Abstract A051: The spatial landscape of clonal somatic copy number alterations in benign and malignant prostate epithelia
Authors: Erickson Andrew , He Mengxiao , Berglund Emelie , Marklund Maja , Mirzazadeh Reza , Schultz Niklas , Kvastad Linda , Andersson Alma , Bergenstråhle Ludvig , Bergenstråhle Joseph , Larsson Ludvig , Galicia Leire Alonso , Shamikh Alia , Basmaci Elisa , De Ståhl Teresita Díaz , Rajakumar Timothy , Doultsinos Dimitrios , Thrane Kim , Ji Andrew L. , Khavari Paul A. , Tarish Firaz , Tanoglidi Anna , Maaskola Jonas , Colling Richard , Mirtti Tuomas , Hamdy Freddie C. , Woodcock Dan J. , Helleday Thomas , Mills Ian G. , Lamb Alastair D. , Lundeberg Joakim 
Published: June 2023

Abstract
Defining the transition from benign to malignant tissue is fundamental to improve early diagnosis of cancer. We provide an unsupervised approach (SpatialInferCNV) to study spatial genome integrity, in situ, to gain molecular insight into clonal relationships. We employed spatially resolved transcriptomics (Visium, 10x Genomics) to infer spatial copy number variations in &gt;120 000 spatial regions across multiple organs, tissues and tumors, including three whole axial prostates. We used this information to deduce clonal relationships between regions harboring 5-20 cells. We perform an in-depth spatial analysis of prostate cancer that includes an unprecedented interrogation of up to 50,000 tissue domains in a single patient. For these domains we inferred genome-wide information, which facilitated data driven clustering in a tissue wide fashion at high resolution. We observed that genome-wide somatic copy number alterations revealed distinct clonal patterns benign tissue and nearby tumours. In a tissue section from patient 1 (section H2_1), we observed that many CNVs occurred in clone C, most notably in chromosomes 8 and 10 encoding a MYC amplification and a PTEN deletion. This clone constituted a region of exclusively benign acinar cells branching off a duct lined by largely diploid cells in clones A and B. The unobserved ancestor to clone C then gave rise to a further unobserved clone, and then clones E, F and G. Our results suggest a model for how genomic instability arises in histologically benign tissue that may represent early events in prostate cancer evolution. Furthermore the spatial information allowed us to identify small clonal units not evident from morphology and hence would be overlooked by pathologists. We present the first comprehensive, large-scale, atlas of genomic evolution at high spatial resolution in prostate cancer. Our study adds an important new approach to the armamentarium of cancer molecular pathology. We highlight the power of an unsupervised approach to capture the molecular and spatial continuums in a tissue context and challenge the rationale for focal therapy in prostate cancer.
Citation Format: Andrew Erickson, Mengxiao He, Emelie Berglund, Maja Marklund, Reza Mirzazadeh, Niklas Schultz, Linda Kvastad, Alma Andersson, Ludvig Bergenstråhle, Joseph Bergenstråhle, Ludvig Larsson, Leire Alonso Galicia, Alia Shamikh, Elisa Basmaci, Teresita Díaz De Ståhl, Timothy Rajakumar, Dimitrios Doultsinos, Kim Thrane, Andrew L. Ji, Paul A. Khavari, Firaz Tarish, Anna Tanoglidi, Jonas Maaskola, Richard Colling, Tuomas Mirtti, Freddie C. Hamdy, Dan J. Woodcock, Thomas Helleday, Ian G. Mills, Alastair D. Lamb, Joakim Lundeberg. The spatial landscape of clonal somatic copy number alterations in benign and malignant prostate epithelia [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A051.