Oral Presentation 32nd Lorne Cancer 2020

Spatially resolved intra tumour heterogeneity in primary and metastatic breast cancer defined by high-throughput CUTseq (#33)

Xiaolu Zhang 1 , Silvano Garnerone 1 , Michele Simonetti 1 , Luuk Harbers 1 , Johan Hartman 2 , magda bienko 1 , Nicola Crosetto 1
  1. Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
  2. Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

Metastatic disease relapse occurs in a substantial fraction of breast cancer (BC), and it remains essentially incurable. Intra tumour heterogeneity (ITH) is fundamental to drug resistance and metastasis in BC. Studies have begun to measure ITH in primary BC, while similar studies in metastases are lacking. Here we applied high-throughput CUTseq to assess ITH of copy number alterations (CNAs) across multiple regions inside individual FFPE sections of primary and metastatic BC lesions, after assessing them by conventional histology. Hierarchical clustering revealed that in most of the cases, multiple small regions clustered together with the corresponding whole section but exceptions showed sub-clonal CNAs detected in some sub-regions but neither in others nor the whole section, which suggested that despite most of the tumour cells within a single tissue section harbour the same CNAs, multi-region sequencing at high spatial resolution should be still strongly encouraged to capture sub-clonal CNAs. Hierarchical clustering trees also revealed that metastatic regions from the same tumour typically clustered together, and apart from the regions of the corresponding primary lesion. Moreover, among all the regions with detectable CNAs, the metastatic regions had a significantly higher burden of amplifications and deletions compared to the primary tumour regions, believed as a result of ongoing genome instability and tumour evolution. Overlapping with the 712 cancer-associated genes in the COSMIC database revealed the top-3 amplified genes in our BC cohort were MYC, NDRG1, and RAD21, while KMTA, PAFAH1B2, POU2AF1 were the three-most frequently deleted genes.