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Genomic alterations and possible druggable mutations in carcinoma of unknown primary (CUP)

Hamidreza Aboulkheyr Es1,2, Hamid Mahdizadeh1,3, Amir Abbas Hedayati Asl3

  • 1Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, P.O. Box: 16635-148, Tehran, Iran.

Scientific Reports
|July 24, 2021
PubMed

Insights

Molecular profiling of Carcinoma of Unknown Primary (CUP) tumors reveals targetable mutations. This personalized approach may identify new diagnostic markers and guide tailored treatments for CUP patients.

Area of Science:

  • Oncology
  • Genomics
  • Translational Medicine

Background:

  • Carcinoma of Unknown Primary (CUP) is a metastatic cancer with an undetectable origin.
  • Current treatments for CUP primarily rely on chemotherapy.
  • Molecular profiling offers a personalized treatment strategy through targeted agents.

Purpose of the Study:

  • To analyze mutation and copy number alterations in CUP.
  • To identify potentially druggable mutations in CUP.
  • To explore diagnostic markers for CUP primary site identification.

Main Methods:

  • Analysis of 1709 CUP samples from the AACR Project Genomics Evidence Neoplasia Information Exchange (GENIE) cohort.
  • Identification of significant mutated genes (SMGs) and copy number alterations.
  • Pan-cancer analysis to compare mutation profiles with other cancer types.

Main Results:

  • Identified 52 significant mutated genes (SMGs) in CUP samples.
  • Found 13 (25%) SMGs were potentially targetable with existing or investigational drugs.
  • TP53 (43%), KRAS (19.90%), KMT2D (12.60%), and CDKN2A (10.30%) were the most frequent mutations.
  • TERT promoter variants were common in CUP and non-small cell lung cancer (NSCLC), suggesting diagnostic potential.

Conclusions:

  • Mutation profiling of CUP tumors reveals actionable targets for personalized therapy.
  • TERT promoter mutations may serve as a diagnostic biomarker for CUP.
  • Genomic analysis paves the way for targeted treatment strategies in CUP.

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