Co-Evolution of Somatic Variation in Primary and Metastatic Colorectal Cancer May Expand Biopsy Indications in the Molecular Era

PLOS ONE, Dec 2019

Introduction Metastasis is thought to be a clonal event whereby a single cell initiates the development of a new tumor at a distant site. However the degree to which primary and metastatic tumors differ on a molecular level remains unclear. To further evaluate these concepts, we used next generation sequencing (NGS) to assess the molecular composition of paired primary and metastatic colorectal cancer tissue specimens. Methods 468 colorectal tumor samples from a large personalized medicine initiative were assessed by targeted gene sequencing of 1,321 individual genes. Eighteen patients produced genomic profiles for 17 paired primary:metastatic (and 2 metastatic:metastatic) specimens. Results An average of 33.3 mutations/tumor were concordant (shared) between matched samples, including common well-known genes (APC, KRAS, TP53). An average of 2.3 mutations/tumor were discordant (unshared) among paired sites. KRAS mutational status was always concordant. The overall concordance rate for mutations was 93.5%; however, nearly all (18/19 (94.7%)) paired tumors showed at least one mutational discordance. Mutations were seen in: TTN, the largest gene (5 discordant pairs), ADAMTS20, APC, MACF1, RASA1, TP53, and WNT2 (2 discordant pairs), SMAD2, SMAD3, SMAD4, FBXW7, and 66 others (1 discordant pair). Conclusions Whereas primary and metastatic tumors displayed little variance overall, co-evolution produced incremental mutations in both. These results suggest that while biopsy of the primary tumor alone is likely sufficient in the chemotherapy-naïve patient, additional biopsies of primary or metastatic disease may be necessary to precisely tailor therapy following chemotherapy resistance or insensitivity in order to adequately account for tumor evolution.

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Co-Evolution of Somatic Variation in Primary and Metastatic Colorectal Cancer May Expand Biopsy Indications in the Molecular Era

May Co-Evolution of Somatic Variation in Primary and Metastatic Colorectal Cancer May Expand Biopsy Indications in the Molecular Era Richard Kim 0 1 2 Michael J. Schell 0 1 2 Jamie K. Teer 0 1 2 Danielle M. Greenawalt 0 1 2 Mingli Yang 0 1 2 Timothy J. Yeatman 0 1 2 0 Current address: AstraZeneca, iMED Oncology , Waltham, MA , United States of America 1 1 Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute , Tampa, FL , United States of America, 2 Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute , Tampa, FL , United States of America , 3 Merck Co , Inc. , Boston, MA , United States of America, 4 Gibbs Cancer Center and Research Institute , Spartanburg, SC , United States of America 2 Academic Editor: Hiromu Suzuki, Sapporo Medical University , JAPAN Metastasis is thought to be a clonal event whereby a single cell initiates the development of a new tumor at a distant site. However the degree to which primary and metastatic tumors differ on a molecular level remains unclear. To further evaluate these concepts, we used next generation sequencing (NGS) to assess the molecular composition of paired primary and metastatic colorectal cancer tissue specimens. - Funding: The study was supported by National Institutes of Health (NIH) nih.gov U01CA157960 (TJY). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Merck Co, Inc/ AstraZeneca provided support in the form of salaries for the author [DMG], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. 468 colorectal tumor samples from a large personalized medicine initiative were assessed by targeted gene sequencing of 1,321 individual genes. Eighteen patients produced genomic profiles for 17 paired primary:metastatic (and 2 metastatic:metastatic) specimens. An average of 33.3 mutations/tumor were concordant (shared) between matched samples, including common well-known genes (APC, KRAS, TP53). An average of 2.3 mutations/ tumor were discordant (unshared) among paired sites. KRAS mutational status was always concordant. The overall concordance rate for mutations was 93.5%; however, nearly all (18/19 (94.7%)) paired tumors showed at least one mutational discordance. Mutations were seen in: TTN, the largest gene (5 discordant pairs), ADAMTS20, APC, MACF1, RASA1, TP53, and WNT2 (2 discordant pairs), SMAD2, SMAD3, SMAD4, FBXW7, and 66 others (1 discordant pair). The specific roles of the author are articulated in the author contributions section. Conclusions Whereas primary and metastatic tumors displayed little variance overall, co-evolution produced incremental mutations in both. These results suggest that while biopsy of the primary tumor alone is likely sufficient in the chemotherapy-nave patient, additional biopsies of primary or metastatic disease may be necessary to precisely tailor therapy following chemotherapy resistance or insensitivity in order to adequately account for tumor evolution. Colorectal cancer (CRC) is the third most common cancer in both men and women [1]. About one third of those patients will eventually succumb to the disease. Many patients will present with synchronous metastatic disease or eventually develop metachronous metastatic disease after the resection of the primary tumor. Recently, to better understand the disease, a genomescale analysis was conducted in colorectal cancer by the TCGA network using tumor and normal samples [2]. In that study, as expected, APC, TP53, KRAS, SMAD4, BRAF and PIK3CA mutations were commonly found. Many additional, less frequently observed mutations were also identified. Because this study was largely limited to the analysis of primary cancers, further insight into metastatic disease was warranted. While the precise mechanisms governing tumor metastasis are still poorly understood, multiple potential explanations have emerged. One notion is that the metastasis is a pure clonal derivative of the primary such that it is nearly genetically identical but for a few new driver genes (Fig 1A) [3]. An extension of this idea is that a tumor might simply undergo a plastic physiological change in gene expression, perhaps unrelated to mutational change, but rather related to environmental clues, resulting in an epithelial to mesenchymal transition (EMT) permitting metastasis [4]. Another notion is that the metastatic lesion is genetically distinct from the primary, due to either the shedding of a highly divergent cell from a heterogeneous primary, or even the origination of a distinct clone (Fig 1B) [5, 6]. A third model suggests primary tumors are genetically similar to metastatic lesions, but not exactly the same. In order to metastasize, the primary tumor must experience additional gain or loss of function via mutation to permit invasion and spread of disease ( (...truncated)


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Richard Kim, Michael J. Schell, Jamie K. Teer, Danielle M. Greenawalt, Mingli Yang, Timothy J. Yeatman. Co-Evolution of Somatic Variation in Primary and Metastatic Colorectal Cancer May Expand Biopsy Indications in the Molecular Era, PLOS ONE, 2015, Volume 10, Issue 5, DOI: 10.1371/journal.pone.0126670