Abstract B001: Elucidating metastatic pathways in pediatric cancers
Authors: Andersson Natalie , Ferro Michele , Jansson Caroline , Karlsson Jenny , Mengelbier Linda Holmquist , Chattopadhyay Subhayan , Gisselsson David 
Published: February 2024

Abstract
The most common cause of death in pediatric cancer patients is a treatment resistant tumor, often further complicated by metastatic spread to multiple sites, making both surgery and radiation therapy unfeasible as curative treatment options. How metastatic spread occurs in pediatric tumors is to a large extent completely unexplored. We aimed to elucidate the evolutionary trajectories of metastatic disease in the pediatric tumors, neuroblastoma, Wilms tumor and germ cell tumors, which are the most common tumors in children besides tumors of the central nervous system and leukemias. More specifically we wanted to decipher when in the evolutionary history of the tumor, metastases appear, whether there were signs of monoclonal or polyclonal spread (one or several subclones from the primary tumor colonizing the same metastatic site), mono- or polyphyletic spread (one subclone or several subclones colonizing several metastatic sites) and intermetastatic spread (subclones from one metastatic site spreading to another). Due to the spatiotemporal genetic heterogeneity of tumors, DNA was extracted from multiple sites from the primary tumor and several metastatic sites for each patient. A total of 174 samples from 18 patients were included. All samples underwent whole genome copy number profiling and a subset also targeted deep sequencing. Phylogenetic trees were reconstructed, allowing spatiotemporal tracking of subclones for each patient. Having a median of 8 (range 4 to 22) samples available per patient we could confirm an extensive genetic heterogeneity within and between the primary tumor and metastases in each patient, stressing the importance of multiregional sampling to fully characterize the disease. In 13 of 18 patients, early metastatic spread was identified and a total of 6 of 18 patients displayed both polyphyletic and polyclonal seeding. Hence metastatic spread can occur several times during tumor evolution, several subclones possess metastatic capability and several different subclones may colonize the same site. We also found that a higher number of subclones from the primary tumor metastasize to the lymph nodes compared to distant sites, suggesting a weaker evolutionary bottleneck for locoregional lymphatic spread. Finally, intermetastatic spread could be identified in 7 out of 11 patients having metastases in at least 2 different distant sites. Our results provide further knowledge of the evolutionary dynamics of metastatic spread in pediatric cancer patients. Metastases often have a different genomic profile than the primary tumor, stressing the need to sample metastases for assessment of therapeutic targets, since metastases may completely lack targets present in the primary, resulting in progression at distant sites despite the primary tumor responding to treatment. We also found that metastatic spread can occur early and several times during tumor evolution. Strikingly, intermetastatic spread is identified as a common feature in pediatric tumors, indicating that metastases alone may act as a hub for further metastatic spread.
Citation Format: Natalie Andersson, Michele Ferro, Caroline Jansson, Jenny Karlsson, Linda Holmquist Mengelbier, Subhayan Chattopadhyay, David Gisselsson. Elucidating metastatic pathways in pediatric cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr B001.