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Pan-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases

By Zheng Hu, Zan Li, Zhicheng Ma, Christina Curtis

Posted 31 Oct 2019
bioRxiv DOI: 10.1101/825240

Metastasis is the primary cause of cancer-related deaths, but the natural history, clonal evolution and patterns of systemic spread are poorly understood. We analyzed exome sequencing data from 458 paired primary tumors (P) or metastasis (M) samples from 136 breast, colorectal and lung cancer patients, including both untreated (n=98) and treated (n=101) metastases. We find that treated metastases often harbored private driver gene mutations whereas untreated metastases did not, suggesting that treatment promotes clonal evolution. Polyclonal seeding was common in lymph node metastases (n=19/35, 54%; mostly untreated) and untreated distant metastases (n=20/70, 29%), but less frequent in treated metastases (n=9/90, 10%). The low number of metastasis-private clonal mutations is consistent with early metastatic seeding, which commonly occurred several years prior to diagnosis in breast (2.4 years, range 0-3.3), lung (3.6 years, range 2.8-3.7) and colorectal (4.1 years, range 3.1-4.6) cancers. Thus, this pan-cancer analysis reveals early systemic spread in three common cancer types. Further, these data suggest that the natural course of metastasis is selectively relaxed relative to early tumor development and that metastasis-private mutations are not drivers of cancer spread but are instead associated with drug resistance.

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