Metastatic cancer remains almost inevitably a lethal disease. A better understanding of disease progression and response to therapies therefore remains of utmost importance. Here, we characterize the genomic differences between early-stage untreated primary tumors and late-stage treated metastatic tumors using a harmonized pan-cancer (re-)analysis of 7,152 whole-genome-sequenced tumors. In general, our analysis shows that metastatic tumors have a low intra-tumor heterogeneity, high genomic instability and increased frequency of structural variants with comparatively a modest increase in the number of small genetic variants. However, these differences are cancer type specific and are heavily impacted by the exposure to cancer therapies. Five cancer types, namely breast, prostate, thyroid, kidney clear carcinoma and pancreatic neuroendocrine, are a clear exception to the rule, displaying an extensive transformation of their genomic landscape in advanced stages. These changes were supported by increased genomic instability and involved substantial differences in tumor mutation burden, clock-based molecular signatures and the landscape of driver alterations as well as a pervasive increase in structural variant burden. The majority of cancer types had either moderate genomic differences (e.g., cervical and colorectal cancers) or highly consistent genomic portraits (e.g., ovarian cancer and skin melanoma) when comparing early- and late-stage disease. Exposure to treatment further scars the tumor genome and introduces an evolutionary bottleneck that selects for known therapy-resistant drivers in approximately half of treated patients. Our data showcases the potential of whole-genome analysis to understand tumor evolution and provides a valuable resource to further investigate the biological basis of cancer and resistance to cancer therapies.

Metastatic cancer remains almost inevitably a lethal disease. A better understanding of disease progression and response to therapies therefore remains of utmost importance. Here, we characterize the genomic differences between early-stage untreated primary tumors and late-stage treated metastatic tumors using a harmonized pan-cancer (re-)analysis of 7,152 whole-genome-sequenced tumors. In general, our analysis shows that metastatic tumors have a low intra-tumor heterogeneity, high genomic instability and increased frequency of structural variants with comparatively a modest increase in the number of small genetic variants. However, these differences are cancer type specific and are heavily impacted by the exposure to cancer therapies. Five cancer types, namely breast, prostate, thyroid, kidney clear carcinoma and pancreatic neuroendocrine, are a clear exception to the rule, displaying an extensive transformation of their genomic landscape in advanced stages. These changes were supported by increased genomic instability and involved substantial differences in tumor mutation burden, clock-based molecular signatures and the landscape of driver alterations as well as a pervasive increase in structural variant burden. The majority of cancer types had either moderate genomic differences (e.g., cervical and colorectal cancers) or highly consistent genomic portraits (e.g., ovarian cancer and skin melanoma) when comparing early- and late-stage disease. Exposure to treatment further scars the tumor genome and introduces an evolutionary bottleneck that selects for known therapy-resistant drivers in approximately half of treated patients. Our data showcases the potential of whole-genome analysis to understand tumor evolution and provides a valuable resource to further investigate the biological basis of cancer and resistance to cancer therapies.