1487 (8.54%) between BRCA2mt vs HRwt; and 9297 (53.4%) between BRCA1mt and HRwt HGSOC. Pathway analysis identified Fatty Acid Metabolism, Myc targets, ROS pathway, Oxidative Phosphorylation, and Wnt B-catenin signaling pathways as differentially regulated between the 3 groups. Conclusions: We describe the genomic, pathway and immunologic analyses in the largest cohort of BRCA1 and 2 mutated HGSOC to date. Both metabolic and immune response pathways are differentially regulated between the groups. Results can potentially inform targeted therapeutic studies based on unique BRCA genotype.

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Abstract Details

Meeting

2022 ASCO Annual Meeting

Session Type

Poster Session

Session Title

Gynecologic Cancer

Track

Gynecologic Cancer

Sub Track

Ovarian Cancer

Citation

J Clin Oncol 40, 2022 (suppl 16; abstr 5580)

DOI

10.1200/JCO.2022.40.16_suppl.5580

Abstract #

5580

Poster Bd #

456

Abstract Disclosures

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