Dissecting the Impact of Mutational Processes on Therapeutic Response in Ovarian Cancer
Abstract
High grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy and while treatment with PARP inhibitors has shown some promise for patients with BRCA1/2 mutations these mutations remain an imperfect predictor for response. Our team has established structural variant-associated mutational processes for patient risk stratification: homologous recombination deficient(HRD) tumors, either associated with BRCA1 mutation-linked duplications (HRD-Dup) or BRCA2 mutation-linked interstitial deletions (HRD-Del), have a better prognosis than homologous recombination proficient tumors, including CDK-12 associated tandem duplications (TD) and foldback inversion (FBI) bearing tumors. Our hypothesis is that these distinct mutational processes confer differential evolutionary capacity on the malignant cells and impact treatment response. Aim 1 proposed to define the contemporary vs vestigial DNA defects resulting from specific structural mutational processes in HGSOC. Analyzing mutational patterns in greater than 22,000 single cell whole genomes (scDNA) from HRD and FBI tumors we observed widespread aneuploidy and continuous whole genome duplication in HR deficient cancer cells, whereas FBI tumors showed early ploidy fixation and large clone-specific variation in local high-level amplifications with substantial breakpoint variability, often impacting oncogenes and increasing genome plasticity. In Aim 2 we planned to define the functional impact of mutational processes on the transcriptome. To probe the effect of mutational processes on gene expression and cellular phenotype we performed single cell RNA sequencing (scRNA-seq) on 42 HGSOC tumors with different mutational signatures. We observed an increased neoantigen burden, inflammatory signaling and ongoing immunoediting in HRD tumors, while FBI tumors exhibited elevated TGFb signaling.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2021
- Accession Number
- AD1166778
Entities
People
- Sohrab Shah
Organizations
- Memorial Sloan Kettering Cancer Center