Real-time genomic characterization of metastatic pancreatic neuroendocrine tumors has prognostic implications and identifies potential germline actionability Journal Article

Authors: Raj, N.; Shah, R.; Stadler, Z.; Mukherjee, S.; Chou, J.; Untch, B.; Li, J.; Kelly, V.; Osoba, M.; Saltz, L. B.; Mandelker, D.; Ladanyi, M.; Berger, M. F.; Klimstra, D. S.; Reidy-Lagunes, D.
Article Title: Real-time genomic characterization of metastatic pancreatic neuroendocrine tumors has prognostic implications and identifies potential germline actionability
Abstract: Purpose We assessed the usefulness of real-time molecular profiling through next-generation sequencing (NGS) in predicting the tumor biology of advanced pancreatic neuroendocrine tumors (panNETs) and in characterizing genomic evolution. Methods Patients with metastatic panNETs were recruited in the routine clinical practice setting (between May 2014 and March 2017) for prospective NGS of their tumors as well as for germline analysis using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) sequencing platform. When possible, NGS was performed at multiple time points. Results NGS was performed in 96 tumor samples from 80 patients. Somatic alterations were identified in 76 of 80 patients (95%). The most commonly altered genes were MEN1 (56%), DAXX (40%), ATRX (25%), and TSC2 (25%). Alterations could be defined in pathways that included chromatin remodeling factors, histone methyltransferases, and mammalian target of rapamycin pathway genes. Somatic loss of heterozygosity was particularly prevalent (55 of 95 tested samples [58%]), and the presence of loss of heterozygosity resulted in improved overall survival (P = .06). Sequencing of pre- and post-treatment samples revealed tumor-grade progression; clonal evolution patterns were also seen (molecular resistance mechanisms and chemotherapy-associated mutagenesis). Germline genetic analysis identified clinically actionable pathogenic or likely pathogenic variants in 14 of 88 patients (16%), including mutations in high-penetrance cancer susceptibility genes (MEN1, TSC2, and VHL). Conclusion A clinical NGS platform reveals pertubations of biologic pathways in metastatic panNETs that may inform prognosis and direct therapies. Repeat sequencing at disease progression reveals increasing tumor grade and genetic evolution, demonstrating that panNETs adopt a more aggressive behavior through time and therapies. In addition to frequent somatic mutations in MEN1 and TSC2, germline mutations in these same genes underlie susceptibility to panNETs and highlight the need to re-evaluate whether germline genetic analysis should be performed for all patients with panNETs. (C) 2018 by American Society of Clinical Oncology
Keywords: sunitinib; temozolomide; genes; management; everolimus; mutations; renal-cell carcinoma; low-grade; setd2; cancer
Journal Title: JCO Precision Oncology
Volume: 2
ISSN: 2473-4284
Publisher: American Society of Clinical Oncology  
Date Published: 2018-01-01
Language: English
ACCESSION: WOS:000462113000001
DOI: 10.1200/po.17.00267
PMCID: PMC6345401
PUBMED: 30687805
Notes: Source: Wos
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MSK Authors
  1. Joanne Fu-Lou Chou
    165 Chou
  2. Leonard B Saltz
    616 Saltz
  3. Zsofia Kinga Stadler
    161 Stadler
  4. Diane Lauren Reidy
    165 Reidy
  5. David S Klimstra
    869 Klimstra
  6. Marc Ladanyi
    907 Ladanyi
  7. Michael Forman Berger
    412 Berger
  8. Brian Untch
    28 Untch
  9. Ronak Hasmukh Shah
    46 Shah
  10. Janet Wing Yui Li
    7 Li
  11. Nitya Prabhakar Raj
    32 Raj
  12. Virginia Bowen Kelly
    2 Kelly
  13. Muyinat Yewande Osoba
    2 Osoba