Cancer of unknown primary and the «seed and soil» hypothesis

The worldwide incidence rate of cancer of unknown primary (CUP) reaches 5% (Kang et al., 2021, Lee and Sanoff, 2020, Yang et al., 2022). CUP has an alarmingly high mortality rate, with 84% of patients succumbing within the first year following diagnosis (Registration, Service, 2018). Under normal circumstances, tumor cell metastasis follows the «seed and soil» hypothesis, displaying a tissue-specific pattern of cancer cell homing behavior based on the microenvironment composition of secondary organs. In this study, we questioned whether seed and soil concept applies to CUP, and whether the pattern of tumor and metastasis manifestations for cancer of known primary (CKP) can be used to inform diagnostic strategies for CUP. We compared data from metastatic and primary CUP foci to the metastasis patterns observed in CKP. Furthermore, we evaluated several techniques for identifying the tissue-of-origin (TOO) in CUP profiling, including DNA, RNA, and epigenetic TOO techniques.