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Hotspot mutation panel testing reveals clonal evolution in a study of 265 paired primary and metastatic tumors.

ABSTRACT: We used a clinical next-generation sequencing (NGS) hotspot mutation panel to investigate clonal evolution in paired primary and metastatic tumors.A total of 265 primary and metastatic tumor pairs were sequenced using a 46-gene cancer mutation panel capable of detecting one or more single-nucleotide variants as well as small insertions/deletions. Mutations were tabulated together with tumor type and percentage, mutational variant frequency, time interval between onset of primary tumor and metastasis, and neoadjuvant therapy status.Of note, 227 of 265 (85.7%) tumor metastasis pairs showed identical mutation calls. Of the tumor pairs with identical mutation calls, 160 (60.4%) possessed defining somatic mutation signatures and 67 (25.3%) did not exhibit any somatic mutations. There were 38 (14.3%) cases that showed at least one novel mutation call between the primary and metastasis. Metastases were almost two times more likely to show novel mutations (n = 20, 7.5%) than primary tumors (n = 12, 4.5%). TP53 was the most common additionally mutated gene in metastatic lesions, followed by PIK3CA and SMAD4. PIK3CA mutations were more often associated with metastasis in colon carcinoma samples.Clinical NGS hotspot panels can be useful in analyzing clonal evolution within tumors as well as in determining subclonal mutations that can expand in future metastases. PIK3CA, SMAD4, and TP53 are most often involved in clonal divergence, providing potential targets that may help guide the clinical management of tumor progression or metastases.

SUBMITTER: Goswami RS

PROVIDER: S-EPMC5015593 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Hotspot mutation panel testing reveals clonal evolution in a study of 265 paired primary and metastatic tumors.

Goswami Rashmi S RS Patel Keyur P KP Singh Rajesh R RR Meric-Bernstam Funda F Kopetz E Scott ES Subbiah Vivek V Alvarez Ricardo H RH Davies Michael A MA Jabbar Kausar J KJ Roy-Chowdhuri Sinchita S Lazar Alexander J AJ Medeiros L Jeffrey LJ Broaddus Russell R RR Luthra Rajyalakshmi R Routbort Mark J MJ

Clinical cancer research : an official journal of the American Association for Cancer Research 20150218 11

<h4>Purpose</h4>We used a clinical next-generation sequencing (NGS) hotspot mutation panel to investigate clonal evolution in paired primary and metastatic tumors.<h4>Experimental design</h4>A total of 265 primary and metastatic tumor pairs were sequenced using a 46-gene cancer mutation panel capable of detecting one or more single-nucleotide variants as well as small insertions/deletions. Mutations were tabulated together with tumor type and percentage, mutational variant frequency, time interv ...[more]

PMID: 25695693

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Project description:Can metastatic-primary (M-P) genomic divergence measured from next generation sequencing reveal the natural history of metastatic dissemination? This remains an open question of utmost importance in facilitating a deeper understanding of metastatic progression, and thereby, improving its prevention. Here, we utilize mathematical and computational modeling to tackle this question as well as to provide a framework that illuminates the fundamental elements and evolutionary determinants of M-P divergence. Our framework facilitates the integration of sequencing detectability of somatic variants, and hence, paves the way towards bridging the measurable between-tumor heterogeneity with analytical modeling and interpretability. We show that the number of somatic variants of the metastatic seeding cell that are experimentally undetectable in the primary tumor, can be characterized as the path of the phylogenetic tree from the last appearing variant of the seeding cell back to the most recent detectable variant. We find that the expected length of this path is principally determined by the decay in detectability of the variants along the seeding cell's lineage; and thus, exhibits a significant dependence on the underlying tumor growth dynamics. A striking implication of this fact, is that dissemination from an advanced detectable subclone of the primary tumor can lead to an abrupt drop in the expected measurable M-P divergence, thereby breaking the previously assumed monotonic relation between seeding time and M-P divergence. This is emphatically verified by our single cell-based spatial tumor growth simulation, where we find that M-P divergence exhibits a non-monotonic relationship with seeding time when the primary tumor grows under branched and linear evolution. On the other hand, a monotonic relationship holds when we condition on the dynamics of progressive diversification, or by restricting the seeding cells to always originate from undetectable subclones. Our results highlight the fact that a precise understanding of tumor growth dynamics is the sine qua non for exploiting M-P divergence to reconstruct the chronology of metastatic dissemination. The quantitative models presented here enable further careful evaluation of M-P divergence in association with crucial evolutionary and sequencing parameters.

Dataset Information

Hotspot mutation panel testing reveals clonal evolution in a study of 265 paired primary and metastatic tumors.

Publications

Hotspot mutation panel testing reveals clonal evolution in a study of 265 paired primary and metastatic tumors.

Similar Datasets

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