Dissecting Ovarian Cancer Tumor-Immune Microenvironments Through 3D In Situ Molecular Profiling
Abstract
High grade serous ovarian cancer (HGSOC) accounts for >75% of ovarian cancers and is the most lethal gynecological malignancy. Unlike other cancer types, HGSOC has not benefited from advances in cancer immunotherapy despite high levels of tumor-infiltrating lymphocytes (TIL) in some cases. This necessitates a deeper investigation into the recognition of tumor cells by host immunity and causal factors of immune cell avoidance, suppression and evasion. HGSOC presents with widespread disease at diagnosis and within-patient variation in immune microenvironments. HGSOC is an archetype tumor of genomic instability, with profound copy number alterations and genomic rearrangements on a genetic background of near ubiquitous mutation in TP53 rendered bi-allelic through loss of heterozygosity of 17p. Somatic and germline alterations in the homologous recombination repair pathway such as BRCA1 and BRCA2 mutations, lead to homologous recombination deficiency (HRD) in approximately half of HGSOCs. Distinct patient strata are associated with endogenous mutational processes inferred from structural variation patterns in whole genome sequencing: HRD subtypes (BRCA1-associated tandem duplications: HRD-Dup; BRCA2-associated interstitial deletions: HRD-Del), foldback-inversion (FBI) bearing tumors and CDK12-associated tandem duplicators (TD), amongst related mutational processes defined by copy number alteration and other recently described structural variation patterns. Notably, the mutational processes are associated with different clinical outcomes, with FBI and TD tumors exhibiting the worst prognoses. The malignant-immune interface is also influenced by these endogenous mutational processes. Specifically, FBI tumors display reduced immune infiltration, in contrast to HRD-Dup and HRD-Del groups which harbor increased levels of cytotoxic T cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2023
- Accession Number
- AD1225965
Entities
People
- Sohrab Shah
Organizations
- Memorial Sloan Kettering Cancer Center