Frequency of mitogen-activated protein kinase and phosphoinositide 3-kinase signaling pathway pathogenic alterations in EUS-FNA sampled malignant lymph nodes in rectal cancer with theranostic potential

Gastrointest Endosc. 2015 Sep;82(3):550-6.e1. doi: 10.1016/j.gie.2015.01.050. Epub 2015 Apr 14.

Abstract

Background: Targeted next-generation sequencing has the potential to stratify a tumor by molecular subtype and aid the development of a biomarker profile for prognostic risk stratification and theranostic potential.

Objective: To assess the frequency and distribution of pathogenic alterations in malignant lymph node cytology specimens.

Design: Multigene molecular profiling of archived malignant EUS-FNA lymph node cytology specimens using the Ion Ampliseq Cancer Hotspot Panel v2, which targets at least 2855 possible mutations within 50 cancer-associated genes.

Setting: Single tertiary referral center.

Patients: Sporadic, treatment naive, locally advanced primary rectal cancer by EUS-FNA (n = 76) who subsequently completed neoadjuvant therapy with on-site oncologic surgery.

Main outcome measurements: The frequency and distribution of pathogenic alterations in malignant lymph node cytology specimens by the mitogen-activated protein kinase (MAPK) or phosphoinositide 3-kinase (PI3K) signaling pathways, by KRAS or NRAS wild-type lymph node status, by extramesenteric lymph node status, and by a complete pathologic response status.

Results: Eleven patients (14.5%) were 50-gene panel wild-type. Sixty-five patients had 139 pathogenic alterations (2 [1-3] per patient) in 13 of 50 evaluated genes. The following represent a spectrum of identified alterations: TP53 (n = 52; 68.4%), APC (n = 36; 47.4%), KRAS (n = 22; 28.9%), FBXW7 (n = 8; 10.5%), NRAS (n = 6; 7.9%), PIK3CA (n = 4; 5.3%), SMAD4 (n = 3; 3.9%), and BRAF (n = 3; 3.9%). Pathogenic alterations were identified in the MAPK and PI3K signaling pathways in 41% and 5% of patients, respectively.

Limitations: Findings were limited to a 50 cancer-associated gene analysis.

Conclusions: Molecular EUS lymph node assessments using cancer "hotspot" panels can identify pathogenic alteration frequency and distribution and have theranostic potential for individualized patient care.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli Protein / genetics
  • Adult
  • Aged
  • Cell Cycle Proteins / genetics
  • Class I Phosphatidylinositol 3-Kinases
  • Endoscopic Ultrasound-Guided Fine Needle Aspiration
  • F-Box Proteins / genetics
  • F-Box-WD Repeat-Containing Protein 7
  • Female
  • GTP Phosphohydrolases / genetics
  • Humans
  • Lymph Nodes / metabolism*
  • Lymph Nodes / pathology
  • Lymphatic Metastasis
  • Male
  • Membrane Proteins / genetics
  • Middle Aged
  • Mitogen-Activated Protein Kinases / genetics*
  • Neoplasm Staging
  • Phosphatidylinositol 3-Kinases / genetics*
  • Precision Medicine
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Rectal Neoplasms / genetics*
  • Rectal Neoplasms / pathology
  • Signal Transduction / genetics
  • Smad4 Protein / genetics
  • Theranostic Nanomedicine
  • Tumor Suppressor Protein p53 / genetics
  • Ubiquitin-Protein Ligases / genetics

Substances

  • APC protein, human
  • Adenomatous Polyposis Coli Protein
  • Cell Cycle Proteins
  • F-Box Proteins
  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • KRAS protein, human
  • Membrane Proteins
  • SMAD4 protein, human
  • Smad4 Protein
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Ubiquitin-Protein Ligases
  • Phosphatidylinositol 3-Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • Mitogen-Activated Protein Kinases
  • GTP Phosphohydrolases
  • NRAS protein, human
  • Proto-Oncogene Proteins p21(ras)